[{"id":"adc-plus-io","kind":"pairing","name":"ADC + checkpoint inhibitor","aka":[],"tldr":"An ADC kills tumour cells in a way that alerts the immune system; a checkpoint inhibitor lets the immune system finish the job.","summary":"Proven in urothelial cancer (EV-302: enfortumab vedotin + pembrolizumab, OS HR 0.47) and TNBC (ASCENT-04: sacituzumab govitecan + pembrolizumab, PFS HR 0.65, approved 2026). TROPION-Breast05 (Dato-DXd + durvalumab) and multiple lung trials follow. Overlapping pneumonitis risk with DXd ADCs needs care.","asOf":"2026-09-04","links":[{"label":"ClinicalTrials.gov NCT04223856: EV-302 / KEYNOTE-A39","url":"https://clinicaltrials.gov/study/NCT04223856"},{"label":"ClinicalTrials.gov NCT05382286: ASCENT-04 / KEYNOTE-D19","url":"https://clinicaltrials.gov/study/NCT05382286"}],"tags":[],"related":[],"cancers":["urothelial","tnbc","nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["enfortumab-vedotin","sacituzumab-govitecan","pembrolizumab"],"companies":[],"institutions":[],"pathways":["cgas-sting"],"terms":[],"trials":["ev-302","ascent-04","tropion-breast05"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"adc","b":"checkpoint-inhibitor","rationale":"TOP1 and tubulin payloads induce immunogenic cell death, cGAS-STING activation, and antigen release; ADCs also deplete immunosuppressive myeloid cells. PD-1 blockade converts the resulting T-cell priming into durable control.","evidence":"Phase 3 positive in two tumour types; multiple ongoing.","pairingType":"combination"},{"id":"ai-pathology-to-adt","kind":"pairing","name":"AI pathology → androgen deprivation duration","aka":[],"tldr":"An AI reading of the biopsy slide says whether adding hormone therapy to radiation will help.","summary":"This diagnostic-therapeutic pairing links Digital pathology & AI to the choice of Androgen deprivation & AR pathway inhibitors in Prostate cancer: an AI reading of the biopsy slide says whether adding hormone therapy to radiation will help. The rationale is that tissue morphology encodes biology beyond the Gleason grade, and because the model was trained on randomised trial cohorts its prediction is causal for treatment effect. ArteraAI Prostate, authorised by the FDA through the de novo pathway in 2025, predicts benefit from short-term androgen deprivation in intermediate-risk disease using slides from RTOG trials, and it is listed by the NCCN. The pairing is reached from the Prostate cancer, Digital pathology & AI and Androgen deprivation entries.","asOf":"2026-09-04","links":[{"label":"Esteva et al., Prostate cancer therapy personalisation via multimodal deep learning on randomised phase 3 trials (npj Digital Medicine 2022)","url":"https://doi.org/10.1038/s41746-022-00613-w"}],"tags":[],"related":[],"cancers":["prostate"],"sections":[],"technologies":[],"targets":[],"drugs":["artera-ai-prostate"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-esteva-npj-digit-med"],"journals":[],"dependsOn":[],"notes":[],"a":"digital-pathology-ai","b":"androgen-deprivation","rationale":"Morphology encodes biology beyond Gleason grade; trained on randomised trial cohorts so the prediction is causal for treatment effect.","evidence":"Validated on phase 3 cohorts; FDA-authorised.","pairingType":"diagnostic-therapeutic"},{"id":"amivantamab-plus-lazertinib","kind":"pairing","name":"Amivantamab + lazertinib (first-line EGFR NSCLC)","aka":[],"tldr":"Blocking EGFR from inside (a pill) and outside (an antibody that also blocks MET) beat osimertinib and added more than a year of survival.","summary":"This combination pairs amivantamab, a bispecific antibody against EGFR and MET, with lazertinib, an oral EGFR inhibitor, as first-line treatment for EGFR-mutant non-small-cell lung cancer. Lazertinib blocks EGFR signalling from inside the cell while amivantamab blocks EGFR and MET at the cell surface and recruits immune effectors, so the pairing pre-empts the two main escape routes from osimertinib, MET amplification and the C797S mutation. The phase 3 MARIPOSA trial compared it with osimertinib and showed a progression-free and overall survival benefit. The price is more toxicity, including rash, paronychia, venous thromboembolism and infusion reactions, plus intravenous visits; subcutaneous amivantamab, introduced in 2025, eases the latter.","asOf":"2026-09-06","links":[{"label":"ClinicalTrials.gov NCT04487080: MARIPOSA","url":"https://clinicaltrials.gov/study/NCT04487080"}],"tags":[],"related":[],"cancers":["nsclc","egfr-mutant-nsclc"],"sections":[],"technologies":[],"targets":["egfr","met"],"drugs":["amivantamab","lazertinib","osimertinib"],"companies":[],"institutions":[],"pathways":[],"terms":["met-amplification","c797s"],"trials":["mariposa"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"amivantamab","b":"lazertinib","rationale":"Lazertinib blocks intracellular EGFR signalling while amivantamab blocks EGFR and MET extracellularly and recruits immune effectors, pre-empting the MET-amplification and C797S escape routes.","evidence":"Phase 3 with OS benefit.","pairingType":"combination"},{"id":"anti-egfr-left-sided","kind":"pairing","name":"Anti-EGFR antibody + chemotherapy in left-sided RAS/BRAF wild-type mCRC","aka":[],"tldr":"In bowel cancers that start on the left and have normal RAS and BRAF genes, adding an EGFR antibody to chemotherapy gives the longest survival seen in first-line trials.","summary":"PARADIGM: OS 37.9 months with panitumumab + mFOLFOX6 in left-sided RAS wild-type disease. FIRE-3 and CALGB 80405 subgroups agree. Right-sided or RAS/BRAF-mutant tumours should get bevacizumab instead. Anti-EGFR rechallenge after a chemotherapy-free interval, guided by ctDNA showing RAS/EGFR clones have receded (CHRONOS), is an emerging strategy.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT02394795: PARADIGM","url":"https://clinicaltrials.gov/study/NCT02394795"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["panitumumab","cetuximab","folfox","folfiri"],"companies":[],"institutions":[],"pathways":[],"terms":["sidedness"],"trials":["paradigm","crystal-fire3"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"panitumumab","b":"folfox","rationale":"Left-sided tumours are EGFR-ligand dependent and RAS wild-type; right-sided tumours carry BRAF, dMMR, and other resistance biology.","evidence":"Phase 3 (PARADIGM) with OS benefit; multiple consistent retrospective analyses.","pairingType":"combination"},{"id":"anti-gd2-plus-chemo-relapse","kind":"pairing","name":"Anti-GD2 antibody + irinotecan-temozolomide (chemoimmunotherapy)","aka":[],"tldr":"Adding the anti-GD2 antibody to relapse chemotherapy doubled response rates in relapsed neuroblastoma, and the idea is now moving into first-line induction.","summary":"Adding the anti-GD2 antibody dinutuximab to irinotecan and temozolomide chemotherapy is a combination pairing for relapsed neuroblastoma that has become the standard treatment at first relapse. Chemotherapy releases antigen and depletes suppressive cells while the antibody directs antibody-dependent cellular cytotoxicity against GD2, a disialoganglioside that chemotherapy does not downregulate. In the randomised phase 2 ANBL1221 trial the irinotecan-temozolomide-dinutuximab arm produced far more responses than the temsirolimus comparator, and a confirmatory expansion supported the result. The concept is now moving into first-line induction in ANBL17P1, which tests dinutuximab during induction, and naxitamab combined with chemotherapy shows a similar pattern.","asOf":"2026-09-07","links":[{"label":"ANBL1221: irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (Lancet Oncology 2017)","url":"https://doi.org/10.1016/S1470-2045(17)30355-8"}],"tags":[],"related":[],"cancers":["neuroblastoma","neuroblastoma-high-risk"],"sections":[],"technologies":[],"targets":["gd2"],"drugs":["dinutuximab","naxitamab","temozolomide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"dinutuximab","b":"temozolomide","rationale":"Chemotherapy releases antigen and depletes suppressive cells while the antibody directs ADCC; GD2 is not downregulated by chemotherapy.","evidence":"Randomised phase 2 (ANBL1221) and confirmatory expansion.","pairingType":"combination"},{"id":"bcma-then-gprc5d","kind":"pairing","name":"BCMA-directed therapy → GPRC5D-directed therapy","aka":[],"tldr":"When a BCMA drug stops working, switching to a drug against a different myeloma protein still produces responses in about two-thirds of patients.","summary":"When a BCMA-directed therapy such as teclistamab stops working in multiple myeloma, switching to the GPRC5D-directed bispecific talquetamab is a sequence pairing that still produces responses in a majority of patients. GPRC5D is an independent antigen with different escape mechanisms, so antigen loss through TNFRSF17 deletion, which drives resistance to BCMA agents, does not affect it; T-cell fitness is the limitation the two share. The evidence comes from the cohort of MonumenTAL-1 that enrolled patients previously treated with T-cell redirection, and the RedirecTT-1 combination of teclistamab with talquetamab has shown high response rates including in extramedullary disease. The data are phase 1/2 and phase 3 combination trials are ongoing; the MajesTEC-1 paper on teclistamab links here.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT04634552: MonumenTAL-1","url":"https://clinicaltrials.gov/study/NCT04634552"}],"tags":[],"related":[],"cancers":["multiple-myeloma"],"sections":[],"technologies":[],"targets":["bcma","gprc5d"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["monumental-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"teclistamab","b":"talquetamab","rationale":"Independent antigen; different escape mechanisms; T-cell fitness is the shared limitation.","evidence":"Phase 1/2 cohorts; phase 3 combinations ongoing.","pairingType":"sequence"},{"id":"tki-plus-blinatumomab-ph-all","kind":"pairing","name":"BCR::ABL1 TKI + blinatumomab (chemotherapy-free Ph+ ALL)","aka":[],"tldr":"A pill that switches off the leukaemia's engine plus an immunotherapy that mops up survivors, with no chemotherapy.","summary":"A BCR::ABL1 tyrosine kinase inhibitor, ponatinib or dasatinib, combined with the CD19 bispecific blinatumomab offers chemotherapy-free treatment for adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia. The TKI collapses the Ph-positive clone quickly, and blinatumomab then clears residual disease at the MRD level, including subclones with kinase mutations, because its CD19 mechanism is independent of the kinase. The D-ALBA (GIMEMA LAL2116) trial with dasatinib and the MD Anderson series with ponatinib achieved molecular remission in most adults with far less toxicity than hyper-CVAD. The evidence is phase 2, and randomised comparisons against chemotherapy-containing regimens such as GIMEMA ALL2820 are under way; PhALLCON is the other linked trial.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT02744768: D-ALBA (GIMEMA LAL2116)","url":"https://clinicaltrials.gov/study/NCT02744768"},{"label":"ClinicalTrials.gov NCT03589326: PhALLCON","url":"https://clinicaltrials.gov/study/NCT03589326"}],"tags":[],"related":[],"cancers":["all-leukemia","all-paediatric-ph-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["ponatinib","dasatinib","blinatumomab"],"companies":[],"institutions":[],"pathways":[],"terms":["ph-positive-all"],"trials":["d-alba","phallcon"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"ponatinib","b":"blinatumomab","rationale":"TKI collapses the Ph+ clone quickly; blinatumomab clears MRD-level disease that harbours TKI-resistant subclones, and its CD19 mechanism is independent of kinase mutations.","evidence":"Phase 2 (D-ALBA, MDACC); phase 3 pending.","pairingType":"combination"},{"id":"prrt-then-alpha-net","kind":"pairing","name":"Beta PRRT → alpha PRRT","aka":[],"tldr":"When lutetium radioligand therapy stops working, alpha-emitting versions can still control the disease.","summary":"This sequence moves from beta-emitting lutetium-177 dotatate to an alpha-emitting radioligand, 212Pb-DOTAMTATE, when beta PRRT stops controlling a neuroendocrine tumour. Alpha particles deliver oxygen-independent clustered DNA damage that beta-resistant clones cannot repair, so the same somatostatin receptor target can be attacked again with a more destructive payload. The phase 2 ALPHAMEDIX-02 trial included a PRRT-exposed cohort in which disease control was maintained in most patients, and ACTION-1 is the randomised phase 3 test of 225Ac-DOTATATE after 177Lu. The pairing belongs to the wider topic of alpha versus beta emitters and targeted alpha therapy.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT05153772: ALPHAMEDIX-02","url":"https://clinicaltrials.gov/study/NCT05153772"},{"label":"ClinicalTrials.gov NCT05477576: ACTION-1","url":"https://clinicaltrials.gov/study/NCT05477576"}],"tags":[],"related":[],"cancers":["neuroendocrine"],"sections":[],"technologies":["targeted-alpha-therapy"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["alpha-vs-beta"],"trials":["alphamedix-02","action-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"lutathera","b":"alphamedix","rationale":"Alpha particles deliver oxygen-independent clustered DNA damage that beta-resistant clones cannot repair.","evidence":"Phase 2 (AlphaMedix); phase 3 pending (ACTION-1).","pairingType":"sequence"},{"id":"beta-then-alpha","kind":"pairing","name":"Beta radioligand → alpha radioligand","aka":[],"tldr":"After lutetium therapy stops working, an actinium version of the same drug can still produce responses.","summary":"This sequence pairing follows Radioligand therapy (beta emitters) with Targeted alpha therapy using the same targeting molecule: after lutetium stops working, an actinium version of the same drug can still produce responses. Alpha particles cause oxygen-independent clustered DNA damage that beta-resistant, hypoxic or small-volume disease cannot repair, as explained in the Alpha vs beta emitters entry. In Prostate cancer, Actinium-225 PSMA agents after Lutetium-177 vipivotide tetraxetan produced PSA responses in retrospective series, and phase 3 trials (AcTION, AlphaBreak) are ongoing. In Neuroendocrine tumours, Actinium-225 DOTATATE (RYZ101) is being tested in ACTION-1 after Lutetium-177 dotatate, so the evidence is retrospective and phase 1/2 with phase 3 pending.","asOf":"2026-09-04","links":[{"label":"ClinicalTrials.gov NCT06402331: AlphaBreak (FPI-2265) & AcTION (225Ac-PSMA-617)","url":"https://clinicaltrials.gov/study/NCT06402331"}],"tags":[],"related":[],"cancers":["prostate","neuroendocrine"],"sections":[],"technologies":[],"targets":[],"drugs":["pluvicto","ac225-psma","lutathera","ryz101"],"companies":[],"institutions":[],"pathways":[],"terms":["alpha-vs-beta"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"radioligand-therapy","b":"targeted-alpha-therapy","rationale":"Alpha particles cause oxygen-independent clustered DNA damage that beta-resistant, hypoxic, or small-volume disease cannot repair.","evidence":"Retrospective and phase 1/2; phase 3 pending.","pairingType":"sequence"},{"id":"blinatumomab-frontline-consolidation","kind":"pairing","name":"Blinatumomab added to frontline chemotherapy","aka":[],"tldr":"Interleaving an immunotherapy with standard chemotherapy cycles improves survival in adults and children with newly diagnosed ALL.","summary":"Adding blinatumomab, a CD19-directed bispecific T-cell engager, to frontline chemotherapy cycles is a combination pairing that improves survival in both adults and children with newly diagnosed B-cell acute lymphoblastic leukaemia. Chemotherapy reduces the bulk of disease and the immunosuppressive burden, after which blinatumomab engages the patient's recovering T cells against residual CD19-positive blasts. Two phase 3 trials, ECOG-ACRIN E1910 in adults who were already in MRD-negative remission and Children's Oncology Group AALL1731 in children with standard-risk disease, were both stopped early because of benefit. Blinatumomab is now a standard part of consolidation regardless of MRD status, and the linked papers describe both trials.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT02003222: ECOG-ACRIN E1910","url":"https://clinicaltrials.gov/study/NCT02003222"},{"label":"ClinicalTrials.gov NCT03914625: COG AALL1731","url":"https://clinicaltrials.gov/study/NCT03914625"}],"tags":[],"related":[],"cancers":["all-leukemia","all-paediatric-standard-risk"],"sections":[],"technologies":[],"targets":["cd19"],"drugs":["blinatumomab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["e1910","aall1731"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"blinatumomab","b":"cytarabine-7-3","rationale":"Chemotherapy reduces bulk and immunosuppressive burden; blinatumomab then engages the patient's recovering T cells against residual CD19+ blasts.","evidence":"Two positive phase 3 trials.","pairingType":"combination"},{"id":"braf-plus-mek","kind":"pairing","name":"BRAF inhibitor + MEK inhibitor","aka":[],"tldr":"Blocking two consecutive steps in the same relay prevents the pathway from rerouting and reduces side effects.","summary":"This combination pairs a BRAF inhibitor with a MEK inhibitor in the RAS / RAF / MEK / ERK (MAPK) pathway, blocking two consecutive steps of the same relay so the pathway cannot reroute. The mechanism is that BRAF inhibitor monotherapy causes paradoxical MEK and ERK reactivation through CRAF dimers, and adding MEK inhibition blocks that escape while reducing paradoxical MAPK activation and the skin cancers it produces. Dabrafenib plus trametinib and Encorafenib plus binimetinib improved progression-free and overall survival over a BRAF inhibitor alone in phase 3 Melanoma trials, and the combination has since gained a tumour-agnostic approval. It is used in Melanoma, Colorectal cancer and Non-small-cell lung cancer and serves as the template for vertical pathway inhibition.","asOf":"2026-09-04","links":[{"label":"ClinicalTrials.gov NCT01909453: COLUMBUS","url":"https://clinicaltrials.gov/study/NCT01909453"}],"tags":[],"related":[],"cancers":["melanoma","colorectal","nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["encorafenib"],"companies":[],"institutions":[],"pathways":["ras-mapk"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"braf","b":"ras-mapk","rationale":"BRAF inhibitor monotherapy causes paradoxical MEK/ERK reactivation via CRAF dimers; adding MEK inhibition blocks the escape.","evidence":"Phase 3 OS benefit in melanoma; tumour-agnostic approval.","pairingType":"combination"},{"id":"braf-mek-neoadjuvant-atc","kind":"pairing","name":"BRAF/MEK inhibition → surgery in anaplastic thyroid cancer","aka":[],"tldr":"Shrink a BRAF-mutant anaplastic thyroid tumour with pills first, then remove what is left; some patients now survive years instead of months.","summary":"This sequence gives the BRAF/MEK inhibitor pair dabrafenib and trametinib, often with pembrolizumab, to shrink a BRAF-mutant anaplastic thyroid cancer before surgery, then removes what remains. Anaplastic thyroid cancer can double in weeks, whereas BRAF/MEK inhibition produces responses within days, buying time for definitive local therapy. The evidence is the anaplastic cohort of the phase 2 ROAR trial plus the MD Anderson institutional series, in which previously unresectable tumours became operable and responders lived far longer than the historical expectation; there is no randomised trial because the disease is so rare. Rapid BRAF testing at diagnosis is now standard so that eligible patients can start the pills immediately.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT02034110: ROAR (anaplastic thyroid cancer cohort)","url":"https://clinicaltrials.gov/study/NCT02034110"}],"tags":[],"related":[],"cancers":["thyroid"],"sections":[],"technologies":[],"targets":["braf"],"drugs":["dabrafenib-trametinib"],"companies":[],"institutions":["md-anderson"],"pathways":[],"terms":[],"trials":["roar-atc"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"dabrafenib-trametinib","b":"surgery","rationale":"ATC doubles in weeks; BRAF/MEK inhibition produces responses within days, buying time for definitive local therapy.","evidence":"Phase 2 ROAR plus institutional series; no randomised trial (rarity).","pairingType":"sequence"},{"id":"btki-plus-venetoclax-fixed-duration","kind":"pairing","name":"BTK inhibitor + venetoclax, fixed duration","aka":[],"tldr":"Block the survival signal and remove the death shield at the same time, for about a year, then stop and stay in remission for years.","summary":"CAPTIVATE and GLOW (ibrutinib), AMPLIFY (acalabrutinib; FDA approved February 2026), SEQUOIA arm D (zanubrutinib), and CELESTIAL (sonrotoclax + zanubrutinib) all show high uMRD and durable PFS after 12-15 months of therapy. Fixed duration reduces cumulative toxicity and cost versus indefinite BTK inhibition.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03836261: AMPLIFY","url":"https://clinicaltrials.gov/study/NCT03836261"},{"label":"ClinicalTrials.gov NCT03462719: GLOW","url":"https://clinicaltrials.gov/study/NCT03462719"}],"tags":[],"related":[],"cancers":["cll"],"sections":[],"technologies":[],"targets":["btk","bcl2"],"drugs":["acalabrutinib","ibrutinib","zanubrutinib","venetoclax","sonrotoclax"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["amplify","glow","captivate","sequoia","celestial-tncll"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"acalabrutinib","b":"venetoclax","rationale":"BTK inhibition mobilises CLL cells out of protective lymph-node niches and increases BCL-2 dependence; venetoclax then kills them. The two resistance mechanisms are independent.","evidence":"Multiple positive phase 3 trials; US approval 2026.","pairingType":"combination"},{"id":"io-varices-caution","kind":"pairing","name":"Caution: bevacizumab-based regimens with untreated varices","aka":[],"tldr":"Immunotherapy plus bevacizumab is standard in liver cancer, but the anti-VEGF part can cause fatal bleeding from swollen veins in the oesophagus unless they are checked first.","summary":"This caution concerns atezolizumab with bevacizumab, the standard first-line regimen in hepatocellular carcinoma, in patients whose liver disease, often from hepatitis B or C, has produced untreated oesophageal varices. VEGF blockade impairs mucosal healing and worsens the effects of portal pressure, and cirrhotic patients commonly have varices, so the anti-VEGF component can cause fatal variceal bleeding. IMbrave150 required endoscopy within six months of enrolment and treatment of any varices found, and upper gastrointestinal bleeding was still observed on atezolizumab-bevacizumab; the trial protocols and label warnings are the evidence. For patients at high bleeding risk, the durvalumab-based STRIDE regimen tested in HIMALAYA, or nivolumab with ipilimumab, are alternatives.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03434379: IMbrave150","url":"https://clinicaltrials.gov/study/NCT03434379"},{"label":"ClinicalTrials.gov NCT03298451: HIMALAYA","url":"https://clinicaltrials.gov/study/NCT03298451"}],"tags":[],"related":[],"cancers":["hcc"],"sections":[],"technologies":[],"targets":[],"drugs":["atezolizumab","durvalumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["imbrave150","himalaya"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"atezolizumab","b":"hbv-hcv","rationale":"VEGF blockade impairs mucosal healing and raises portal pressure effects; cirrhotic patients have varices.","evidence":"Trial protocols and label warnings.","pairingType":"caution"},{"id":"bleomycin-omission-caution","kind":"pairing","name":"Caution: bleomycin lung toxicity, especially with brentuximab or G-CSF","aka":[],"tldr":"Bleomycin scars the lungs; combining it with brentuximab was fatal in early trials, and PET-adapted therapy now lets most patients skip it.","summary":"Bleomycin scars the lungs, and this caution pairing warns that the risk is compounded when it is combined with brentuximab vedotin or given alongside G-CSF. In the phase 1 study of brentuximab plus ABVD, pulmonary toxicity was frequent and some patients died, so the phase 3 ECHELON-1 trial dropped bleomycin and used brentuximab with AVD. The RATHL trial showed that bleomycin can be omitted after a negative interim PET scan, so PET-adapted therapy now lets most patients with Hodgkin lymphoma avoid it; the rationale is additive pneumotoxicity and the small contribution bleomycin makes once PET2 is negative. Toxicity also rises with age, renal impairment, G-CSF and oxygen exposure, and the record is also linked from the record on germ cell tumours of childhood and adolescence.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT00678327: RATHL","url":"https://clinicaltrials.gov/study/NCT00678327"},{"label":"ClinicalTrials.gov NCT01712490: ECHELON-1","url":"https://clinicaltrials.gov/study/NCT01712490"}],"tags":[],"related":[],"cancers":["hodgkin-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["rathl","echelon-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"brentuximab-vedotin","b":"pet-adapted-therapy","rationale":"Additive pneumotoxicity; bleomycin adds little efficacy once PET2 is negative.","evidence":"Phase 1 toxicity signal; RATHL phase 3 non-inferiority.","pairingType":"caution"},{"id":"caution-pd1-first-line-ovarian","kind":"pairing","name":"Caution: checkpoint inhibitors in first-line ovarian cancer","aka":[],"tldr":"Immunotherapy added to first-line chemotherapy has failed to extend survival in ovarian cancer in every large trial so far; its only win is in PD-L1-positive platinum-resistant disease.","summary":"IMagyn050 (atezolizumab), JAVELIN Ovarian 100 (avelumab), and DUO-O (durvalumab ± olaparib) showed no OS benefit in newly diagnosed disease. KEYNOTE-B96 (pembrolizumab + weekly paclitaxel) is the exception, in PD-L1-positive platinum-resistant relapse. Ovarian cancer is immunologically 'cold' with low TMB.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03737643: DUO-O / ENGOT-ov46","url":"https://clinicaltrials.gov/study/NCT03737643"},{"label":"ClinicalTrials.gov NCT05116189: KEYNOTE-B96 / ENGOT-ov65","url":"https://clinicaltrials.gov/study/NCT05116189"}],"tags":[],"related":[],"cancers":["ovarian"],"sections":[],"technologies":[],"targets":["pd1","pdl1"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["duo-o","keynote-b96"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"checkpoint-inhibitor","b":"ovarian","rationale":"Low neoantigen burden, immunosuppressive ascites, and myeloid-rich microenvironment blunt T-cell responses; chemotherapy-induced priming appears necessary for benefit.","evidence":"Three negative first-line phase 3 trials; one positive relapsed-setting trial.","pairingType":"caution"},{"id":"cit-in-del17p-caution","kind":"pairing","name":"Caution: chemoimmunotherapy in del(17p)/TP53 CLL","aka":[],"tldr":"Chemotherapy-based regimens barely work when the p53 gene is lost; these patients need BTK inhibitors or venetoclax from the start.","summary":"This caution concerns rituximab-based chemoimmunotherapy in chronic lymphocytic leukaemia with del(17p) or TP53 mutation. Alkylators and purine analogues kill through p53-dependent apoptosis, so loss of TP53 removes the mechanism: FCR and BR give only short remissions in these patients and may select resistant clones. The pattern is consistent across the CLL8 and CLL10 trials and registry data, and guidelines from NCCN, ESMO and iwCLL restrict chemoimmunotherapy to fit patients with intact TP53 and mutated IGHV, with targeted therapy preferred even there. Patients with del(17p) or TP53 aberration should start on a BTK inhibitor such as zanubrutinib, tested in SEQUOIA, or on venetoclax.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03336333: SEQUOIA","url":"https://clinicaltrials.gov/study/NCT03336333"}],"tags":[],"related":[],"cancers":["cll"],"sections":[],"technologies":[],"targets":[],"drugs":["rituximab","zanubrutinib","venetoclax"],"companies":[],"institutions":[],"pathways":[],"terms":["del17p-tp53"],"trials":["sequoia"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"rituximab","b":"del17p-tp53","rationale":"Alkylators and purine analogues kill via p53-dependent apoptosis; TP53 loss removes the mechanism.","evidence":"Consistent across CLL8, CLL10, and registry data.","pairingType":"caution"},{"id":"doxorubicin-cardio-caution","kind":"pairing","name":"Caution: cumulative anthracycline dose and the heart","aka":[],"tldr":"Every dose of doxorubicin adds to a lifetime total; above roughly 450 mg/m2 heart failure risk rises steeply, so sarcoma and lymphoma regimens are capped and hearts are monitored.","summary":"Every dose of doxorubicin adds to a lifetime cumulative total, and this caution pairing links the anthracycline with cardio-oncology because the risk of heart failure rises steeply above roughly 450 mg/m2. The mechanism is topoisomerase II beta-mediated damage to cardiomyocytes that is dose-dependent and irreversible, and the risk is higher with chest radiotherapy, trastuzumab and at the extremes of age. Decades of cohort data and randomised trials of dexrazoxane support the warning, and mitigation includes dexrazoxane, liposomal doxorubicin, continuous infusion and echocardiographic surveillance. The caution applies in sarcoma, Hodgkin lymphoma, diffuse large B-cell lymphoma and triple-negative breast cancer, where regimens are capped and hearts are monitored.","asOf":"2026-09-07","links":[{"label":"Swain et al., Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials (Cancer 2003)","url":"https://doi.org/10.1002/cncr.11407"}],"tags":[],"related":[],"cancers":["sarcoma","hodgkin-lymphoma","dlbcl","tnbc"],"sections":[],"technologies":["cardio-oncology"],"targets":[],"drugs":["doxorubicin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-swain-cancer"],"journals":[],"dependsOn":[],"notes":[],"a":"doxorubicin","b":"cardio-oncology","rationale":"Topoisomerase IIβ-mediated cardiomyocyte damage is dose-dependent and irreversible.","evidence":"Decades of cohort data; dexrazoxane RCTs.","pairingType":"caution"},{"id":"hpv-deescalation-caution","kind":"pairing","name":"Caution: de-escalating radiation on HPV status alone","aka":[],"tldr":"Being HPV-positive is not enough to justify less radiation; trials that tried it saw more relapses.","summary":"This caution warns against reducing radiotherapy for HPV-positive, p16-positive head and neck cancer on the basis of HPV status alone. HPV-positive tumours are heterogeneous in smoking exposure, nodal burden and biology, so a single marker over-selects patients for less treatment. Multiple randomised trials bear this out: the 60 Gy arms of NRG-HN005, and the cetuximab-substitution trials RTOG 1016 and De-ESCALaTE, all underperformed standard cisplatin chemoradiation with modern external beam radiotherapy, with more relapses. The current approach is response-adapted selection, or selection guided by circulating tumour HPV DNA, rather than HPV status at diagnosis.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03952585: NRG-HN002 & NRG-HN005 (HPV+ de-escalation)","url":"https://clinicaltrials.gov/study/NCT03952585"}],"tags":[],"related":[],"cancers":["head-and-neck"],"sections":[],"technologies":["cthpv-dna"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["hpv-p16"],"trials":["nrg-hn002-hn005"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"hpv-p16","b":"imrt-igrt","rationale":"HPV-positive tumours are heterogeneous in smoking exposure, nodal burden, and biology; a single marker over-selects.","evidence":"Multiple randomised trials.","pairingType":"caution"},{"id":"ild-overlap-caution","kind":"pairing","name":"Caution: DXd ADC + agents with pneumonitis risk","aka":[],"tldr":"Enhertu and its DXd cousins can inflame the lungs; combining them with immunotherapy, radiation, or mTOR inhibitors stacks that risk.","summary":"This caution pairing concerns combining Trastuzumab deruxtecan or Datopotamab deruxtecan with agents that carry their own pneumonitis risk. These DXd ADCs can inflame the lungs, and adding immunotherapy, radiation or mTOR inhibitors stacks that risk through overlapping mechanisms that make the cause hard to attribute, as the Interstitial lung disease (ILD) / pneumonitis entry explains. ILD affects a notable minority of patients on T-DXd, checkpoint inhibitors such as Durvalumab and Pembrolizumab add a further small risk, and trials such as DESTINY-Breast07/08 and TROPION-Breast05 use careful monitoring. The evidence is toxicity data from those trials, and the pairing informs the idea of finding the lowest effective doses in a combination.","asOf":"2026-09-04","links":[{"label":"Powell et al., Pooled analysis of drug-related interstitial lung disease and pneumonitis in trastuzumab deruxtecan trials (ESMO Open 2022)","url":"https://doi.org/10.1016/j.esmoop.2022.100554"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab-deruxtecan","datopotamab-deruxtecan","durvalumab","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":["ild"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-powell-esmo-open"],"journals":[],"dependsOn":[],"notes":[],"a":"trastuzumab-deruxtecan","b":"ild","rationale":"Distinct but overlapping mechanisms of pneumonitis; additive toxicity with limited ability to attribute cause.","evidence":"Toxicity data from combination trials.","pairingType":"caution"},{"id":"btki-ibrutinib-cardiac-caution","kind":"pairing","name":"Caution: ibrutinib in patients with cardiac risk","aka":[],"tldr":"Ibrutinib raises the risk of irregular heart rhythm, high blood pressure, and sudden cardiac events; second-generation BTK inhibitors are safer choices for patients with heart disease.","summary":"This caution pairs ibrutinib with cardio-oncology: the first-generation BTK inhibitor raises the risk of atrial fibrillation, hypertension and ventricular arrhythmia or sudden cardiac death in chronic lymphocytic leukaemia patients, through off-target inhibition of CSK and TEC kinases in cardiomyocytes and the vasculature. Long-term ibrutinib data carry these signals, and the head-to-head phase 3 trials ELEVATE-RR and ALPINE showed markedly less atrial fibrillation with the second-generation inhibitors acalabrutinib and zanubrutinib, which are therefore safer choices for patients with heart disease; pharmacovigilance data agree. Anticoagulation for atrial fibrillation adds bleeding risk with any BTK inhibitor, so the cardiac and bleeding risks have to be weighed together.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03734016: ALPINE","url":"https://clinicaltrials.gov/study/NCT03734016"}],"tags":[],"related":[],"cancers":["cll"],"sections":[],"technologies":["cardio-oncology"],"targets":[],"drugs":["ibrutinib","acalabrutinib","zanubrutinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["alpine"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"ibrutinib","b":"cardio-oncology","rationale":"Off-target inhibition of CSK and TEC in cardiomyocytes and vasculature.","evidence":"Head-to-head phase 3 (ELEVATE-RR, ALPINE); pharmacovigilance.","pairingType":"caution"},{"id":"il2-anti-gd2-caution","kind":"pairing","name":"Caution: IL-2 added to anti-GD2 therapy","aka":[],"tldr":"Interleukin-2 was part of the original immunotherapy package but a large European trial showed it adds toxicity and no benefit, so it has been dropped.","summary":"Interleukin-2 was part of the original anti-GD2 immunotherapy package for high-risk neuroblastoma, and this caution pairing records why it has been dropped. In the R2 randomised comparison of the SIOPEN HR-NBL1 trial, adding subcutaneous IL-2 to dinutuximab beta produced no meaningful improvement in event-free survival but far more severe toxicity. The rationale is that IL-2 expands regulatory T cells and causes capillary leak, whereas the NK-cell-mediated antibody-dependent cytotoxicity that the anti-GD2 antibody relies on is sufficiently supported by GM-CSF. European protocols omit IL-2 and the Children's Oncology Group has since removed it as well in ANBL1531, so the combination now stands as a warning example within the broader cytokine therapy record.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT01704716: SIOPEN HR-NBL1","url":"https://clinicaltrials.gov/study/NCT01704716"}],"tags":[],"related":[],"cancers":["neuroblastoma","neuroblastoma-high-risk"],"sections":[],"technologies":[],"targets":[],"drugs":["dinutuximab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["hr-nbl1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"dinutuximab","b":"cytokine-therapy","rationale":"IL-2 expands regulatory T cells and causes capillary leak; NK-mediated ADCC is sufficiently supported by GM-CSF.","evidence":"Randomised phase 3 (HR-NBL1).","pairingType":"caution"},{"id":"inotuzumab-then-transplant-caution","kind":"pairing","name":"Caution: inotuzumab before transplant (veno-occlusive disease)","aka":[],"tldr":"The CD22 ADC is an excellent bridge to transplant, but too many cycles or the wrong conditioning can cause severe liver damage after the transplant.","summary":"This caution pairing concerns inotuzumab ozogamicin, the CD22 antibody-drug conjugate, used as a bridge to allogeneic stem cell transplantation in acute lymphoblastic leukaemia. Its calicheamicin payload damages the hepatic sinusoidal endothelium, which is then further injured by conditioning chemotherapy, and the result can be severe veno-occlusive disease after transplant. In INO-VATE a substantial fraction of patients who proceeded to transplant developed veno-occlusive disease, and the risk rises with more than two cycles of inotuzumab, dual-alkylator conditioning and prior hepatic injury; the label carries a boxed warning. Current guidance is to limit inotuzumab to two cycles before transplant, avoid busulfan-thiotepa conditioning, and consider defibrotide prophylaxis.","asOf":"2026-09-07","links":[{"label":"INO-VATE: inotuzumab ozogamicin, a CD22 antibody-drug conjugate, versus chemotherapy for relapsed adult B-cell ALL (New England Journal of Medicine 2016)","url":"https://doi.org/10.1056/NEJMoa1509277"}],"tags":[],"related":[],"cancers":["all-leukemia"],"sections":[],"technologies":["allogeneic-hsct"],"targets":[],"drugs":["inotuzumab-ozogamicin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"inotuzumab-ozogamicin","b":"allogeneic-hsct","rationale":"Calicheamicin damages hepatic sinusoidal endothelium, which is then further injured by conditioning chemotherapy.","evidence":"INO-VATE safety data; label boxed warning.","pairingType":"caution"},{"id":"lag3-adjuvant-caution","kind":"pairing","name":"Caution: LAG-3 blockade outside active disease","aka":[],"tldr":"LAG-3 blockers helped in measurable melanoma with one drug pairing, but failed as adjuvant therapy and with a different PD-1 partner.","summary":"This caution notes that LAG-3 blockade in melanoma has succeeded in only one setting: relatlimab with nivolumab in unresectable, measurable disease, as shown in RELATIVITY-047. The same pairing failed as adjuvant therapy in RELATIVITY-098, and the alternative LAG-3 antibody fianlimab with cemiplimab failed in a first-line phase 3 reported in 2026. LAG-3 is expressed on exhausted T cells inside tumours, so without tumour present, or with different antibody properties and comparators, the effect may vanish. Two negative phase 3 trials against one positive one mean the benefit cannot be assumed to transfer to the adjuvant setting or to a different PD-1 partner.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03470922: RELATIVITY-047","url":"https://clinicaltrials.gov/study/NCT03470922"},{"label":"ClinicalTrials.gov NCT05002569: RELATIVITY-098","url":"https://clinicaltrials.gov/study/NCT05002569"}],"tags":[],"related":[],"cancers":["melanoma"],"sections":[],"technologies":[],"targets":["lag3"],"drugs":["relatlimab-nivolumab","fianlimab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["relativity-047","relativity-098","fianlimab-phase3-melanoma"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"relatlimab-nivolumab","b":"fianlimab","rationale":"LAG-3 is expressed on exhausted T cells inside tumours; without tumour, or with different antibody properties and comparators, the effect may vanish.","evidence":"Two negative phase 3 trials versus one positive.","pairingType":"caution"},{"id":"caution-mis-radical-hysterectomy","kind":"pairing","name":"Caution: minimally invasive radical hysterectomy for early cervical cancer","aka":[],"tldr":"Keyhole radical hysterectomy, though less painful, led to more recurrences and deaths than open surgery in the LACC trial. Open surgery is the standard until protective techniques are proven.","summary":"This caution pairing concerns minimally invasive, laparoscopic or robotic, radical hysterectomy for early cervical cancer. Although keyhole surgery is less painful, the phase 3 LACC trial found that it led to more recurrences and more deaths than open radical hysterectomy, and large cohort studies have confirmed the finding. The leading explanation is that laparoscopic manipulation of the cervix disseminates tumour cells, with carbon dioxide insufflation and the uterine manipulator the suspected culprits. Open surgery is therefore the standard, while the RACC and ROCC trials test whether manipulator-free techniques with vaginal closure can make the minimally invasive approach safe.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT00614211: LACC (Laparoscopic Approach to Cervical Cancer)","url":"https://clinicaltrials.gov/study/NCT00614211"}],"tags":[],"related":[],"cancers":["cervical"],"sections":[],"technologies":["robotic-surgery"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["lacc"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"robotic-surgery","b":"cervical","rationale":"Laparoscopic manipulation of the cervix is thought to disseminate tumour cells.","evidence":"Phase 3 (negative for MIS) plus large cohorts.","pairingType":"caution"},{"id":"io-rechallenge-caution-rcc","kind":"pairing","name":"Caution: PD-1 rechallenge after progression on immunotherapy (RCC)","aka":[],"tldr":"Restarting immunotherapy alongside a targeted pill after immunotherapy has already failed adds side effects and no benefit.","summary":"This caution pairing concerns restarting an immune checkpoint inhibitor together with an anti-angiogenic tyrosine kinase inhibitor in renal cell carcinoma after the disease has already progressed on immunotherapy. Two phase 3 trials tested it and both were negative: CONTACT-03 compared atezolizumab plus cabozantinib with cabozantinib alone, and TiNivo-2 compared nivolumab plus tivozanib with tivozanib alone. The explanation is that acquired resistance to PD-1 blockade is not overcome by adding a VEGF-directed TKI, and the apparent activity of IO-TKI after IO in earlier single-arm studies reflected the TKI. After progression on immunotherapy, single-agent cabozantinib, tivozanib or axitinib, or belzutifan, is standard, and immunotherapy rechallenge is reserved for clinical trials.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT04338269: CONTACT-03","url":"https://clinicaltrials.gov/study/NCT04338269"},{"label":"ClinicalTrials.gov NCT04987203: TiNivo-2","url":"https://clinicaltrials.gov/study/NCT04987203"}],"tags":[],"related":[],"cancers":["rcc"],"sections":[],"technologies":[],"targets":[],"drugs":["atezolizumab","cabozantinib","tivozanib","nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["contact-03","tinivo-2"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"checkpoint-inhibitor","b":"antiangiogenic","rationale":"Acquired resistance to PD-1 blockade is not overcome by adding a VEGF-TKI; the apparent activity of IO-TKI after IO in single-arm studies reflected the TKI.","evidence":"Two negative phase 3 trials.","pairingType":"caution"},{"id":"proton-vs-imrt","kind":"pairing","name":"Caution: proton therapy vs IMRT","aka":[],"tldr":"Protons stop inside the tumour; modern X-ray beams (IMRT) still exit through healthy tissue. That physical difference only matters if it changes cure or late harm enough to justify the cost, which randomised adult trials have not settled.","summary":"IMRT and pencil-beam protons can both shape high dose around a target. Protons remove the exit dose and raise linear energy transfer at the Bragg peak; IMRT is cheaper, more widely available, and has a larger randomised evidence base. Adult comparisons are mixed: some oesophageal data favour protons on toxicity; prostate and breast trials (PARTIQoL, RADCOMP) are the tests of whether late-tissue alpha/beta plus variable RBE produce a real window. Paediatric cases and re-irradiation near critical organs remain the clearest established uses. Do not treat proton as automatically better than IMRT.","asOf":"2026-09-04","links":[{"label":"PARTIQoL (NCT01617161)","url":"https://clinicaltrials.gov/study/NCT01617161"},{"label":"RADCOMP (NCT02603341)","url":"https://clinicaltrials.gov/study/NCT02603341"}],"tags":["radiation-wave5"],"related":["idea-bio2-let-rbe-ab-selects-protons","idea-fund-proton-coverage-with-evidence"],"cancers":["prostate","breast-hr-positive","esophageal","nsclc","medulloblastoma","chordoma"],"sections":["radiation"],"technologies":["proton-therapy","imrt-igrt","intensity-modulated-proton-therapy","linear-quadratic-model"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["linear-energy-transfer","relative-biological-effectiveness","alpha-beta-ratio","bragg-peak"],"trials":["partiqol","radcomp"],"people":[],"bottlenecks":["b-surgery-radiation-innovation"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"proton-therapy","b":"imrt-igrt","rationale":"No exit dose and a distal LET rise can spare a late-responding organ or, if the edge sits in that organ, harm it. Alpha/beta of tumour versus late tissue decides whether that physical difference is biologically large.","evidence":"Paediatric and skull-base use is established on integral-dose grounds. Adult randomised evidence is mixed and still accruing (PARTIQoL, RADCOMP, NRG oesophagus and lung).","pairingType":"caution"},{"id":"bispecific-infection-prophylaxis","kind":"pairing","name":"Caution: T-cell redirectors and infections","aka":[],"tldr":"Myeloma bispecifics and CAR-T suppress antibody production so profoundly that infections, not the cancer, became a leading cause of death in early trials.","summary":"This caution pairing records that BCMA-directed T-cell redirectors in multiple myeloma, teclistamab, elranatamab and linvoseltamab, suppress antibody production so profoundly that infections rather than the cancer became a leading cause of death in early trials. BCMA is expressed on normal plasma cells, and continuous T-cell engagement causes T-cell exhaustion and deep humoral immunodeficiency; in MajesTEC-1 severe infections were frequent, including fatal COVID-19 and pneumonia, and hypogammaglobulinaemia was almost universal. The pattern held across MajesTEC-1, MagnetisMM-3 and LINKER-MM1 and is less marked with GPRC5D agents. Immunoglobulin replacement, antiviral and PJP prophylaxis, vaccination, and response-adapted dosing every two to four weeks are now standard.","asOf":"2026-09-07","links":[{"label":"MajesTEC-1: teclistamab, an off-the-shelf BCMA bispecific antibody, in heavily pretreated myeloma (New England Journal of Medicine 2022)","url":"https://doi.org/10.1056/NEJMoa2203478"}],"tags":[],"related":[],"cancers":["multiple-myeloma"],"sections":[],"technologies":[],"targets":[],"drugs":["teclistamab","elranatamab","linvoseltamab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"teclistamab","b":"crs","rationale":"BCMA is expressed on normal plasma cells; continuous T-cell engagement causes T-cell exhaustion and profound humoral immunodeficiency.","evidence":"Consistent across MajesTEC-1, MagnetisMM-3, LINKER-MM1; lower with GPRC5D agents.","pairingType":"caution"},{"id":"tigit-plus-pd1-caution","kind":"pairing","name":"Caution: TIGIT + PD-(L)1 blockade","aka":[],"tldr":"Adding a TIGIT blocker to PD-1/PD-L1 blockade looked good in phase 2 and then failed repeatedly in phase 3.","summary":"This caution pairing concerns adding a TIGIT blocker to Immune checkpoint inhibitors against PD-1 or PD-L1, a combination that looked promising in phase 2 and then failed repeatedly in phase 3. SKYSCRAPER-01 (Tiragolumab plus atezolizumab in Non-small-cell lung cancer), SKYSCRAPER-02 in Small-cell lung cancer and other trials were negative, the phase 2 signals did not reproduce, and Roche and others discontinued most TIGIT programmes in 2024-25. The reason for failure is unclear: Fc-effector requirements, patient selection and redundancy with PD-1 are the proposed explanations. The episode is cited in the idea that no accelerated approval should be granted for a combination without proof that each part contributes, and it is linked from the Tiragolumab and TIGIT entries.","asOf":"2026-09-04","links":[{"label":"SKYSCRAPER-01: tiragolumab plus atezolizumab in previously untreated PD-L1-high non-small-cell lung cancer, phase 3 (Journal of Clinical Oncology 2026)","url":"https://doi.org/10.1200/JCO-25-02777"},{"label":"CITYSCAPE: tiragolumab plus atezolizumab versus placebo plus atezolizumab as first-line treatment for PD-L1-selected NSCLC, phase 2 (Lancet Oncology 2022)","url":"https://doi.org/10.1016/S1470-2045(22)00226-1"}],"tags":[],"related":[],"cancers":["nsclc","sclc"],"sections":[],"technologies":[],"targets":["tigit","pdl1"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-cho-lancet-oncol","paper-peters-j-clin-oncol"],"journals":[],"dependsOn":[],"notes":[],"a":"tigit","b":"checkpoint-inhibitor","rationale":"Unclear; Fc-effector requirements, patient selection, and redundancy with PD-1 are proposed explanations.","evidence":"Multiple negative phase 3.","pairingType":"caution"},{"id":"adc-after-adc-caution","kind":"pairing","name":"Caution: TOP1 ADC immediately after TOP1 ADC","aka":[],"tldr":"Giving a second ADC with the same kind of payload straight after the first often does not work well.","summary":"This caution pairing concerns giving a second antibody-drug conjugate with a topoisomerase 1 payload straight after a first, for example Sacituzumab govitecan after Trastuzumab deruxtecan, in Triple-negative breast cancer (TNBC) and HR-positive / HER2-negative breast cancer. Payload resistance (SLFN11 loss, TOP1 mutations, ABCG2 efflux) is shared across TOP1 ADCs regardless of antigen, so switching antigen does not overcome it. Retrospective series, including SATEEN and BRE-354 at ESMO Breast 2026, show shorter progression-free survival for the second TOP1 ADC, particularly back-to-back; some data suggest an intervening chemotherapy restores sensitivity. Prospective sequencing trials are ongoing; see the ADC sequencing entry and the idea of payload-class switching.","asOf":"2026-09-04","links":[{"label":"Abelman et al., Sequential use of antibody-drug conjugate after antibody-drug conjugate in metastatic breast cancer (ASCO 2023, abstract 1022)","url":"https://doi.org/10.1200/jco.2023.41.16_suppl.1022"}],"tags":[],"related":[],"cancers":["tnbc","breast-hr-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["trastuzumab-deruxtecan","sacituzumab-govitecan","datopotamab-deruxtecan"],"companies":[],"institutions":[],"pathways":[],"terms":["adc-sequencing"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"trastuzumab-deruxtecan","b":"sacituzumab-govitecan","rationale":"Payload resistance (SLFN11 loss, TOP1 mutations, ABCG2 efflux) is shared across TOP1 ADCs regardless of antigen; antigen switching does not overcome it.","evidence":"Retrospective; prospective trials pending.","pairingType":"caution"},{"id":"bispecific-plus-adc-lymphoma","kind":"pairing","name":"CD20 bispecific + CD79b ADC (mosunetuzumab + polatuzumab)","aka":[],"tldr":"Pairing a CD20 bispecific with a CD79b ADC lets two targeted drugs with different mechanisms replace chemotherapy in relapsed lymphoma.","summary":"This combination pairs the CD20 bispecific antibody mosunetuzumab with the CD79b antibody-drug conjugate polatuzumab vedotin in relapsed diffuse large B-cell lymphoma, replacing chemotherapy with two targeted drugs of different mechanism. The ADC debulks the tumour, lowering antigen load and with it the risk of cytokine release syndrome, and the bispecific then consolidates through T-cell killing; the toxicities of the two do not overlap. The phase 3 SUNMO trial, reported in 2025, was positive for progression-free survival against R-GemOx. The regimen is fixed-duration and can be given as an outpatient, and it sits alongside the EPCORE NHL-1 paper on epcoritamab as part of the shift to bispecific-based treatment in relapsed large B-cell lymphoma.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT05171647: SUNMO","url":"https://clinicaltrials.gov/study/NCT05171647"}],"tags":[],"related":[],"cancers":["dlbcl"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["sunmo"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"mosunetuzumab","b":"polatuzumab-vedotin","rationale":"ADC debulks and reduces antigen load and CRS risk; bispecific consolidates with T-cell killing. Their toxicities do not overlap.","evidence":"Phase 3 positive (PFS).","pairingType":"combination"},{"id":"cd38-plus-triplet","kind":"pairing","name":"CD38 antibody added to PI-IMiD-dex (quadruplet induction)","aka":[],"tldr":"Adding a CD38 antibody to the standard three-drug induction roughly halves progression risk in newly diagnosed myeloma.","summary":"Adding a CD38 antibody, daratumumab or isatuximab, to the proteasome inhibitor, immunomodulatory drug and dexamethasone triplet creates the quadruplet induction now standard for newly diagnosed multiple myeloma whether or not a transplant is planned. The drug classes act through non-overlapping mechanisms: bortezomib imposes proteasome stress, lenalidomide drives cereblon-mediated degradation, and the CD38 antibody adds Fc-mediated plasma-cell killing with immunomodulation. Four positive phase 3 trials support it, PERSEUS with daratumumab-VRd around transplant, CEPHEUS, IMROZ with isatuximab-VRd, and MAIA with daratumumab-Rd in older patients, and MAIA also showed an overall survival benefit. Across these trials the quadruplet sharply reduced the risk of progression.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03710603: PERSEUS","url":"https://clinicaltrials.gov/study/NCT03710603"},{"label":"ClinicalTrials.gov NCT03652064: CEPHEUS","url":"https://clinicaltrials.gov/study/NCT03652064"}],"tags":[],"related":[],"cancers":["multiple-myeloma"],"sections":[],"technologies":[],"targets":[],"drugs":["daratumumab","isatuximab","bortezomib","lenalidomide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["perseus","cepheus","imroz"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"daratumumab","b":"lenalidomide","rationale":"Non-overlapping mechanisms: proteasome stress, cereblon-mediated degradation, and Fc-mediated plasma-cell killing with immunomodulation.","evidence":"Four positive phase 3 trials; OS benefit in MAIA.","pairingType":"combination"},{"id":"cdk46-plus-endocrine","kind":"pairing","name":"CDK4/6 inhibitor + endocrine therapy","aka":[],"tldr":"Cut the fuel (oestrogen) and jam the engine (CDK4/6) at the same time.","summary":"This combination pairs CDK4/6 inhibitors with Endocrine therapy (SERMs, AIs, SERDs) in HR-positive / HER2-negative breast cancer, cutting the fuel and jamming the engine at once. The mechanism is that the oestrogen receptor drives cyclin D1 transcription, so blocking CDK4/6 shuts the downstream engine and residual ER signalling or an ESR1 mutation cannot bypass it, linking the Oestrogen receptor signalling and p53 / RB / cell-cycle checkpoint pathways. Multiple phase 3 trials (MONALEESA, MONARCH 2) showed improved progression-free and overall survival in advanced disease, and NATALEE and monarchE showed adjuvant benefit. The linked drugs are Palbociclib, Ribociclib and Abemaciclib, and the pairing is regarded as one of the most successful combinations in oncology.","asOf":"2026-09-04","links":[{"label":"NATALEE: three years of ribociclib after surgery in a broad population of hormone-receptor-positive early breast cancer (New England Journal of Medicine 2024)","url":"https://doi.org/10.1056/NEJMoa2305488"}],"tags":[],"related":[],"cancers":["breast-hr-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["palbociclib","ribociclib","abemaciclib"],"companies":[],"institutions":[],"pathways":["er-signaling","p53-cell-cycle"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"cdk46-inhibitor","b":"endocrine-therapy","rationale":"ER drives cyclin D1 transcription; CDK4/6 inhibition blocks the downstream engine so that residual ER signalling or ESR1 mutation cannot bypass it.","evidence":"Multiple phase 3 with OS benefit.","pairingType":"combination"},{"id":"chemo-io-then-maintenance-sclc","kind":"pairing","name":"Chemo-immunotherapy induction → maintenance intensification (SCLC)","aka":[],"tldr":"Chemo-immunotherapy followed by maintenance in small-cell lung cancer gives four cycles of chemotherapy plus immunotherapy, then keeps the immunotherapy going and adds a second drug to hold the disease longer.","summary":"This sequence pairing in extensive-stage small-cell lung cancer follows four cycles of platinum plus etoposide with immunotherapy by a maintenance phase in which atezolizumab continues and lurbinectedin is added. The rationale is that the disease almost always relapses soon after induction, so attacking residual disease during the response window with a non-cross-resistant agent should delay relapse. The phase 3 IMforte trial showed that adding lurbinectedin to atezolizumab maintenance improved overall survival, leading to FDA approval in 2025, and DeLLphi-305 is testing tarlatamab in the same maintenance slot. Maintenance intensification is the first new first-line strategy in this cancer since chemo-immunotherapy itself.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT05091567: IMforte","url":"https://clinicaltrials.gov/study/NCT05091567"},{"label":"ClinicalTrials.gov NCT06211036: DeLLphi-305","url":"https://clinicaltrials.gov/study/NCT06211036"}],"tags":[],"related":[],"cancers":["sclc"],"sections":[],"technologies":[],"targets":[],"drugs":["lurbinectedin","atezolizumab","tarlatamab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["imforte","dellphi-305"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"platinum-etoposide","b":"lurbinectedin","rationale":"Extensive-stage SCLC almost always relapses within months of induction; targeting residual disease during the response window with a non-cross-resistant agent delays relapse.","evidence":"Phase 3 IMforte positive (2025, FDA approved); DeLLphi-305 pending.","pairingType":"sequence"},{"id":"chemo-io-first-line-endometrial","kind":"pairing","name":"Chemotherapy + PD-1/PD-L1 blockade, first-line advanced endometrial cancer","aka":[],"tldr":"Three trials with three different antibodies agree: adding immunotherapy to first chemotherapy for advanced endometrial cancer roughly triples progression-free time in dMMR tumours and helps the rest modestly.","summary":"Adding a PD-1 or PD-L1 antibody to first-line carboplatin-based chemotherapy for advanced or recurrent endometrial cancer is a combination pairing supported by three positive phase 3 trials with three different antibodies: RUBY with dostarlimab, NRG-GY018 / KEYNOTE-868 with pembrolizumab, and DUO-E with durvalumab with or without olaparib. Tumours with mismatch repair deficiency carry thousands of neoantigens and gain the most, while chemotherapy provides antigen release and lymphodepletion that appear to extend a more modest benefit into mismatch repair-proficient disease. RUBY also demonstrated an overall survival benefit. The consistency across these trials makes it the most reliably replicated regimen in gynaecological oncology.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03981796: RUBY / ENGOT-EN6 / GOG-3031","url":"https://clinicaltrials.gov/study/NCT03981796"},{"label":"ClinicalTrials.gov NCT03914612: NRG-GY018 / KEYNOTE-868","url":"https://clinicaltrials.gov/study/NCT03914612"}],"tags":[],"related":[],"cancers":["endometrial"],"sections":[],"technologies":[],"targets":[],"drugs":["dostarlimab","pembrolizumab","durvalumab"],"companies":[],"institutions":[],"pathways":[],"terms":["msi"],"trials":["ruby","nrg-gy018-keynote-868","duo-e"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"checkpoint-inhibitor","b":"carboplatin","rationale":"dMMR tumours carry thousands of neoantigens; chemotherapy provides antigen release and lymphodepletion that appear to extend benefit into pMMR disease.","evidence":"Three positive phase 3 trials; OS benefit shown in RUBY.","pairingType":"combination"},{"id":"cldn18-antibody-then-adc","kind":"pairing","name":"CLDN18.2 antibody first line → CLDN18.2 ADC or CAR-T on progression","aka":[],"tldr":"Hit Claudin 18.2 twice: first with a plain antibody plus chemotherapy, then with an ADC or engineered cells when the cancer comes back.","summary":"Zolbetuximab + chemotherapy is approved first line; CLARITY-Gastric 01 showed an OS benefit for the CLDN18.2 ADC sonesitatug vedotin in later lines (July 2026); satri-cel CAR-T is approved in China. Whether prior zolbetuximab reduces ADC benefit (antigen persistence, ADCC-selected clones) is the key unknown.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03504397: SPOTLIGHT & GLOW","url":"https://clinicaltrials.gov/study/NCT03504397"},{"label":"ClinicalTrials.gov NCT06346392: CLARITY-Gastric 01","url":"https://clinicaltrials.gov/study/NCT06346392"}],"tags":[],"related":[],"cancers":["gastric"],"sections":[],"technologies":[],"targets":["cldn18-2"],"drugs":["zolbetuximab","cmg901","satricabtagene-autoleucel"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["spotlight-glow","clarity-gastric01"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"zolbetuximab","b":"cmg901","rationale":"CLDN18.2 is a lineage antigen that tends to persist; the three modalities kill by different mechanisms (ADCC/CDC, payload, T cells).","evidence":"Phase 3 for each agent individually; sequencing data pending.","pairingType":"sequence"},{"id":"cross-then-nivolumab","kind":"pairing","name":"CROSS chemoradiation → surgery → adjuvant nivolumab if residual disease","aka":[],"tldr":"Chemotherapy and radiation, then surgery, then a year of immunotherapy if the operation shows cancer was still there. This is the current curative-intent pathway.","summary":"CROSS gives 10-year OS of 38%; CheckMate 577 adds DFS 22.4 vs 11.0 months in the ~70% with residual disease after resection (OS HR 0.85, not significant). Patients with pathologic complete response do not receive nivolumab. SANO offers surveillance instead of surgery for clinical complete responders.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT02743494: CheckMate 577","url":"https://clinicaltrials.gov/study/NCT02743494"}],"tags":[],"related":[],"cancers":["esophageal"],"sections":[],"technologies":[],"targets":[],"drugs":["nivolumab","carboplatin","paclitaxel"],"companies":[],"institutions":[],"pathways":[],"terms":["neoadjuvant-adjuvant","clinical-complete-response"],"trials":["cross","checkmate-577","sano"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"cross","b":"nivolumab","rationale":"Residual disease after chemoradiation marks high relapse risk; radiation-induced immunogenic cell death primes T cells that PD-1 blockade sustains.","evidence":"Phase 3 for each step (CROSS, CheckMate 577); the sequence is guideline standard.","pairingType":"sequence"},{"id":"ctdna-genotype-gist-tki","kind":"pairing","name":"ctDNA KIT genotyping → TKI selection in GIST","aka":[],"tldr":"A blood test that reads which resistance mutation a GIST has acquired, so the second drug can be chosen to fit it.","summary":"In gastrointestinal stromal tumour, reading the acquired KIT resistance mutation from a plasma ctDNA liquid biopsy and choosing the next tyrosine kinase inhibitor to fit it is a diagnostic-therapeutic pairing. Secondary KIT mutations differ between metastases within the same patient, and plasma captures all of them, while drug sensitivity differs by exon. An exploratory analysis of INTRIGUE showed that ripretinib far outperformed sunitinib only in tumours with KIT exon 11 plus exon 17 or 18 mutations, whereas sunitinib was better for exon 13 or 14 mutations. The phase 3 INSIGHT trial tested this prospectively with ctDNA-based selection and was positive in 2026, making it the first genotype-directed sequencing paradigm in sarcoma.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT05734105: INSIGHT","url":"https://clinicaltrials.gov/study/NCT05734105"}],"tags":[],"related":[],"cancers":["sarcoma"],"sections":[],"technologies":[],"targets":["kit"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["insight-gist"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"liquid-biopsy","b":"ripretinib","rationale":"Secondary KIT mutations are heterogeneous across metastases; plasma captures them all, and drug sensitivity differs by exon.","evidence":"Exploratory INTRIGUE analysis; prospective INSIGHT phase 3.","pairingType":"diagnostic-therapeutic"},{"id":"ctdna-mrd-to-adjuvant","kind":"pairing","name":"ctDNA MRD → adjuvant therapy decision","aka":[],"tldr":"A ctDNA MRD blood test after surgery decides who gets more treatment and who is spared it.","summary":"This diagnostic-therapeutic pairing links MRD / molecular residual disease testing to the adjuvant decision, here with Immune checkpoint inhibitors: a ctDNA blood test after surgery decides who gets more treatment and who is spared it. Minimal / molecular residual disease (MRD) identifies the minority who will relapse, concentrating toxic therapy where it helps. In phase 3 IMvigor011, Atezolizumab given only to ctDNA-positive Bladder & urothelial cancer patients improved survival and was approved in 2026; in the randomised phase 2 DYNAMIC trial, ctDNA-negative Colorectal cancer patients safely skipped chemotherapy. It is being tested in Triple-negative breast cancer (TNBC) after KEYNOTE-522, in NSCLC and in breast cancer (ZEST, c-TRAK), often with Signatera.","asOf":"2026-09-04","links":[{"label":"ClinicalTrials.gov NCT04660344: IMvigor011","url":"https://clinicaltrials.gov/study/NCT04660344"},{"label":"ClinicalTrials.gov ACTRN12615000381583: DYNAMIC","url":"https://clinicaltrials.gov/study/ACTRN12615000381583"}],"tags":[],"related":[],"cancers":["urothelial","colorectal","tnbc"],"sections":[],"technologies":[],"targets":[],"drugs":["atezolizumab","signatera"],"companies":[],"institutions":[],"pathways":[],"terms":["mrd"],"trials":["imvigor011","dynamic"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"mrd-testing","b":"checkpoint-inhibitor","rationale":"MRD identifies the ~30-40% who will relapse, concentrating toxic therapy where it helps and sparing the rest.","evidence":"Phase 3 (IMvigor011) and randomised phase 2 (DYNAMIC).","pairingType":"diagnostic-therapeutic"},{"id":"durvalumab-plus-bcg","kind":"pairing","name":"Durvalumab + BCG in BCG-naive high-risk NMIBC","aka":[],"tldr":"Systemic immunotherapy layered on top of bladder BCG reduced recurrence, at the cost of systemic side effects in a disease usually treated locally.","summary":"Durvalumab given systemically alongside intravesical BCG in BCG-naive high-risk non-muscle-invasive bladder cancer is a combination pairing that reduced recurrence at the cost of systemic side effects in a disease usually treated locally. The rationale is that BCG primes a local Th1 immune response in the bladder, and PD-L1 blockade prevents that response from becoming exhausted while potentially reaching micrometastatic disease. The phase 3 POTOMAC trial was positive for disease-free survival and led to approval in May 2026. The result is not automatically a class effect, because ALBAN, which tested atezolizumab plus BCG, was negative, while CREST, which tested sasanlimab plus BCG, was positive.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03528694: POTOMAC","url":"https://clinicaltrials.gov/study/NCT03528694"}],"tags":[],"related":[],"cancers":["urothelial"],"sections":[],"technologies":[],"targets":[],"drugs":["durvalumab","bcg-intravesical"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["potomac"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"durvalumab","b":"bcg-intravesical","rationale":"BCG primes a local Th1 response; PD-L1 blockade prevents its exhaustion and may reach micrometastatic disease.","evidence":"One positive phase 3 (POTOMAC), one negative (ALBAN), one positive with a different agent (CREST).","pairingType":"combination"},{"id":"pet-adapted-her2-deescalation","kind":"pairing","name":"Early FDG-PET response → chemotherapy omission (HER2+)","aka":[],"tldr":"A PET scan after two cycles of antibodies alone identifies women who can be cured without chemotherapy.","summary":"This diagnostic-therapeutic pairing uses an early FDG PET scan to decide who can omit chemotherapy in HER2-positive breast cancer treated with dual HER2 blockade. After two cycles of trastuzumab and pertuzumab alone, with or without endocrine therapy, a metabolic response on PET predicts a pathological complete response to antibody-only treatment, and that complete response in turn predicts an excellent long-term outcome. In the randomised phase 2 PHERGain trial, PET responders continued the antibodies without chemotherapy and those reaching a pathological complete response skipped it altogether; the trial met its co-primary endpoints. The phase 3 PHERGain-2 trial and similar response-adapted designs such as WSG-ADAPT are now testing the approach more broadly.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03161353: PHERGain","url":"https://clinicaltrials.gov/study/NCT03161353"}],"tags":[],"related":[],"cancers":["breast-her2-positive"],"sections":[],"technologies":["fdg-pet"],"targets":[],"drugs":["trastuzumab","pertuzumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["phergain"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"fdg-pet","b":"dual-her2-blockade","rationale":"Metabolic response at 2 cycles predicts pCR to antibody-only therapy; pCR predicts excellent long-term outcome.","evidence":"Randomised phase 2 meeting co-primary endpoints; phase 3 pending.","pairingType":"diagnostic-therapeutic"},{"id":"car-t-before-transplant-lbcl","kind":"pairing","name":"Early relapse: CAR-T before transplant","aka":[],"tldr":"If large B-cell lymphoma comes back within a year, CAR-T should come before, not after, a transplant attempt.","summary":"This sequence rule says that when large B-cell lymphoma relapses within a year of first-line treatment, CAR-T cell therapy should be given before, not after, an attempt at high-dose therapy and autologous stem cell transplant. Chemorefractory disease rarely gets as far as transplant because it must first respond to salvage chemotherapy, whereas CAR-T does not require chemosensitivity. Two positive phase 3 trials, ZUMA-7 with axi-cel and TRANSFORM with liso-cel, showed better event-free survival for CAR-T than salvage chemotherapy plus transplant, and ZUMA-7 also showed an overall survival benefit; the negative BELINDA trial is explained by its design. Transplant remains the option for late relapses that respond to salvage.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03391466: ZUMA-7","url":"https://clinicaltrials.gov/study/NCT03391466"},{"label":"ClinicalTrials.gov NCT03575351: TRANSFORM","url":"https://clinicaltrials.gov/study/NCT03575351"}],"tags":[],"related":[],"cancers":["dlbcl"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["zuma-7","transform","belinda"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"car-t","b":"autologous-stem-cell-transplant","rationale":"Chemorefractory disease rarely reaches transplant (36% in ZUMA-7 control arm); CAR-T does not require chemosensitivity.","evidence":"Two positive phase 3 trials; one negative (BELINDA) explained by design.","pairingType":"sequence"},{"id":"tki-then-adc-lung","kind":"pairing","name":"EGFR TKI → ADC on progression","aka":[],"tldr":"After the lung cancer pill stops working, an ADC that does not care which resistance mutation emerged.","summary":"This sequence pairing follows an EGFR tyrosine kinase inhibitor, Osimertinib, with an antibody-drug conjugate, Datopotamab deruxtecan, on progression in EGFR-mutant Non-small-cell lung cancer: after the pill stops working, an ADC that does not care which resistance mutation emerged takes over. The rationale is that resistance to TKIs is heterogeneous (C797S, MET, histologic transformation), and ADCs bypass genotype by exploiting antigen expression instead. Datopotamab deruxtecan was approved in 2025 after osimertinib and chemotherapy on phase 3 data, and Patritumab deruxtecan (HER3-DXd) and Izalontamab brengitecan (iza-bren) target the same setting. Amivantamab plus chemotherapy, tested in MARIPOSA-2, is the alternative strategy at this point in the sequence.","asOf":"2026-09-04","links":[{"label":"HERTHENA-Lung01: patritumab deruxtecan in EGFR-mutated NSCLC after EGFR TKI (Journal of Clinical Oncology 2023)","url":"https://doi.org/10.1200/JCO.23.01476"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["osimertinib","datopotamab-deruxtecan","patritumab-deruxtecan","izalontamab-brengitecan","amivantamab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"osimertinib","b":"datopotamab-deruxtecan","rationale":"Resistance to TKIs is heterogeneous (C797S, MET, transformation); ADCs bypass genotype by exploiting antigen expression.","evidence":"Approval; phase 3 data.","pairingType":"sequence"},{"id":"egfr-bispecific-plus-pd1-hnscc","kind":"pairing","name":"EGFR-directed bispecific + PD-1 blockade","aka":[],"tldr":"Pairing a new EGFR antibody with immunotherapy tripled the response rate seen with immunotherapy alone in early trials.","summary":"This combination pairs an EGFR-directed bispecific antibody, petosemtamab or ficerafusp alfa, with the PD-1 inhibitor pembrolizumab in head and neck squamous cell carcinoma. EGFR blockade with ADCC-competent antibodies induces immunogenic cell death and, in the case of ficerafusp, also removes TGF-beta-mediated immune exclusion; PD-1 blockade then sustains the resulting T-cell response. In phase 2 single-arm studies, petosemtamab with pembrolizumab produced a response rate far above that expected with immunotherapy alone, and ficerafusp alfa with pembrolizumab produced durable responses in HPV-negative disease. Both pairings are now in registrational phase 3 trials, LiGeR-HN1 and FORTIFI-HN01, so the evidence remains uncontrolled for the moment.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT06525220: LiGeR-HN1","url":"https://clinicaltrials.gov/study/NCT06525220"},{"label":"ClinicalTrials.gov NCT06788990: FORTIFI-HN01","url":"https://clinicaltrials.gov/study/NCT06788990"}],"tags":[],"related":[],"cancers":["head-and-neck"],"sections":[],"technologies":[],"targets":["egfr","pd1"],"drugs":["petosemtamab","ficerafusp-alfa","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["liger-hn1","fortifi-hn01"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"petosemtamab","b":"pembrolizumab","rationale":"EGFR blockade with ADCC-competent antibodies induces immunogenic cell death and, for ficerafusp, removes TGF-β-mediated exclusion; PD-1 blockade sustains the resulting T-cell response.","evidence":"Phase 2 single-arm data; phase 3 pending (LiGeR-HN1, FORTIFI-HN01).","pairingType":"combination"},{"id":"ev-pembro-continuum","kind":"pairing","name":"Enfortumab vedotin + pembrolizumab across the bladder cancer continuum","aka":[],"tldr":"The ADC-immunotherapy pair that doubled survival in advanced disease now also works around surgery, in fit and unfit patients alike.","summary":"Enfortumab vedotin, a Nectin-4-directed antibody-drug conjugate, combined with pembrolizumab is the first regimen to displace platinum chemotherapy at every stage of a common solid tumour, bladder and urothelial cancer. Nectin-4 is expressed on almost all urothelial cancers, and the MMAE payload induces immunogenic cell death and dendritic-cell maturation that the PD-1 antibody then exploits. Three positive phase 3 trials underpin it: EV-302 / KEYNOTE-A39 in metastatic disease, where survival improved substantially over chemotherapy, EV-303 / KEYNOTE-905 in cisplatin-ineligible muscle-invasive disease, approved in November 2025, and EV-304 / KEYNOTE-B15 in cisplatin-eligible disease, positive in December 2025. The pairing now serves fit and unfit patients alike.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT04223856: EV-302 / KEYNOTE-A39","url":"https://clinicaltrials.gov/study/NCT04223856"},{"label":"ClinicalTrials.gov NCT03924895: EV-303 / KEYNOTE-905","url":"https://clinicaltrials.gov/study/NCT03924895"}],"tags":[],"related":[],"cancers":["urothelial"],"sections":[],"technologies":[],"targets":[],"drugs":["enfortumab-vedotin","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["ev-302","ev-303","ev-304"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"enfortumab-vedotin","b":"pembrolizumab","rationale":"Nectin-4 is near-universal in urothelial cancer; MMAE induces immunogenic cell death and dendritic-cell maturation that pembrolizumab exploits.","evidence":"Three positive phase 3 trials.","pairingType":"combination"},{"id":"flt3i-plus-7-3","kind":"pairing","name":"FLT3 inhibitor + intensive chemotherapy","aka":[],"tldr":"Adding a FLT3 blocker to standard chemotherapy is the proven way to improve survival in FLT3-mutated AML.","summary":"This combination adds a FLT3 inhibitor, quizartinib or midostaurin, to intensive cytarabine and anthracycline induction chemotherapy, the 7+3 regimen, in FLT3-mutated acute myeloid leukaemia. Chemotherapy debulks the leukaemia while FLT3 inhibition removes the proliferative driver and suppresses the resistant subclone that would otherwise cause relapse. Two positive phase 3 trials with different molecules, RATIFY with midostaurin and QuANTUM-First with quizartinib, both improved overall survival, and quizartinib is continued as maintenance after induction. Maintenance with gilteritinib after transplant, tested in MORPHO, adds further protection in patients who are MRD-positive.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT00651261: RATIFY (CALGB 10603)","url":"https://clinicaltrials.gov/study/NCT00651261"},{"label":"ClinicalTrials.gov NCT02668653: QuANTUM-First","url":"https://clinicaltrials.gov/study/NCT02668653"}],"tags":[],"related":[],"cancers":["aml"],"sections":[],"technologies":[],"targets":["flt3"],"drugs":["midostaurin","quizartinib","gilteritinib","cytarabine-7-3"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["ratify","quantum-first"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"quizartinib","b":"cytarabine-7-3","rationale":"Chemotherapy debulks; FLT3 inhibition removes the proliferative driver and suppresses the resistant subclone that would otherwise relapse.","evidence":"Two positive phase 3 trials with different molecules.","pairingType":"combination"},{"id":"g12d-plus-pan-ras","kind":"pairing","name":"G12D-selective + pan-RAS(ON) inhibitor (zoldonrasib + daraxonrasib)","aka":[],"tldr":"A drug that hits the exact mutation plus a drug that hits every RAS protein, so the tumour cannot escape through a wild-type RAS cousin.","summary":"This combination pairs zoldonrasib, a KRAS G12D-selective inhibitor, with daraxonrasib, a pan-RAS(ON) inhibitor, in pancreatic ductal adenocarcinoma carrying the G12D mutation. The mutant-selective drug spares normal tissue, while the pan-RAS drug blocks the wild-type RAS and secondary-mutation escape routes that limit single agents, giving vertical suppression of adaptive RAS reactivation along the RAS/RAF/MEK/ERK pathway. The clinical evidence comes from RMC-9805-001 (NCT06040541), registered as a phase 1/1b study of zoldonrasib alone or with daraxonrasib in KRAS G12D-mutant solid tumours. At ESMO GI 2026 (abstract 341O) Revolution Medicines reported the combination in 60 patients with RAS G12D metastatic pancreatic cancer after one or more prior lines of therapy (30 second-line, 30 third-line or later; data cutoff 9 February 2026): objective response 50% in the second-line cohort and 47% in the later-line cohort, with disease control of 97% and 90%, per the company release. These are company-reported figures from a small, non-randomised cohort, not a registry result or a peer-reviewed publication. It illustrates how a mutation-specific and a pathway-wide inhibitor can be layered so that the tumour cannot escape through a wild-type RAS relative.","asOf":"2026-09-21","links":[{"label":"ClinicalTrials.gov NCT06040541 (RMC-9805-001)","url":"https://clinicaltrials.gov/study/NCT06040541"},{"label":"Revolution Medicines release, ESMO GI 2026 abstract 341O (GlobeNewswire, 2 July 2026)","url":"https://www.globenewswire.com/news-release/2026/07/02/3321282/0/en/revolution-medicines-presents-phase-1-2-clinical-data-for-zoldonrasib-combination-regimens-in-patients-with-ras-g12d-metastatic-pancreatic-cancer-at-esmo-gastrointestinal-cancers-c.html"}],"tags":[],"related":[],"cancers":["pancreatic"],"sections":[],"technologies":[],"targets":["kras"],"drugs":["zoldonrasib","daraxonrasib"],"companies":[],"institutions":[],"pathways":["ras-mapk"],"terms":[],"trials":["nct06040541"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"zoldonrasib","b":"daraxonrasib","rationale":"Mutant-selective inhibition spares normal tissue, while pan-RAS coverage blocks the wild-type RAS and secondary-mutation escape routes seen with single agents.","evidence":"Phase 1/1b (RMC-9805-001, NCT06040541); combination cohort n=60 in previously treated RAS G12D metastatic PDAC (30 second-line, 30 third-line or later), company report at ESMO GI 2026.","pairingType":"combination"},{"id":"gemcis-plus-io-btc","kind":"pairing","name":"Gemcitabine-cisplatin + PD-(L)1 blockade in biliary cancer","aka":[],"tldr":"Chemotherapy plus immunotherapy is now the first treatment for advanced bile duct cancer, with a small average gain and a minority of long survivors.","summary":"Gemcitabine plus cisplatin combined with a PD-1 or PD-L1 checkpoint inhibitor is now the first-line standard for advanced biliary tract cancer, including gallbladder cancer. The pairing rests on chemotherapy-induced immunogenic cell death working together with checkpoint blockade in a group of cancers whose stroma is inflamed. Two phase 3 trials support it: TOPAZ-1 added durvalumab and KEYNOTE-966 added pembrolizumab to the chemotherapy backbone, and both were positive, with a modest average gain and a minority of patients who become long-term survivors. No predictive biomarker, whether PD-L1, tumour mutational burden or microsatellite instability, reliably identifies who those long survivors will be.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03875235: TOPAZ-1","url":"https://clinicaltrials.gov/study/NCT03875235"},{"label":"ClinicalTrials.gov NCT04003636: KEYNOTE-966","url":"https://clinicaltrials.gov/study/NCT04003636"}],"tags":[],"related":[],"cancers":["cholangiocarcinoma","gallbladder"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["topaz-1","keynote-966"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"gemcitabine-cisplatin","b":"checkpoint-inhibitor","rationale":"Chemotherapy-induced immunogenic cell death plus checkpoint blockade; biliary cancers have an inflamed stroma.","evidence":"Two phase 3 trials.","pairingType":"combination"},{"id":"genomic-assay-to-chemo-omission","kind":"pairing","name":"Gene-expression assay → chemotherapy omission","aka":[],"tldr":"A gene test on the tumour decides who can skip chemotherapy without losing protection.","summary":"This diagnostic-therapeutic pairing uses a gene-expression assay on the tumour, chiefly Oncotype DX and also MammaPrint, to decide which women with HR-positive, HER2-negative breast cancer can safely omit adjuvant cytotoxic chemotherapy. Proliferation- and oestrogen-receptor-related gene expression predicts both chemosensitivity and prognosis better than clinical and pathological factors alone. TAILORx in node-negative disease and RxPONDER in postmenopausal women with one to three involved nodes found no chemotherapy benefit at a recurrence score of 25 or below, and MINDACT with MammaPrint concurs; together these are three large prospective trials. Premenopausal women with intermediate scores still gain from chemotherapy, possibly through ovarian suppression.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT00310180: TAILORx","url":"https://clinicaltrials.gov/study/NCT00310180"},{"label":"ClinicalTrials.gov NCT01272037: RxPONDER (SWOG S1007)","url":"https://clinicaltrials.gov/study/NCT01272037"}],"tags":[],"related":[],"cancers":["breast-hr-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["oncotype-dx","mammaprint"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["tailorx","rxponder"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"oncotype-dx","b":"cytotoxic-chemotherapy","rationale":"Proliferation and ER-related gene expression predicts chemosensitivity and prognosis better than clinicopathologic factors alone.","evidence":"Three large prospective trials (>20,000 women).","pairingType":"diagnostic-therapeutic"},{"id":"germline-to-parp","kind":"pairing","name":"Germline BRCA test → adjuvant PARP inhibitor","aka":[],"tldr":"A blood test for inherited BRCA mutations unlocks a year of olaparib after surgery, which improves survival.","summary":"This diagnostic-therapeutic pairing links Germline (hereditary) testing for inherited BRCA1 / BRCA2 (HRD) mutations to a year of adjuvant Olaparib, one of the PARP inhibitors, after surgery. The rationale is synthetic lethality confined to BRCA-deficient cells, so the drug is only worth giving once the inherited mutation is confirmed. The phase 3 OlympiA trial showed that adjuvant olaparib improved invasive disease-free survival and overall survival in this population. Because the treatment depends on the test, every patient with Triple-negative breast cancer (TNBC) or high-risk HR-positive / HER2-negative breast cancer needs germline testing at diagnosis, which is why the pairing is linked from the TNBC and Germline testing entries.","asOf":"2026-09-04","links":[{"label":"ClinicalTrials.gov NCT02032823: OlympiA","url":"https://clinicaltrials.gov/study/NCT02032823"}],"tags":[],"related":[],"cancers":["tnbc","breast-hr-positive"],"sections":[],"technologies":[],"targets":["brca"],"drugs":["olaparib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["olympia"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"germline-testing","b":"parp-inhibitor","rationale":"Synthetic lethality confined to BRCA-deficient cells.","evidence":"Phase 3 OS benefit.","pairingType":"diagnostic-therapeutic"},{"id":"her2-gastric-sequence","kind":"pairing","name":"HER2 sequence in gastric cancer: zanidatamab/trastuzumab + chemo ± PD-1 → T-DXd","aka":[],"tldr":"For HER2-positive stomach cancer, an antibody-plus-chemotherapy first, then Enhertu when it progresses. Both steps now have phase 3 proof.","summary":"First line: trastuzumab + chemotherapy + pembrolizumab (KEYNOTE-811, PD-L1 CPS ≥1) or zanidatamab + chemotherapy ± tislelizumab (HERIZON-GEA-01, PFS 12.4 vs 8.1 months). Second line: T-DXd (DESTINY-Gastric04, OS 14.7 vs 11.4 months). HER2 loss after first-line therapy occurs in ~30%, so re-biopsy or ctDNA before T-DXd is advisable.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT05152147: HERIZON-GEA-01","url":"https://clinicaltrials.gov/study/NCT05152147"},{"label":"ClinicalTrials.gov NCT04704934: DESTINY-Gastric04","url":"https://clinicaltrials.gov/study/NCT04704934"}],"tags":[],"related":[],"cancers":["gastric"],"sections":[],"technologies":[],"targets":["her2"],"drugs":["zanidatamab","trastuzumab","trastuzumab-deruxtecan","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["herizon-gea-01","destiny-gastric04","toga"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"zanidatamab","b":"trastuzumab-deruxtecan","rationale":"Antibody blockade and ADC payload delivery are distinct mechanisms; HER2 expression usually persists at progression.","evidence":"Phase 3 for each step; the sequence itself is inferred, not randomised.","pairingType":"sequence"},{"id":"her2-low-to-tdxd","kind":"pairing","name":"HER2-low scoring → T-DXd","aka":[],"tldr":"Reading the faint end of the HER2 stain decides who gets Enhertu.","summary":"This diagnostic-therapeutic pairing links Histopathology & immunohistochemistry scoring of HER2 to treatment with Trastuzumab deruxtecan (T-DXd): reading the faint end of the HER2 stain decides who gets Enhertu. The rationale is that the bystander payload needs only minimal antigen for uptake, so the immunohistochemistry cut-off is a delivery threshold rather than a driver threshold. In the phase 3 DESTINY-Breast04 and DESTINY-Breast06 trials, HER2-low (IHC 1+ or 2+) and HER2-ultralow (IHC 0 with faint staining) tumours predicted T-DXd benefit in HR-positive / HER2-negative breast cancer and Triple-negative breast cancer (TNBC). Reproducibility at the low end is poor, so AI-assisted HER2 scoring is being validated, as pursued in the idea AI quantification of HER2-low and HER2-ultralow.","asOf":"2026-09-04","links":[{"label":"ClinicalTrials.gov NCT03734029: DESTINY-Breast04","url":"https://clinicaltrials.gov/study/NCT03734029"},{"label":"ClinicalTrials.gov NCT04494425: DESTINY-Breast06","url":"https://clinicaltrials.gov/study/NCT04494425"}],"tags":[],"related":[],"cancers":["breast-hr-positive","tnbc"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["her2-low"],"trials":["destiny-breast04","destiny-breast06"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"histopathology-ihc","b":"trastuzumab-deruxtecan","rationale":"Bystander payload needs only minimal antigen for uptake; IHC cut-off is a delivery threshold not a driver threshold.","evidence":"Phase 3 (DESTINY-Breast04/06).","pairingType":"diagnostic-therapeutic"},{"id":"hipec-at-interval-surgery","kind":"pairing","name":"HIPEC at interval cytoreductive surgery","aka":[],"tldr":"Heated intraperitoneal cisplatin during interval surgery, after neoadjuvant chemotherapy, extends survival in stage III disease.","summary":"Hyperthermic intraperitoneal chemotherapy delivered with platinum during interval cytoreductive surgery, after neoadjuvant chemotherapy for stage III ovarian cancer, is a combination pairing that extended survival in the phase 3 OVHIPEC-1 trial without additional major complications, and the benefit was confirmed at ten years of follow-up; a Korean trial is supportive. The rationale is direct high-dose exposure of residual microscopic peritoneal disease at the moment of maximal cytoreduction, with hyperthermia enhancing platinum uptake into tumour cells. The benefit appears specific to the interval-surgery setting. HIPEC at primary surgery is still being tested in OVHIPEC-2.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT00426257: OVHIPEC-1","url":"https://clinicaltrials.gov/study/NCT00426257"}],"tags":[],"related":[],"cancers":["ovarian"],"sections":[],"technologies":["hipec"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["ovhipec-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"hipec","b":"carboplatin","rationale":"Direct high-dose exposure of residual microscopic peritoneal disease at the moment of maximal cytoreduction, with hyperthermia enhancing platinum uptake.","evidence":"Phase 3 with OS benefit; one supportive Korean trial.","pairingType":"combination"},{"id":"histology-directs-first-line-meso","kind":"pairing","name":"Histology → first-line choice in mesothelioma","aka":[],"tldr":"Read the tumour type under the microscope first: non-epithelioid tumours should get immunotherapy up front; epithelioid tumours can reasonably get either immunotherapy or chemo-immunotherapy.","summary":"In mesothelioma the histological subtype read by histopathology and immunohistochemistry now directs the first-line choice, making this a diagnostic-therapeutic pairing. Sarcomatoid and biphasic tumours are chemoresistant but more immune-infiltrated, whereas epithelioid tumours retain sensitivity to pemetrexed-based chemotherapy. In pre-specified subgroups of CheckMate 743, nivolumab plus ipilimumab gave a large survival advantage over chemotherapy in non-epithelioid disease but only a small one in epithelioid disease, and pembrolizumab plus chemotherapy in IND.227 / KEYNOTE-483 and BEAT-meso showed the same pattern. Guidelines therefore favour immunotherapy up front for non-epithelioid tumours, while epithelioid tumours can receive either immunotherapy or chemo-immunotherapy.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT02899299: CheckMate 743","url":"https://clinicaltrials.gov/study/NCT02899299"},{"label":"ClinicalTrials.gov NCT02784171: IND.227 / KEYNOTE-483","url":"https://clinicaltrials.gov/study/NCT02784171"}],"tags":[],"related":[],"cancers":["mesothelioma"],"sections":[],"technologies":[],"targets":[],"drugs":["nivolumab","ipilimumab","pembrolizumab","pemetrexed"],"companies":[],"institutions":[],"pathways":[],"terms":["epithelioid-vs-sarcomatoid"],"trials":["checkmate-743","keynote-483"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"histopathology-ihc","b":"checkpoint-inhibitor","rationale":"Sarcomatoid tumours are chemoresistant but more immune-infiltrated; epithelioid tumours retain chemosensitivity.","evidence":"Pre-specified subgroup analyses of two phase 3 trials plus BEAT-meso.","pairingType":"diagnostic-therapeutic"},{"id":"risk-directed-first-line-rcc","kind":"pairing","name":"IMDC risk → first-line regimen choice (RCC)","aka":[],"tldr":"A simple clinical score decides between two immunotherapies together or one immunotherapy with a targeted pill.","summary":"Intermediate/poor risk: nivolumab-ipilimumab (durable remissions, treatment-free survival) or an IO-TKI doublet (higher response rate, less primary progression). Favourable risk: IO-TKI doublet or TKI alone, since IO-IO shows no OS gain there. Sarcomatoid features favour IO-based therapy regardless of risk.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT02231749: CheckMate 214","url":"https://clinicaltrials.gov/study/NCT02231749"}],"tags":[],"related":[],"cancers":["rcc"],"sections":[],"technologies":[],"targets":[],"drugs":["nivolumab","ipilimumab","pembrolizumab","axitinib","cabozantinib","lenvatinib"],"companies":[],"institutions":[],"pathways":[],"terms":["imdc-risk","sarcomatoid-rcc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"checkpoint-inhibitor","b":"kinase-inhibitors","rationale":"CheckMate 214 benefit is confined to intermediate/poor risk; IO-TKI trials show PFS benefit across groups.","evidence":"Subgroup analyses of four phase 3 trials; no head-to-head IO-IO vs IO-TKI trial.","pairingType":"diagnostic-therapeutic"},{"id":"io-before-surgery-hnscc","kind":"pairing","name":"Immunotherapy before surgery rather than with chemoradiation (HNSCC)","aka":[],"tldr":"In head and neck cancer, immunotherapy works when given before surgery but not when given alongside chemoradiation.","summary":"This sequence rule in head and neck squamous cell carcinoma places immune checkpoint inhibitors before surgery rather than concurrently with modern external beam chemoradiation. T-cell priming needs an intact tumour and functioning lymphatics, and chemoradiation destroys both while the drug is on board; radiation-induced lymphopenia, steroids and loss of the antigen-rich primary are the proposed explanations. KEYNOTE-689, which gave pembrolizumab before and after surgery, improved event-free survival, whereas JAVELIN Head and Neck 100 and KEYNOTE-412, which gave it with chemoradiation, both failed. One positive phase 3 against two negative ones makes timing, not the drug, the lesson; the concept sits under neoadjuvant, adjuvant and perioperative therapy.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03765918: KEYNOTE-689","url":"https://clinicaltrials.gov/study/NCT03765918"},{"label":"ClinicalTrials.gov NCT02952586: JAVELIN Head and Neck 100","url":"https://clinicaltrials.gov/study/NCT02952586"}],"tags":[],"related":[],"cancers":["head-and-neck"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":["neoadjuvant-adjuvant"],"trials":["keynote-689","javelin-hn-100"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"checkpoint-inhibitor","b":"imrt-igrt","rationale":"T-cell priming needs an intact tumour and functioning lymphatics; chemoradiation destroys both while the drug is on board.","evidence":"One positive phase 3 versus two negative ones with the alternative sequence.","pairingType":"sequence"},{"id":"io-first-then-braf-mek","kind":"pairing","name":"Immunotherapy first, then BRAF/MEK (BRAF-mutant melanoma)","aka":[],"tldr":"In BRAF-mutant melanoma, start with immunotherapy and keep the targeted pills in reserve; the reverse order costs lives.","summary":"This sequence rule for BRAF-mutant melanoma is to start with immune checkpoint inhibitors, nivolumab with ipilimumab, and to keep the BRAF/MEK inhibitors dabrafenib and trametinib, or encorafenib-based therapy, in reserve. Immunotherapy responses are durable and can be curative, whereas BRAF/MEK responses are fast but nearly always temporary, so using the durable option first preserves the fast option as a rescue. The phase 3 DREAMseq trial showed a clear overall survival advantage for immunotherapy first, and the phase 2 SECOMBIT trial was concordant. Targeted therapy still works after immunotherapy, but immunotherapy after targeted therapy underperforms, possibly because progression on BRAF/MEK inhibitors is rapid and the tumours are immunologically cold.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT02224781: DREAMseq (ECOG-ACRIN EA6134)","url":"https://clinicaltrials.gov/study/NCT02224781"}],"tags":[],"related":[],"cancers":["melanoma"],"sections":[],"technologies":[],"targets":["braf"],"drugs":["nivolumab","ipilimumab","dabrafenib-trametinib","encorafenib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["dreamseq"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"checkpoint-inhibitor","b":"dabrafenib-trametinib","rationale":"Immunotherapy responses are durable and can be curative; BRAF/MEK responses are fast but nearly always temporary. Using the durable option first preserves the fast option as a rescue.","evidence":"Phase 3 DREAMseq; phase 2 SECOMBIT concordant.","pairingType":"sequence"},{"id":"induction-chemo-then-crt","kind":"pairing","name":"Induction chemotherapy → chemoradiation (locally advanced cervical cancer)","aka":[],"tldr":"Six weeks of cheap chemotherapy before chemoradiation cut deaths by 40% (INTERLACE), while chemotherapy after chemoradiation did nothing (OUTBACK). Order matters.","summary":"Six weeks of carboplatin-based induction chemotherapy before definitive chemoradiation for locally advanced cervical cancer is a sequence pairing that improved survival in the phase 3 INTERLACE trial. By contrast, OUTBACK / ANZGOG 0902 / GOG-0274 gave adjuvant chemotherapy after chemoradiation and found no benefit but considerably more toxicity, so the order matters. The rationale is that induction achieves early systemic control of micrometastases while patients are still fit, whereas chemotherapy after radiation suffers from poor compliance and marrow toxicity. Because the induction drugs are cheap, the approach is deliverable in low- and middle-income countries where pembrolizumab is not, and it pairs with modern external beam radiotherapy and brachytherapy.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT01566240: INTERLACE","url":"https://clinicaltrials.gov/study/NCT01566240"},{"label":"ClinicalTrials.gov NCT01414608: OUTBACK / ANZGOG 0902 / GOG-0274","url":"https://clinicaltrials.gov/study/NCT01414608"}],"tags":[],"related":[],"cancers":["cervical"],"sections":[],"technologies":["imrt-igrt","brachytherapy"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["interlace","outback"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"carboplatin","b":"imrt-igrt","rationale":"Early systemic control of micrometastases while patients are fit; adjuvant chemotherapy after radiation suffers poor compliance and marrow toxicity.","evidence":"One positive phase 3 (induction) and one negative phase 3 (adjuvant).","pairingType":"sequence"},{"id":"kras-plus-egfr-crc","kind":"pairing","name":"KRAS G12C inhibitor + anti-EGFR antibody (colorectal)","aka":[],"tldr":"In colorectal cancer, a KRAS blocker alone has little effect because the cell turns EGFR up; adding an EGFR antibody stops that.","summary":"This combination pairs KRAS & RAS inhibitors (the G12C inhibitors Sotorasib and Adagrasib) with an anti-EGFR antibody in Colorectal cancer. The mechanism is that colorectal epithelium has strong EGFR-driven adaptive feedback that reactivates the RAS / RAF / MEK / ERK (MAPK) pathway within hours of KRAS inhibition, so a KRAS blocker alone has little effect and adding an EGFR antibody stops the rebound. Sotorasib plus panitumumab was approved on the phase 3 CodeBreaK 300 trial, which showed a progression-free survival benefit, and adagrasib plus cetuximab was approved on KRYSTAL-1, with response rates considerably higher in combination than with monotherapy. The pairing is a stop on the KRAS roadmap from undruggable to G12C to pan-RAS.","asOf":"2026-09-04","links":[{"label":"ClinicalTrials.gov NCT05198934: CodeBreaK 300","url":"https://clinicaltrials.gov/study/NCT05198934"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["sotorasib","adagrasib"],"companies":[],"institutions":[],"pathways":["ras-mapk"],"terms":[],"trials":["codebreak-300"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"kras-inhibitors","b":"egfr","rationale":"Colorectal epithelium has strong EGFR-driven adaptive feedback that reactivates MAPK within hours of KRAS inhibition.","evidence":"Phase 3 (CodeBreaK 300) PFS benefit.","pairingType":"combination"},{"id":"lenvatinib-plus-pembrolizumab","kind":"pairing","name":"Lenvatinib + pembrolizumab (pMMR endometrial cancer after platinum)","aka":[],"tldr":"An anti-angiogenic pill makes immunotherapy work in endometrial cancers that would otherwise ignore it, at the cost of significant side effects.","summary":"Lenvatinib plus pembrolizumab is a combination pairing for mismatch repair-proficient endometrial cancer that has progressed after platinum chemotherapy. VEGFR inhibition by lenvatinib reduces immunosuppressive myeloid cells and normalises tumour vessels so that T cells can enter, turning a cancer that largely ignores PD-1 monotherapy into one that responds. In the phase 3 KEYNOTE-775 / Study 309 trial the combination improved overall survival compared with chemotherapy both in all comers and in the pMMR population, but dose reductions and discontinuations for toxicity were common. In the first-line setting LEAP-001 failed to beat chemotherapy, so the pairing lives in the second line. It is one instance of the broader pattern of PD-1 blockade plus VEGF inhibition.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03517449: KEYNOTE-775 / Study 309","url":"https://clinicaltrials.gov/study/NCT03517449"}],"tags":[],"related":["io-plus-vegf"],"cancers":["endometrial"],"sections":[],"technologies":[],"targets":["vegf","pd1"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-775"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"lenvatinib","b":"pembrolizumab","rationale":"VEGFR inhibition reduces immunosuppressive myeloid cells and normalises vessels for T-cell entry; the combination overcame PD-1 monotherapy's ~13% response rate in pMMR disease.","evidence":"Phase 3 OS benefit (second line); negative first-line trial.","pairingType":"combination"},{"id":"redifferentiation-rai","kind":"pairing","name":"MAPK inhibitor redifferentiation → radioiodine","aka":[],"tldr":"A short course of a MEK or BRAF pill can coax iodine-resistant thyroid cancer into taking up iodine again, letting radioactive iodine work once more.","summary":"This sequence uses a short course of a small-molecule MAPK pathway inhibitor, such as selumetinib or dabrafenib with trametinib, to restore radioiodine uptake in radioiodine-refractory thyroid cancer, followed by treatment with radioactive iodine. MAPK signalling suppresses the sodium-iodide symporter, and blocking the pathway for four to six weeks re-expresses NIS, so the tumour takes up iodine again. Selumetinib, reported in NEJM in 2013, and later dabrafenib and trametinib restored uptake in a substantial share of refractory patients, especially those with RAS mutations, and durable responses followed in some; the evidence is multiple phase 2 series. The adjuvant version of the approach, tested in ASTRA, was negative, so redifferentiation is reserved for refractory disease.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT01843062: ASTRA","url":"https://clinicaltrials.gov/study/NCT01843062"}],"tags":[],"related":[],"cancers":["thyroid"],"sections":[],"technologies":["kinase-inhibitors","radioiodine-therapy"],"targets":[],"drugs":["radioactive-iodine","dabrafenib-trametinib"],"companies":[],"institutions":[],"pathways":["ras-mapk"],"terms":["rai-refractory"],"trials":["astra"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"kinase-inhibitors","b":"radioiodine-therapy","rationale":"MAPK signalling suppresses the sodium-iodide symporter; blocking it for 4-6 weeks re-expresses NIS.","evidence":"Multiple phase 2 series; ASTRA negative in the adjuvant setting.","pairingType":"sequence"},{"id":"menin-plus-venetoclax-hma","kind":"pairing","name":"Menin inhibitor + venetoclax + azacitidine","aka":[],"tldr":"Combining the newest leukaemia drug class with the venetoclax backbone is producing remission rates in frontline NPM1 and KMT2A leukaemia that single agents never reached.","summary":"This combination adds a menin inhibitor, ziftomenib or revumenib, to venetoclax and azacitidine as frontline treatment for acute myeloid leukaemia driven by NPM1 mutation or KMT2A rearrangement. Menin inhibition forces the leukaemia cells to differentiate and lowers their dependence on the BCL-2 family, venetoclax kills the primed cells, and azacitidine sensitises both steps. Early cohorts of KOMET-007 with ziftomenib and of the BEAT-AML and SAVE studies with revumenib report composite remission rates in newly diagnosed patients that single agents never reached, and phase 3 registration trials are under way; the evidence is phase 1 and 2 so far. Differentiation syndrome and cytopenias are the management challenge. The pairing builds on the VIALE-A and AUGMENT-101 papers.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT02993523: VIALE-A","url":"https://clinicaltrials.gov/study/NCT02993523"}],"tags":[],"related":[],"cancers":["aml"],"sections":[],"technologies":[],"targets":["menin","npm1","kmt2a"],"drugs":["ziftomenib","revumenib","venetoclax","azacitidine"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"ziftomenib","b":"venetoclax","rationale":"Menin inhibition forces differentiation and lowers BCL-2 family dependence; venetoclax kills the primed cells; azacitidine sensitises both.","evidence":"Phase 1/2; phase 3 ongoing.","pairingType":"combination"},{"id":"neoadjuvant-io-dmmr","kind":"pairing","name":"Neoadjuvant checkpoint inhibitor → surgery (or no surgery) in dMMR colorectal cancer","aka":[],"tldr":"Test the tumour for a broken DNA spell-checker; if it has one, immunotherapy before surgery melts most tumours and in the rectum can replace surgery altogether.","summary":"This diagnostic-therapeutic pairing links universal testing for mismatch repair deficiency or microsatellite instability at diagnosis of colorectal cancer with neoadjuvant immune checkpoint blockade. dMMR tumours carry thousands of frameshift neoantigens and respond to checkpoint inhibitors far more than to chemotherapy, and a primary tumour left in place provides antigen for priming. In NICHE-2 a short course of nivolumab plus ipilimumab before colon surgery produced pathological complete responses in most patients, the MSK dostarlimab rectal cohort and AZUR-1 showed that rectal tumours can reach clinical complete response and avoid surgery, and the phase 3 ATOMIC trial showed a benefit from adjuvant atezolizumab. MMR testing is the gate that opens all of these options.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03026140: NICHE-2","url":"https://clinicaltrials.gov/study/NCT03026140"},{"label":"ClinicalTrials.gov NCT05723562: AZUR-1","url":"https://clinicaltrials.gov/study/NCT05723562"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["nivolumab","ipilimumab","dostarlimab","atezolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":["msi","neoadjuvant-adjuvant","clinical-complete-response"],"trials":["niche-2","azur-1","atomic"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"checkpoint-inhibitor","b":"msi","rationale":"dMMR tumours carry thousands of frameshift neoantigens and respond to checkpoint blockade far more than chemotherapy; a primary tumour in situ provides antigen for priming.","evidence":"Phase 2 single-arm (NICHE-2, AZUR-1) and phase 3 adjuvant (ATOMIC).","pairingType":"diagnostic-therapeutic"},{"id":"neoadjuvant-io-response-adapted","kind":"pairing","name":"Neoadjuvant immunotherapy → response-adapted adjuvant","aka":[],"tldr":"Treat before surgery, look at the removed tumour, and only continue treatment if the response was incomplete.","summary":"This sequence gives immune checkpoint inhibitors before surgery in melanoma, examines the removed tumour and lymph nodes, and continues adjuvant therapy only when the pathological response was incomplete. The intact tumour and nodes supply antigen and T-cell priming, and pathological response is a reliable early read-out that allows treatment to be de-escalated. The phase 3 NADINA trial used two neoadjuvant cycles of nivolumab and ipilimumab, then surgery, then adjuvant therapy only for partial or non-responders, and most patients were spared a year of adjuvant treatment. The phase 2 SWOG S1801 trial showed that pembrolizumab works better when part of the course is given before surgery. The design feeds the idea of pre-surgery platform trials judged on pathological response.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT04949113: NADINA","url":"https://clinicaltrials.gov/study/NCT04949113"},{"label":"ClinicalTrials.gov NCT03698019: SWOG S1801","url":"https://clinicaltrials.gov/study/NCT03698019"}],"tags":[],"related":[],"cancers":["melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["nivolumab","ipilimumab","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":["major-pathological-response"],"trials":["nadina","swog-s1801"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"checkpoint-inhibitor","b":"sentinel-node","rationale":"The intact tumour and nodes provide antigen and T-cell priming; pathological response is a reliable early readout that lets therapy be de-escalated.","evidence":"Phase 3 NADINA, phase 2 SWOG S1801.","pairingType":"sequence"},{"id":"oncolytic-plus-pd1","kind":"pairing","name":"Oncolytic virus + PD-1 blockade","aka":[],"tldr":"An oncolytic virus blows up tumour cells and inflames the tumour; PD-1 blockade then exploits the inflammation.","summary":"This combination pairs Oncolytic viruses with Immune checkpoint inhibitors in Melanoma: the virus blows up tumour cells and inflames the tumour, and PD-1 blockade then exploits the inflammation. The mechanism is that viral lysis releases antigens and virus-encoded GM-CSF, and the resulting interferon response upregulates PD-L1, which nivolumab blocks. RP1 (Vusolimogene oderparepvec) plus Nivolumab received accelerated approval in August 2026 for PD-1-refractory melanoma on the IGNYTE study, which produced responses including in uninjected lesions. By contrast, Talimogene laherparepvec plus pembrolizumab did not improve outcomes in the first-line setting (MASTERKEY-265), showing that the treatment setting matters.","asOf":"2026-09-04","links":[{"label":"MASTERKEY-265: talimogene laherparepvec plus pembrolizumab in advanced melanoma, phase 3 (Journal of Clinical Oncology 2023)","url":"https://doi.org/10.1200/JCO.22.00343"}],"tags":[],"related":[],"cancers":["melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["vusolimogene-oderparepvec","nivolumab","talimogene-laherparepvec"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-chesney-j-clin-oncol"],"journals":[],"dependsOn":[],"notes":[],"a":"oncolytic-virus","b":"checkpoint-inhibitor","rationale":"Viral lysis releases antigens and encoded GM-CSF; interferon response upregulates PD-L1, which nivolumab blocks.","evidence":"Accelerated approval in refractory setting; negative in first line for older agent.","pairingType":"combination"},{"id":"oral-serd-plus-cdk46-after-esr1","kind":"pairing","name":"Oral SERD + CDK4/6 inhibitor after ESR1 emergence","aka":[],"tldr":"When an ESR1 mutation appears, swap the aromatase inhibitor for an oral SERD and keep the CDK4/6 inhibitor going.","summary":"This sequence swaps the aromatase inhibitor for the oral SERD camizestrant when an ESR1 mutation emerges in HR-positive, HER2-negative breast cancer, while the CDK4/6 inhibitor continues. ESR1 mutations make the oestrogen receptor ligand-independent, which neutralises aromatase inhibitors but not degraders, and the tumour's dependence on CDK4/6 persists. SERENA-6 tested the switch at the moment ESR1 appeared in ctDNA, and EMBER-3 paired imlunestrant with abemaciclib; both phase 3 trials were positive for progression-free survival, and camizestrant received FDA accelerated approval in 2026. Replacing the aromatase inhibitor up front without molecular selection, as in persevERA, failed, so the timing of the switch is the point.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT04964934: SERENA-6","url":"https://clinicaltrials.gov/study/NCT04964934"},{"label":"ClinicalTrials.gov NCT04975308: EMBER-3","url":"https://clinicaltrials.gov/study/NCT04975308"}],"tags":[],"related":[],"cancers":["breast-hr-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["camizestrant","imlunestrant","abemaciclib"],"companies":[],"institutions":[],"pathways":[],"terms":["esr1-mutation"],"trials":["serena-6","ember-3"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"camizestrant","b":"cdk46-inhibitor","rationale":"ESR1 mutations make ER ligand-independent, neutralising AIs but not degraders; CDK4/6 dependence persists.","evidence":"Two positive phase 3 trials; FDA accelerated approval (camizestrant) 2026.","pairingType":"sequence"},{"id":"parp-plus-arpi","kind":"pairing","name":"PARP inhibitor + AR pathway inhibitor (prostate)","aka":[],"tldr":"In prostate cancer, blocking androgen signalling makes cells more dependent on PARP, and PARP inhibition weakens AR signalling in turn.","summary":"This combination pairs PARP inhibitors with Androgen deprivation & AR pathway inhibitors in Prostate cancer. The mechanism is bidirectional cross-talk: the androgen receptor regulates DNA repair genes and PARP is an AR co-factor, so blocking androgen signalling makes cells more dependent on PARP while PARP inhibition weakens AR signalling, creating synergy that extends beyond BRCA-mutant tumours and linking the DNA damage response & homologous recombination and Androgen receptor signalling pathways. Three phase 3 trials support it: PROpel (Olaparib with abiraterone), TALAPRO-2 (Talazoparib with enzalutamide, which showed an overall survival benefit) and MAGNITUDE (Niraparib with abiraterone). The benefit is largest in HRR-mutant tumours and present in some all-comer analyses.","asOf":"2026-09-04","links":[{"label":"PROpel: abiraterone and olaparib for metastatic castration-resistant prostate cancer (NEJM Evidence 2022)","url":"https://doi.org/10.1056/EVIDoa2200043"},{"label":"TALAPRO-2: talazoparib plus enzalutamide in first-line metastatic castration-resistant prostate cancer (Lancet 2023)","url":"https://doi.org/10.1016/S0140-6736(23)01055-3"}],"tags":[],"related":[],"cancers":["prostate"],"sections":[],"technologies":[],"targets":[],"drugs":["olaparib","talazoparib","niraparib"],"companies":[],"institutions":[],"pathways":["ddr","ar-signaling"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-clarke-nejm-evid"],"journals":[],"dependsOn":[],"notes":[],"a":"parp-inhibitor","b":"androgen-deprivation","rationale":"AR regulates DNA repair genes; PARP is an AR co-factor. Bidirectional cross-talk creates synergy beyond BRCA-mutant tumours.","evidence":"Three phase 3 trials, OS benefit in TALAPRO-2.","pairingType":"combination"},{"id":"parp-plus-bevacizumab","kind":"pairing","name":"PARP inhibitor + bevacizumab maintenance (HRD-positive)","aka":[],"tldr":"In tumours with faulty DNA repair, adding olaparib to bevacizumab maintenance roughly doubled progression-free time and improved survival.","summary":"In newly diagnosed advanced ovarian cancer with homologous recombination deficiency, adding the PARP inhibitor olaparib to bevacizumab maintenance is a combination pairing that markedly prolonged progression-free time and improved overall survival in the phase 3 PAOLA-1 / ENGOT-ov25 trial, with no benefit seen in HRD-negative tumours. The mechanistic rationale is that anti-angiogenic hypoxia may push tumour cells into HRD-like states and greater dependence on PARP, and the two agents have non-overlapping toxicity. The combination was approved in 2020. Because the benefit was confined to the HRD-positive subgroup, the pairing made HRD testing a routine first-line decision in ovarian cancer.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT02477644: PAOLA-1 / ENGOT-ov25","url":"https://clinicaltrials.gov/study/NCT02477644"}],"tags":[],"related":[],"cancers":["ovarian"],"sections":[],"technologies":[],"targets":["parp","vegf"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["hrd"],"trials":["paola-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"olaparib","b":"bevacizumab","rationale":"Anti-angiogenic hypoxia may increase HRD-like states and PARP dependence; the two agents have non-overlapping toxicity.","evidence":"Phase 3 with OS benefit in HRD-positive subgroup.","pairingType":"combination"},{"id":"pd1-plus-avd-hodgkin","kind":"pairing","name":"PD-1 blockade + AVD chemotherapy","aka":[],"tldr":"Immunotherapy given alongside standard chemotherapy from day one cures more advanced Hodgkin lymphoma with less nerve damage.","summary":"Giving nivolumab alongside AVD chemotherapy, whose anthracycline component is doxorubicin, from the first cycle is a combination pairing for advanced-stage classical Hodgkin lymphoma. Reed-Sternberg cells carry amplification of the PD-L1 locus at 9p24.1 and depend on immune evasion, so chemotherapy debulks the disease while PD-1 blockade engages the abundant reactive T cells already present in the tumour. In the phase 3 SWOG S1826 trial nivolumab-AVD improved progression-free survival compared with brentuximab vedotin-AVD and caused much less peripheral neuropathy, and the regimen was approved in March 2026 for patients aged 12 and over. Supporting phase 2 evidence comes from cohort D of CheckMate 205, and the linked S1826 paper covers adolescents and adults.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03907488: SWOG S1826","url":"https://clinicaltrials.gov/study/NCT03907488"},{"label":"ClinicalTrials.gov NCT02181738: CheckMate 205","url":"https://clinicaltrials.gov/study/NCT02181738"}],"tags":[],"related":[],"cancers":["hodgkin-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["swog-s1826","checkmate-205"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"nivolumab","b":"doxorubicin","rationale":"Reed-Sternberg cells are PD-L1-amplified (9p24.1) and immune-dependent; chemotherapy debulks while PD-1 blockade engages the abundant reactive T cells in the tumour.","evidence":"Phase 3 (S1826) positive; phase 2 CheckMate 205 cohort D.","pairingType":"combination"},{"id":"io-plus-crt-cervical","kind":"pairing","name":"PD-1 blockade + chemoradiation (locally advanced cervical cancer)","aka":[],"tldr":"Adding pembrolizumab to curative chemoradiation improved survival in high-risk locally advanced cervical cancer (KEYNOTE-A18); durvalumab in a broader population did not (CALLA).","summary":"Adding pembrolizumab to curative chemoradiation, including brachytherapy, is a combination pairing for high-risk locally advanced cervical cancer that improved overall survival in the phase 3 KEYNOTE-A18 / ENGOT-cx11 / GOG-3047 trial and gained FDA approval for FIGO stage III to IVA disease in 2024. The rationale is that radiation releases tumour antigen and upregulates PD-L1, making the tumour immunogenic, and PD-1 blockade given concurrently and then as maintenance sustains the response. The sister trial CALLA, which used durvalumab in a broader population, was negative, possibly because it enrolled lower-risk patients and used a different drug. Cost limits use of the approach outside high-income countries, and it belongs to the wider family of radiotherapy plus immunotherapy pairings.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT04221945: KEYNOTE-A18 / ENGOT-cx11 / GOG-3047","url":"https://clinicaltrials.gov/study/NCT04221945"}],"tags":[],"related":["radiation-plus-io"],"cancers":["cervical"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-a18"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"pembrolizumab","b":"brachytherapy","rationale":"Radiation-induced antigen release and PD-L1 upregulation make the tumour immunogenic; concurrent and maintenance PD-1 blockade sustains the response.","evidence":"Phase 3 OS benefit (KEYNOTE-A18); negative sister trial (CALLA).","pairingType":"combination"},{"id":"pd1-plus-chemo-pdl1-low","kind":"pairing","name":"PD-1 blockade + chemotherapy in PD-L1-low NSCLC","aka":[],"tldr":"When the tumour shows little PD-L1, immunotherapy alone is weak, but adding chemotherapy makes it work for most patients.","summary":"This combination gives a PD-1 checkpoint inhibitor together with cytotoxic chemotherapy in non-small-cell lung cancer whose PD-L1 tumour proportion score is low. Chemotherapy releases tumour antigen and depletes suppressive cells, priming an immune response that PD-1 blockade then sustains, and the benefit does not depend on the PD-L1 level. KEYNOTE-189 in non-squamous and KEYNOTE-407 in squamous disease showed an overall survival benefit across PD-L1 strata, including tumours with essentially no PD-L1 expression. POSEIDON adds tremelimumab to durvalumab and chemotherapy for PD-L1-negative and STK11- or KEAP1-mutant disease. Pembrolizumab with chemotherapy is now the standard control arm against which every new first-line lung regimen is measured.","asOf":"2026-09-06","links":[{"label":"ClinicalTrials.gov NCT02142738: KEYNOTE-024 & KEYNOTE-189","url":"https://clinicaltrials.gov/study/NCT02142738"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab","tremelimumab","durvalumab"],"companies":[],"institutions":[],"pathways":[],"terms":["tps"],"trials":["keynote-024-189"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"checkpoint-inhibitor","b":"cytotoxic-chemotherapy","rationale":"Chemotherapy releases antigen and depletes suppressive cells, priming a response that PD-1 blockade sustains; benefit is independent of PD-L1 level.","evidence":"Multiple phase 3 with 5-year OS data.","pairingType":"combination"},{"id":"io-plus-vegf","kind":"pairing","name":"PD-1 blockade + VEGF inhibition","aka":[],"tldr":"Normalising the tumour's blood vessels lets immune cells in, and VEGF blockade removes an immunosuppressive signal.","summary":"This combination pairs Immune checkpoint inhibitors with Anti-angiogenic therapy against VEGF. VEGF suppresses dendritic cell maturation, promotes Tregs and MDSCs and produces leaky vessels that block T-cell infiltration, so normalising the vessels lets immune cells in and removes an immunosuppressive signal, linking the VEGF angiogenesis and PD-1 / PD-L1 immune checkpoint pathways. It is standard in Renal cell carcinoma (pembrolizumab-axitinib, nivolumab-cabozantinib), Hepatocellular carcinoma (atezolizumab-bevacizumab) and Endometrial cancer (lenvatinib-pembrolizumab), on multiple phase 3 trials with overall survival benefit. Ivonescimab fuses both functions into one molecule and beat pembrolizumab in Non-small-cell lung cancer.","asOf":"2026-09-04","links":[{"label":"CLEAR: lenvatinib plus pembrolizumab versus sunitinib as first treatment for advanced kidney cancer (New England Journal of Medicine 2021)","url":"https://doi.org/10.1056/NEJMoa2035716"},{"label":"ClinicalTrials.gov NCT05499390: HARMONi-2","url":"https://clinicaltrials.gov/study/NCT05499390"}],"tags":[],"related":[],"cancers":["rcc","hcc","endometrial","nsclc"],"sections":[],"technologies":[],"targets":[],"drugs":["ivonescimab","atezolizumab","pembrolizumab"],"companies":[],"institutions":[],"pathways":["vegf-angiogenesis","pd1-checkpoint"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"checkpoint-inhibitor","b":"antiangiogenic","rationale":"VEGF suppresses dendritic cell maturation, promotes Tregs and MDSCs, and produces leaky vessels that block T-cell infiltration.","evidence":"Multiple phase 3 OS benefits; bispecific validation.","pairingType":"combination"},{"id":"io-then-til","kind":"pairing","name":"PD-1 failure → TIL therapy","aka":[],"tldr":"When checkpoint blockade fails in melanoma, harvesting and expanding the patient's own tumour-reactive T cells still works in a third of patients.","summary":"This sequence pairing follows failure of Immune checkpoint inhibitors with TIL therapy in Melanoma: when checkpoint blockade fails, harvesting and expanding the patient's own tumour-reactive T cells can still produce responses. The rationale is that checkpoint failure often reflects too few tumour-reactive T cells rather than none, and TIL therapy multiplies them a thousand-fold, supplying cells that were quantitatively insufficient rather than absent. Lifileucel received accelerated approval for use after anti-PD-1 therapy such as Pembrolizumab, and long-term durability data support the approach. The pairing is reached from the Melanoma entry and illustrates how a cell therapy can rescue a setting where antibodies have stopped working.","asOf":"2026-09-04","links":[{"label":"ClinicalTrials.gov NCT02360579: C-144-01","url":"https://clinicaltrials.gov/study/NCT02360579"}],"tags":[],"related":[],"cancers":["melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["lifileucel","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"checkpoint-inhibitor","b":"til-therapy","rationale":"Checkpoint failure often reflects too few tumour-reactive T cells; TIL therapy multiplies them a thousand-fold.","evidence":"Accelerated approval; 5-year durability data.","pairingType":"sequence"},{"id":"vaccine-plus-pd1","kind":"pairing","name":"Personalised neoantigen vaccine + PD-1 blockade","aka":[],"tldr":"The vaccine teaches the immune system what to hunt; PD-1 blockade stops the tumour from switching the hunters off.","summary":"This combination pairs Personalised neoantigen (mRNA) vaccines with Immune checkpoint inhibitors: the vaccine teaches the immune system what to hunt and PD-1 blockade stops the tumour switching the hunters off. The mechanism is that vaccine-primed T cells encounter PD-L1 in the tumour and in residual disease, and checkpoint blockade preserves their effector function, while the adjuvant setting offers low tumour burden and time to mount immunity. In Melanoma, Intismeran autogene plus Pembrolizumab reduced recurrence in a phase 2b study and the phase 3 INTerpath-001 (V940-001) trial was positive in August 2026. In Pancreatic ductal adenocarcinoma, Autogene cevumeran plus atezolizumab is the corresponding pairing, described in the Rojas 2023 paper.","asOf":"2026-09-04","links":[{"label":"ClinicalTrials.gov NCT05933577: INTerpath-001 (V940-001)","url":"https://clinicaltrials.gov/study/NCT05933577"}],"tags":[],"related":[],"cancers":["melanoma","pancreatic"],"sections":[],"technologies":[],"targets":[],"drugs":["intismeran-autogene","pembrolizumab","autogene-cevumeran"],"companies":[],"institutions":[],"pathways":["pd1-checkpoint"],"terms":[],"trials":["interpath-001"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"neoantigen-mrna-vaccine","b":"checkpoint-inhibitor","rationale":"Vaccine-primed T cells encounter PD-L1 in the tumour and residual disease; checkpoint blockade preserves their effector function. Adjuvant setting gives low tumour burden and time to mount immunity.","evidence":"Phase 3 positive (melanoma).","pairingType":"combination"},{"id":"pi3k-pathway-plus-endocrine","kind":"pairing","name":"PI3K/AKT-pathway inhibitor + endocrine therapy (± CDK4/6)","aka":[],"tldr":"Blocking the PI3K growth pathway alongside hormone therapy works only when the tumour carries a mutation in that pathway, and works best early.","summary":"This combination adds a PI3K or AKT pathway inhibitor, such as inavolisib, capivasertib or alpelisib, to endocrine therapy such as fulvestrant, sometimes with a CDK4/6 inhibitor, in HR-positive, HER2-negative breast cancer. PI3K pathway activation is a dominant escape from oestrogen receptor dependence, so blocking both removes the tumour's two survival inputs and works best early in the disease course. SOLAR-1 with alpelisib, CAPItello-291 with capivasertib and INAVO120 with inavolisib plus palbociclib and fulvestrant were all positive phase 3 trials, with benefit restricted to, or largest in, tumours carrying PIK3CA, AKT1 or PTEN alterations, and INAVO120 also showed an overall survival gain. Hyperglycaemia, rash and diarrhoea differ by agent and shape the choice between them.","asOf":"2026-09-07","links":[{"label":"INAVO120: inavolisib-based therapy in PIK3CA-mutated advanced breast cancer (NEJM 2024)","url":"https://doi.org/10.1056/NEJMoa2404625"},{"label":"CAPItello-291: capivasertib in hormone receptor-positive advanced breast cancer (NEJM 2023)","url":"https://doi.org/10.1056/NEJMoa2214131"}],"tags":[],"related":[],"cancers":["breast-hr-positive"],"sections":[],"technologies":[],"targets":["pik3ca","akt"],"drugs":["inavolisib","capivasertib","alpelisib","fulvestrant"],"companies":[],"institutions":[],"pathways":["pi3k-akt-mtor","er-signaling"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"inavolisib","b":"endocrine-therapy","rationale":"PI3K pathway activation is a dominant escape from ER dependence; combined blockade removes both survival inputs.","evidence":"Three positive phase 3 trials with biomarker selection.","pairingType":"combination"},{"id":"platinum-plus-hrd","kind":"pairing","name":"Platinum chemotherapy in HRD tumours","aka":[],"tldr":"DNA-crosslinking chemotherapy is especially effective in tumours that cannot repair double-strand breaks.","summary":"This combination pairs Platinum agents with tumours carrying BRCA1 / BRCA2 (HRD) defects, because DNA-crosslinking chemotherapy is especially effective in cells that cannot repair double-strand breaks. The mechanism is that interstrand crosslinks need homologous recombination to repair, so HRD cells accumulate lethal double-strand breaks, as described in the DNA damage response & homologous recombination pathway. Multiple randomised trials support it: Carboplatin raises pathological complete response in Triple-negative breast cancer (TNBC) in GeparSixto and BrighTNess, with greater benefit in BRCA-mutant or HRD tumours. In Ovarian cancer, platinum sensitivity defines the treatable population, and the pairing is linked from the TNBC, Platinum agents and BRCA1 / BRCA2 (HRD) entries.","asOf":"2026-09-04","links":[{"label":"TNT trial: carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups (Nature Medicine 2018)","url":"https://doi.org/10.1038/s41591-018-0009-7"}],"tags":[],"related":[],"cancers":["tnbc","ovarian"],"sections":[],"technologies":[],"targets":[],"drugs":["carboplatin"],"companies":[],"institutions":[],"pathways":["ddr"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-tutt-nat-med"],"journals":[],"dependsOn":[],"notes":[],"a":"platinum","b":"brca","rationale":"Interstrand crosslinks need homologous recombination to repair; HRD cells accumulate lethal double-strand breaks.","evidence":"Multiple randomised trials.","pairingType":"combination"},{"id":"psma-pet-to-rlt","kind":"pairing","name":"PSMA PET → PSMA radioligand therapy","aka":[],"tldr":"The scan shows whether the target is there; the treatment uses the same address. Only patients whose tumours light up are treated.","summary":"This diagnostic-therapeutic pairing links PSMA PET to Radioligand therapy (beta emitters) against PSMA in Prostate cancer: the scan shows whether the target is there, the treatment uses the same address, and only patients whose tumours light up are treated. Identical ligand chemistry means imaging biodistribution predicts therapeutic biodistribution and enables dosimetry. VISION and PSMAfore required PSMA PET positivity, so the pairing is embedded in phase 3 design and drug labels, and the standardised uptake value predicts response. The linked agents are Piflufolastat F-18 / Pylarify TruVu and Lutetium-177 vipivotide tetraxetan, and the pairing is the archetype of Theranostics now being copied for FAP, TROP2, HER2 and CAIX.","asOf":"2026-09-04","links":[{"label":"VISION: lutetium-177 PSMA-617 radioligand therapy extends survival in advanced prostate cancer (New England Journal of Medicine 2021)","url":"https://doi.org/10.1056/NEJMoa2107322"},{"label":"ClinicalTrials.gov NCT03392428: TheraP (ANZUP 1603)","url":"https://clinicaltrials.gov/study/NCT03392428"}],"tags":[],"related":[],"cancers":["prostate"],"sections":[],"technologies":[],"targets":["psma"],"drugs":["pylarify","pluvicto"],"companies":[],"institutions":[],"pathways":[],"terms":["theranostics"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"psma-pet","b":"radioligand-therapy","rationale":"Identical ligand chemistry means imaging biodistribution predicts therapeutic biodistribution; also enables dosimetry.","evidence":"Embedded in phase 3 design and labels.","pairingType":"diagnostic-therapeutic"},{"id":"radiation-plus-io","kind":"pairing","name":"Radiotherapy + immunotherapy","aka":[],"tldr":"Radiation turns the irradiated tumour into a vaccine; immunotherapy spreads the response.","summary":"This combination pairs SBRT / SABR (stereotactic radiotherapy) and other radiotherapy with Immune checkpoint inhibitors: radiation turns the irradiated tumour into a vaccine and immunotherapy spreads the response. Radiation induces immunogenic cell death, cGAS-STING innate sensing, MHC upregulation and antigen release, and PD-L1 rises afterwards, which checkpoint blockade counters. Phase 3 trials are positive in consolidation settings, notably PACIFIC (Durvalumab after chemoradiation in Non-small-cell lung cancer, with overall survival benefit), KEYNOTE-A18 in Cervical cancer and NRG/RTOG trials. The Abscopal effect with SBRT plus immunotherapy is real but inconsistent, with PEMBRO-RT positive and other trials negative, so timing, dose and site matter.","asOf":"2026-09-04","links":[{"label":"ADRIATIC: durvalumab after chemoradiotherapy for limited-stage small-cell lung cancer (New England Journal of Medicine 2024)","url":"https://doi.org/10.1056/NEJMoa2404873"}],"tags":[],"related":[],"cancers":["nsclc","cervical","sclc"],"sections":[],"technologies":[],"targets":[],"drugs":["durvalumab","pembrolizumab"],"companies":[],"institutions":[],"pathways":["cgas-sting"],"terms":["abscopal-effect"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"sbrt","b":"checkpoint-inhibitor","rationale":"Radiation induces immunogenic cell death, cGAS-STING signalling, MHC upregulation, and antigen release; PD-L1 rises after radiation, which checkpoint blockade counters.","evidence":"Phase 3 positive in consolidation settings; abscopal effect less consistent.","pairingType":"combination"},{"id":"targeted-before-io-nsclc","kind":"pairing","name":"Sequence: targeted therapy before immunotherapy in driver-positive NSCLC","aka":[],"tldr":"If a lung cancer has a targetable mutation, give the pill first; immunotherapy works poorly in these tumours and raises the risk of severe side effects when a pill follows.","summary":"This sequence rule says that in non-small-cell lung cancer with a targetable driver such as EGFR, ALK, ROS1 or RET, a small-molecule kinase inhibitor comes first and immune checkpoint inhibitors later. Oncogene-addicted tumours have a low mutational burden and an immunosuppressive microenvironment, so PD-1 blockade works poorly, as the IMMUNOTARGET series showed, and the immune priming it leaves behind raises the risk of pneumonitis when osimertinib follows. Randomised first-line trials such as LIBRETTO-431, CROWN and MARIPOSA make targeted therapy with drugs such as osimertinib, lorlatinib and selpercatinib the standard. Chemotherapy, with or without an antibody-drug conjugate or immunotherapy, is held for later lines.","asOf":"2026-09-06","links":[{"label":"ClinicalTrials.gov NCT04194944: LIBRETTO-431","url":"https://clinicaltrials.gov/study/NCT04194944"},{"label":"ClinicalTrials.gov NCT03052608: CROWN","url":"https://clinicaltrials.gov/study/NCT03052608"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":["egfr","alk","ret","ros1"],"drugs":["osimertinib","lorlatinib","selpercatinib","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["libretto-431","crown","mariposa"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"kinase-inhibitors","b":"checkpoint-inhibitor","rationale":"Oncogene-addicted tumours have low TMB and immunosuppressive microenvironments; immune priming persists and interacts with subsequent TKIs.","evidence":"Randomised first-line TKI trials plus retrospective toxicity data.","pairingType":"sequence"},{"id":"tarlatamab-vs-idxd-sequence","kind":"pairing","name":"Sequencing DLL3 engager and B7-H3 ADC in relapsed SCLC","aka":[],"tldr":"Two new relapsed-disease options with different targets and mechanisms. Which comes first, and whether one works after the other, is unknown.","summary":"This sequencing question in relapsed small-cell lung cancer concerns tarlatamab, a DLL3-directed T-cell engager, and ifinatamab deruxtecan (I-DXd), a B7-H3-directed antibody-drug conjugate with a topoisomerase 1 payload. Tarlatamab has shown a survival benefit in DeLLphi-304, while I-DXd has produced high response rates and is in the phase 3 IDeate-Lung02 trial. Because the two drugs hit different antigens and kill by different mechanisms, they are expected not to be cross-resistant, and their toxicity profiles also differ, cytokine release syndrome for one and interstitial lung disease and neutropenia for the other, which could allow a patient-based choice. No prospective data yet say which should come first or whether one works after the other, so the pairing remains a concept.","asOf":"2026-09-07","links":[],"tags":[],"related":[],"cancers":["sclc"],"sections":[],"technologies":[],"targets":["dll3","b7h3"],"drugs":["tarlatamab","ifinatamab-deruxtecan"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"tarlatamab","b":"ifinatamab-deruxtecan","rationale":"Distinct targets and killing mechanisms; toxicity profiles (CRS vs ILD/neutropenia) also differ, allowing patient-based choice.","evidence":"No prospective sequencing data; concept.","pairingType":"sequence"},{"id":"sstr-pet-to-prrt","kind":"pairing","name":"SSTR PET → PRRT","aka":[],"tldr":"SSTR PET followed by PRRT is the original theranostic pair: the scan with the diagnostic isotope decides who gets the same molecule with the therapeutic isotope.","summary":"This diagnostic-therapeutic pairing links somatostatin receptor PET, using gallium-68 or copper-64 DOTATATE, to peptide receptor radionuclide therapy with lutetium-177 dotatate or 177Lu-edotreotide in neuroendocrine tumours. Because the imaging and therapeutic agents share identical peptide chemistry, the biodistribution seen on the scan predicts where the therapy will be delivered, which is the founding logic of theranostics. Every pivotal PRRT trial, including NETTER-1, NETTER-2 and COMPETE, required SSTR-avid disease on imaging, and both the intensity of uptake, graded on the Krenning scale, and the absence of FDG-avid lesions lacking SSTR predict benefit. The same template was later copied by PSMA theranostics in prostate cancer.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03049189: COMPETE","url":"https://clinicaltrials.gov/study/NCT03049189"}],"tags":[],"related":[],"cancers":["neuroendocrine"],"sections":[],"technologies":[],"targets":["sstr2"],"drugs":["lutathera","itm-11"],"companies":[],"institutions":[],"pathways":[],"terms":["theranostics"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"sstr-pet","b":"prrt","rationale":"Identical peptide chemistry means imaging biodistribution predicts therapy delivery.","evidence":"Embedded in all pivotal PRRT trials.","pairingType":"diagnostic-therapeutic"},{"id":"tace-plus-systemic","kind":"pairing","name":"TACE + immunotherapy/anti-VEGF","aka":[],"tldr":"Adding drugs to the catheter procedure keeps intermediate-stage liver cancer under control for longer, though a survival gain is still unproven.","summary":"This combination adds immune checkpoint inhibitors, with or without anti-VEGF therapy, to transarterial chemoembolisation for intermediate-stage hepatocellular carcinoma. TACE releases tumour antigen and induces hypoxia-driven VEGF; PD-1 or PD-L1 blockade exploits the former and anti-angiogenic therapy counters the latter. Three phase 3 trials, EMERALD-1, LEAP-012 and EMERALD-3, all improved progression-free survival, but LEAP-012's final overall survival analysis and EMERALD-1's non-significant trend leave the survival question open. Toxicity roughly doubles with the added drugs, so the trade-off is longer disease control against more side effects without a proven gain in survival.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03778957: EMERALD-1","url":"https://clinicaltrials.gov/study/NCT03778957"},{"label":"ClinicalTrials.gov NCT04246177: LEAP-012","url":"https://clinicaltrials.gov/study/NCT04246177"}],"tags":[],"related":[],"cancers":["hcc"],"sections":[],"technologies":["tace","antiangiogenic"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["emerald-1","leap-012","emerald-3"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"tace","b":"checkpoint-inhibitor","rationale":"TACE releases antigen and induces hypoxia-driven VEGF; PD-(L)1 blockade exploits the former and anti-VEGF counters the latter.","evidence":"Three positive phase 3 trials for PFS; no OS benefit shown.","pairingType":"combination"},{"id":"trop2-pet-to-adc","kind":"pairing","name":"TROP2 PET → TROP2 ADC selection","aka":[],"tldr":"Proposed: a TROP2 PET scan to choose between three TROP2 ADCs and predict who will respond, since tissue staining has not worked.","summary":"This proposed diagnostic-therapeutic pairing uses TROP2 PET to choose among the TROP2 Antibody-drug conjugate (ADC) agents Sacituzumab govitecan, Datopotamab deruxtecan and Sacituzumab tirumotecan and to predict who will respond, since tissue staining has not worked. The rationale is that ASCENT showed benefit regardless of TROP2 immunohistochemistry, possibly because one archival sample misses heterogeneity and dynamics that whole-body PET could capture. First-in-human TROP2 tracers exist (89Zr antibodies, 68Ga and 18F nanobodies) but there are no outcome data yet, so the evidence is concept plus phase 1 imaging. It would also allow monitoring of antigen loss on progression and rational ADC sequencing in Triple-negative breast cancer (TNBC) and Non-small-cell lung cancer.","asOf":"2026-09-04","links":[],"tags":[],"related":["idea-trop2-pet-selection"],"cancers":["tnbc","nsclc"],"sections":[],"technologies":[],"targets":["trop2"],"drugs":["sacituzumab-govitecan","datopotamab-deruxtecan","sacituzumab-tirumotecan"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"trop2-pet","b":"adc","rationale":"ASCENT showed benefit regardless of IHC TROP2, possibly because IHC on one archival sample misses heterogeneity and dynamics; whole-body PET could capture both.","evidence":"Concept; phase 1 imaging studies.","pairingType":"diagnostic-therapeutic"},{"id":"tucatinib-triplet-brain-mets","kind":"pairing","name":"Tucatinib + trastuzumab + capecitabine for brain metastases","aka":[],"tldr":"The one regimen proven in a randomised trial to help HER2-positive brain metastases, extending survival in those patients by six months.","summary":"This combination gives tucatinib with trastuzumab and capecitabine to patients with HER2-positive breast cancer and brain metastases. Tucatinib is a small, HER2-selective molecule that crosses the blood-brain barrier, capecitabine adds a cytotoxic effect that is active in the central nervous system, and trastuzumab maintains systemic control. In the phase 3 HER2CLIMB trial, which included dedicated analyses of patients with brain metastases, the regimen improved intracranial progression-free survival and overall survival and produced responses in both untreated and previously treated brain lesions. It remains the one regimen shown in a randomised trial to help HER2-positive brain metastases, and it allows whole-brain radiation to be deferred in selected cases.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT02614794: HER2CLIMB","url":"https://clinicaltrials.gov/study/NCT02614794"}],"tags":[],"related":[],"cancers":["breast-her2-positive"],"sections":[],"technologies":[],"targets":[],"drugs":["tucatinib","trastuzumab"],"companies":[],"institutions":[],"pathways":[],"terms":["her2-brain-metastases"],"trials":["her2climb"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"tucatinib","b":"trastuzumab","rationale":"Tucatinib is a small, HER2-selective molecule that crosses the blood-brain barrier; capecitabine adds CNS-active cytotoxic effect; trastuzumab maintains systemic control.","evidence":"Phase 3 (HER2CLIMB) with dedicated CNS analyses.","pairingType":"combination"},{"id":"venetoclax-plus-hma","kind":"pairing","name":"Venetoclax + hypomethylating agent","aka":[],"tldr":"Azacitidine primes leukaemia cells for death; venetoclax removes the BCL-2 shield. Together they roughly doubled remissions in older AML.","summary":"This combination pairs venetoclax with the hypomethylating agent azacitidine in acute myeloid leukaemia, chiefly in older patients who cannot have intensive chemotherapy. Azacitidine lowers MCL-1 and induces NOXA, which increases the leukaemia cells' dependence on BCL-2, and venetoclax then blocks BCL-2 and removes that last shield, driving intrinsic apoptosis. The phase 3 VIALE-A trial showed an overall survival benefit and a higher remission rate than azacitidine alone, and the regimen is now available fully orally with decitabine-cedazuridine plus venetoclax, supported by ASCERTAIN-V and introduced in 2026. The duration of venetoclax within each cycle is being shortened from 28 days to 14 to reduce cytopenias without losing efficacy.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT02993523: VIALE-A","url":"https://clinicaltrials.gov/study/NCT02993523"},{"label":"ClinicalTrials.gov NCT04657081: ASCERTAIN-V","url":"https://clinicaltrials.gov/study/NCT04657081"}],"tags":[],"related":[],"cancers":["aml"],"sections":[],"technologies":[],"targets":[],"drugs":["venetoclax","azacitidine","decitabine-cedazuridine"],"companies":[],"institutions":[],"pathways":["apoptosis-bcl2"],"terms":[],"trials":["viale-a","ascertain-v"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"venetoclax","b":"azacitidine","rationale":"Azacitidine lowers MCL-1 and induces NOXA, increasing dependence on BCL-2, which venetoclax then blocks.","evidence":"Phase 3 (VIALE-A) OS benefit; ASCERTAIN-V for the oral backbone.","pairingType":"combination"},{"id":"venetoclax-plus-obinutuzumab","kind":"pairing","name":"Venetoclax + obinutuzumab (12 months)","aka":[],"tldr":"Venetoclax plus obinutuzumab, one year of a pill plus an antibody, was the first fixed-duration, chemotherapy-free CLL regimen, with half of patients still in remission at six years.","summary":"This combination gives one year of venetoclax, a BCL-2 inhibitor, with the CD20 antibody obinutuzumab in chronic lymphocytic leukaemia; it was the first fixed-duration, chemotherapy-free regimen for the disease. Obinutuzumab debulks the leukaemia and reduces the risk of tumour lysis syndrome before venetoclax is ramped up, and adds antibody-dependent cellular cytotoxicity, while venetoclax clears measurable residual disease. The evidence is two positive phase 3 trials: CLL14 in unfit patients, where a large share remain in remission at long follow-up, and CLL13 (GAIA) in fit patients, where obinutuzumab outperformed rituximab as the venetoclax partner and adding ibrutinib deepened the effect further. The regimen is described in the CLL14 paper.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT02242942: CLL14","url":"https://clinicaltrials.gov/study/NCT02242942"},{"label":"ClinicalTrials.gov NCT02950051: CLL13 / GAIA","url":"https://clinicaltrials.gov/study/NCT02950051"}],"tags":[],"related":[],"cancers":["cll"],"sections":[],"technologies":[],"targets":["bcl2","cd20"],"drugs":["venetoclax","obinutuzumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["cll14","cll13-gaia"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"venetoclax","b":"obinutuzumab","rationale":"Obinutuzumab debulks and reduces TLS risk before venetoclax ramp-up and adds ADCC-mediated killing; venetoclax clears MRD.","evidence":"Two positive phase 3 trials.","pairingType":"combination"}]