{"id":"tnbc-history","name":"TNBC roadmap: from 'nothing to target' to ADC + immunotherapy first line","route":"/roadmaps/tnbc-history/","eras":[{"era":"2000-2015","title":"Chemotherapy only","description":"Basal-like subtype defined (2000); TNBC named by exclusion (2007). Anthracycline-taxane chemotherapy; carboplatin added (2014). Median metastatic OS was about 13-18 months, and EGFR, VEGF, and PARP inhibitor (iniparib) trials failed repeatedly.","status":"historic","refs":[{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/","status":"approved","tldr":"Carboplatin is a platinum chemotherapy that crosslinks DNA; it is part of the standard pre-surgery regimen for triple-negative breast cancer."},{"id":"platinum","kind":"technology","name":"Platinum agents","route":"/technologies/platinum/","status":"standard-of-care","tldr":"Platinum agents such as cisplatin and carboplatin work by crosslinking DNA. They are curative in testicular cancer and central to lung, ovarian, bladder, head and neck, and TNBC treatment."}],"trials":[],"papers":[]},{"era":"2018-2020","title":"Immunotherapy and PARP arrive","description":"The pivotal trials are IMpassion130 (atezolizumab, later withdrawn), OlympiAD/EMBRACA (PARP inhibitors in gBRCA), KEYNOTE-355 (pembrolizumab CPS ≥10 first line), ASCENT (sacituzumab govitecan).","status":"historic","refs":[{"id":"impassion130","kind":"trial","name":"IMpassion130","route":"/trials/impassion130/","status":"mixed","tldr":"IMpassion130 was the first immunotherapy success in breast cancer, later undermined when a sister trial failed and the approval was withdrawn."},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/","status":"approved","tldr":"Olaparib was the first PARP inhibitor, and turned an inherited BRCA mutation from a risk factor into a drug target, including after surgery in breast cancer."},{"id":"talazoparib","kind":"drug","name":"Talazoparib","route":"/drugs/talazoparib/","status":"approved","tldr":"Talazoparib is a PARP inhibitor that traps PARP on DNA about 100 times more strongly than olaparib, which is why it works at a 1 mg daily dose. It is approved for germline BRCA-mutant HER2-negative breast cancer and, with enzalutamide, for HRR-mutant castration-resistant prostate cancer; anaemia is its dominant side effect."},{"id":"keynote-355","kind":"trial","name":"KEYNOTE-355","route":"/trials/keynote-355/","status":"positive","tldr":"Established immunotherapy plus chemotherapy as first-line treatment for metastatic triple-negative breast cancer with PD-L1 expression."},{"id":"ascent","kind":"trial","name":"ASCENT","route":"/trials/ascent/","status":"positive","tldr":"The trial that proved a TROP2 ADC could nearly double survival in heavily pretreated triple-negative breast cancer."}],"trials":[{"id":"impassion130","name":"IMpassion130","route":"/trials/impassion130/","outcomes":[{"endpoint":"Progression-free survival, PD-L1+ (SP142 IC ≥1%)","primary":true,"unit":"months","arms":[{"name":"Atezolizumab + nab-paclitaxel","n":185,"value":7.5},{"name":"Placebo + nab-paclitaxel","n":184,"value":5}],"hr":0.62,"ci":[0.49,0.78],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1809615"},{"endpoint":"Overall survival, PD-L1+","unit":"months","arms":[{"name":"Atezolizumab + nab-paclitaxel","value":25.4,"note":"Not formally tested under the hierarchical design"},{"name":"Placebo + nab-paclitaxel","value":17.9}],"hr":0.67,"ci":[0.53,0.86],"source":"https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30689-8/fulltext"},{"endpoint":"Overall survival, ITT","unit":"months","arms":[{"name":"Atezolizumab + nab-paclitaxel","value":21,"note":"Not significant"},{"name":"Placebo + nab-paclitaxel","value":18.7}],"hr":0.87,"ci":[0.75,1.02],"source":"https://doi.org/10.1056/NEJMoa1809615"}],"setting":"First-line metastatic TNBC: atezolizumab + nab-paclitaxel","enrolled":902,"enrolledBasis":"registry"},{"id":"keynote-355","name":"KEYNOTE-355","route":"/trials/keynote-355/","outcomes":[{"endpoint":"Overall survival, PD-L1 CPS ≥10","primary":true,"unit":"months","arms":[{"name":"Pembrolizumab + chemotherapy","n":220,"value":23},{"name":"Placebo + chemotherapy","n":103,"value":16.1}],"hr":0.73,"ci":[0.55,0.95],"p":"0.0185","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2202809"},{"endpoint":"Progression-free survival, PD-L1 CPS ≥10","primary":true,"unit":"months","arms":[{"name":"Pembrolizumab + chemotherapy","value":9.7},{"name":"Placebo + chemotherapy","value":5.6}],"hr":0.66,"ci":[0.5,0.88],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2202809"},{"endpoint":"Overall survival, CPS ≥1","unit":"months","arms":[{"name":"Pembrolizumab + chemotherapy","value":17.6,"note":"Not significant"},{"name":"Placebo + chemotherapy","value":16}],"hr":0.86,"ci":[0.72,1.04],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2202809"}],"setting":"First-line metastatic TNBC: pembrolizumab + chemotherapy vs chemotherapy","enrolled":882,"enrolledBasis":"registry"},{"id":"ascent","name":"ASCENT","route":"/trials/ascent/","outcomes":[{"endpoint":"Progression-free survival (patients without brain metastases)","primary":true,"unit":"months","arms":[{"name":"Sacituzumab govitecan","n":235,"value":5.6},{"name":"Chemotherapy (TPC)","n":233,"value":1.7}],"hr":0.41,"ci":[0.32,0.52],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2028485"},{"endpoint":"Overall survival","unit":"months","arms":[{"name":"Sacituzumab govitecan","value":12.1},{"name":"Chemotherapy (TPC)","value":6.7}],"hr":0.48,"ci":[0.38,0.59],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2028485"},{"endpoint":"Objective response rate","unit":"%","arms":[{"name":"Sacituzumab govitecan","value":35},{"name":"Chemotherapy (TPC)","value":5}],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2028485"}],"setting":"Pretreated metastatic TNBC: sacituzumab govitecan vs chemotherapy","enrolled":529,"enrolledBasis":"registry"}],"papers":[]},{"era":"2021-2022","title":"Curative setting transformed","description":"KEYNOTE-522 makes chemo-immunotherapy the standard for stage II-III; OlympiA adds adjuvant olaparib for gBRCA. DESTINY-Breast04 makes HER2-low TNBC eligible for T-DXd.","status":"historic","refs":[{"id":"keynote-522","kind":"trial","name":"KEYNOTE-522","route":"/trials/keynote-522/","status":"positive","tldr":"The trial that added immunotherapy to pre-surgery chemotherapy for triple-negative breast cancer and, uniquely, improved survival."},{"id":"olympia","kind":"trial","name":"OlympiA","route":"/trials/olympia/","status":"positive","tldr":"Showed that a year of a PARP inhibitor after standard treatment improves survival in women with inherited BRCA mutations."},{"id":"destiny-breast04","kind":"trial","name":"DESTINY-Breast04","route":"/trials/destiny-breast04/","status":"positive","tldr":"Created a new category of breast cancer, HER2-low, by showing Enhertu works in tumours previously called HER2-negative."}],"trials":[{"id":"keynote-522","name":"KEYNOTE-522","route":"/trials/keynote-522/","outcomes":[{"endpoint":"Pathologic complete response (ypT0/Tis ypN0)","primary":true,"unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","n":401,"value":64.8},{"name":"Placebo + chemotherapy","n":201,"value":51.2}],"p":"0.00055","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1910549"},{"endpoint":"Event-free survival at 5 years","primary":true,"unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","n":784,"value":81.2},{"name":"Placebo + chemotherapy","n":390,"value":72.2}],"hr":0.65,"ci":[0.51,0.83],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2409932"},{"endpoint":"Overall survival at 5 years","unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","value":86.6},{"name":"Placebo + chemotherapy","value":81.7}],"hr":0.66,"ci":[0.5,0.87],"p":"0.002","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2409932"},{"endpoint":"Event-free survival at 7 years","unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","value":78.3},{"name":"Placebo + chemotherapy","value":69.8}],"source":"https://www.lbbc.org/news/pivotal-progress-in-tnbc-asco-2026"},{"endpoint":"Overall survival at 7 years","unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","value":85.1},{"name":"Placebo + chemotherapy","value":77.2}],"source":"https://www.lbbc.org/news/pivotal-progress-in-tnbc-asco-2026"}],"setting":"Early-stage (II-III) TNBC: pembrolizumab + chemotherapy before surgery, pembrolizumab after","enrolled":1174,"enrolledBasis":"registry"},{"id":"olympia","name":"OlympiA","route":"/trials/olympia/","outcomes":[{"endpoint":"Invasive disease-free survival at 3 years","primary":true,"unit":"%","arms":[{"name":"Olaparib","n":921,"value":85.9},{"name":"Placebo","n":915,"value":77.1}],"hr":0.58,"ci":[0.41,0.82],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2105215"},{"endpoint":"Overall survival at 4 years","unit":"%","arms":[{"name":"Olaparib","value":89.8},{"name":"Placebo","value":86.4}],"hr":0.68,"ci":[0.47,0.97],"p":"0.009","source":"https://www.annalsofoncology.org/article/S0923-7534(22)04165-7/fulltext"},{"endpoint":"Overall survival at 6 years","unit":"%","arms":[{"name":"Olaparib","value":87.5},{"name":"Placebo","value":83.2}],"hr":0.72,"ci":[0.56,0.93],"source":"https://clinicaltrials.gov/study/NCT02032823"}],"setting":"Adjuvant olaparib for one year in germline BRCA-mutated, HER2-negative, high-risk early breast cancer","enrolled":1837,"enrolledBasis":"registry"},{"id":"destiny-breast04","name":"DESTINY-Breast04","route":"/trials/destiny-breast04/","outcomes":[{"endpoint":"Progression-free survival, HR+ cohort (BICR)","primary":true,"unit":"months","arms":[{"name":"Trastuzumab deruxtecan","n":331,"value":10.1},{"name":"Chemotherapy (TPC)","n":163,"value":5.4}],"hr":0.51,"ci":[0.4,0.64],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2203690"},{"endpoint":"Overall survival, all patients","unit":"months","arms":[{"name":"Trastuzumab deruxtecan","n":373,"value":23.4},{"name":"Chemotherapy (TPC)","n":184,"value":16.8}],"hr":0.64,"ci":[0.49,0.84],"p":"0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2203690"},{"endpoint":"Progression-free survival, HR-negative (TNBC) cohort","unit":"months","arms":[{"name":"Trastuzumab deruxtecan","n":40,"value":8.5,"note":"Exploratory cohort"},{"name":"Chemotherapy (TPC)","n":18,"value":2.9}],"hr":0.46,"ci":[0.24,0.89],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2203690"}],"setting":"HER2-low metastatic breast cancer after chemotherapy: T-DXd vs chemotherapy","enrolled":557,"enrolledBasis":"registry"}],"papers":[]},{"era":"2024-2026","title":"ADCs move to first line; bispecific ADC succeeds","description":"KEYNOTE-522 OS benefit confirmed. ASCENT-03/04 and TROPION-Breast02 read out positive, bringing first-line approvals for sacituzumab govitecan and Dato-DXd (2026). Iza-bren posts a positive phase 3 (2026). TIL-based de-escalation in stage I gains evidence.","status":"current","refs":[{"id":"ascent-03","kind":"trial","name":"ASCENT-03","route":"/trials/ascent-03/","status":"positive","tldr":"Moved Trodelvy into first-line use for triple-negative patients who cannot receive immunotherapy."},{"id":"ascent-04","kind":"trial","name":"ASCENT-04 / KEYNOTE-D19","route":"/trials/ascent-04/","status":"positive","tldr":"Showed that pairing an ADC with immunotherapy beats chemotherapy plus immunotherapy in first-line PD-L1-positive TNBC."},{"id":"tropion-breast02","kind":"trial","name":"TROPION-Breast02","route":"/trials/tropion-breast02/","status":"positive","tldr":"The first trial to show an overall survival benefit for a first-line ADC in triple-negative breast cancer."},{"id":"bl-b01d1-307","kind":"trial","name":"BL-B01D1-307","route":"/trials/bl-b01d1-307/","status":"positive","tldr":"The first phase 3 win for a bispecific ADC, in triple-negative breast cancer, announced February 2026."},{"id":"tils","kind":"term","name":"Tumour-infiltrating lymphocytes (TILs)","route":"/terms/tils/","tldr":"Immune cells that have got inside the tumour. More of them means better outcomes in triple-negative breast cancer."}],"trials":[{"id":"ascent-03","name":"ASCENT-03","route":"/trials/ascent-03/","outcomes":[{"endpoint":"Progression-free survival (BICR)","primary":true,"unit":"months","arms":[{"name":"Sacituzumab govitecan","n":279,"value":9.7},{"name":"Chemotherapy (TPC)","n":279,"value":6.9}],"hr":0.62,"ci":[0.5,0.77],"p":"<0.0001","source":"https://dailyreporter.esmo.org/esmo-congress-2025/breast-cancer/survival-improvements-observed-with-first-line-antibody-drug-conjugates-in-triple-negative-breast-cancer"},{"endpoint":"Objective response rate","unit":"%","arms":[{"name":"Sacituzumab govitecan","value":48},{"name":"Chemotherapy (TPC)","value":44}]},{"endpoint":"Overall survival","unit":"months","arms":[{"name":"Sacituzumab govitecan","note":"Immature at the primary analysis; crossover to sacituzumab permitted on progression."},{"name":"Chemotherapy (TPC)"}]}],"setting":"First-line metastatic TNBC, not candidates for PD-1 inhibitors: sacituzumab govitecan vs chemotherapy","enrolled":558,"enrolledNote":"ClinicalTrials.gov lists 623 participants (actual); the NEJM 2025 primary analysis covered 558 randomised patients.","enrolledBasis":"randomised"},{"id":"ascent-04","name":"ASCENT-04 / KEYNOTE-D19","route":"/trials/ascent-04/","outcomes":[{"endpoint":"Progression-free survival (BICR)","primary":true,"unit":"months","arms":[{"name":"Sacituzumab govitecan + pembrolizumab","n":221,"value":11.2},{"name":"Chemotherapy + pembrolizumab","n":222,"value":7.8}],"hr":0.65,"ci":[0.51,0.84],"p":"0.0009","source":"https://dailyreporter.esmo.org/esmo-congress-2025/breast-cancer/survival-improvements-observed-with-first-line-antibody-drug-conjugates-in-triple-negative-breast-cancer"},{"endpoint":"Objective response rate","unit":"%","arms":[{"name":"Sacituzumab govitecan + pembrolizumab","value":60},{"name":"Chemotherapy + pembrolizumab","value":53}],"source":"https://doi.org/10.1056/NEJMoa2508959"},{"endpoint":"Overall survival","unit":"months","arms":[{"name":"Sacituzumab govitecan + pembrolizumab","note":"Immature; PFS2 favoured the ADC arm in the ASCO 2026 update."},{"name":"Chemotherapy + pembrolizumab"}],"source":"https://doi.org/10.1056/NEJMoa2508959"}],"setting":"First-line PD-L1+ (CPS ≥10) metastatic TNBC: sacituzumab govitecan + pembrolizumab vs chemotherapy + pembrolizumab","enrolled":443,"enrolledBasis":"registry"},{"id":"tropion-breast02","name":"TROPION-Breast02","route":"/trials/tropion-breast02/","outcomes":[{"endpoint":"Progression-free survival (BICR)","primary":true,"unit":"months","arms":[{"name":"Datopotamab deruxtecan","n":323,"value":10.8},{"name":"Chemotherapy (ICC)","n":321,"value":5.6}],"hr":0.57,"ci":[0.47,0.69],"p":"<0.0001","source":"https://www.annalsofoncology.org/article/S0923-7534(26)00130-4/fulltext"},{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"Datopotamab deruxtecan","value":23.7},{"name":"Chemotherapy (ICC)","value":18.7}],"hr":0.79,"ci":[0.64,0.98],"p":"0.0291","source":"https://www.astrazeneca.com/media-centre/press-releases/2025/datroway-demonstrated-an-unprecedented-median-overall-survival-improvement-of-five-months-vs-chemotherapy-as-1st-line-treatment-for-patients-with-metastatic-triple-negative-breast-cancer-for-whom-immunotherapy-was-not-an-option-in-tropion-breast02.html"}],"setting":"First-line metastatic TNBC, not candidates for PD-1/PD-L1: Dato-DXd vs chemotherapy","enrolled":644,"enrolledBasis":"registry"},{"id":"bl-b01d1-307","name":"BL-B01D1-307","route":"/trials/bl-b01d1-307/","outcomes":[{"endpoint":"Progression-free survival (BICR)","primary":true,"unit":"months","arms":[{"name":"Izalontamab brengitecan","n":207,"value":8.5},{"name":"Chemotherapy (TPC)","n":211,"value":3.1}],"hr":0.29,"ci":[0.22,0.38],"p":"<0.0001","source":"https://www.onclive.com/view/iza-bren-yields-pfs-and-os-benefits-vs-chemo-in-previously-treated-advanced-tnbc"},{"endpoint":"Overall survival (interim, median follow-up 11 months)","primary":true,"unit":"months","arms":[{"name":"Izalontamab brengitecan","value":15.9},{"name":"Chemotherapy (TPC)","value":12.5}],"hr":0.6,"ci":[0.42,0.85],"p":"0.0019","source":"https://www.onclive.com/view/iza-bren-yields-pfs-and-os-benefits-vs-chemo-in-previously-treated-advanced-tnbc"},{"endpoint":"Confirmed objective response rate (BICR)","unit":"%","arms":[{"name":"Izalontamab brengitecan","value":51.7},{"name":"Chemotherapy (TPC)","value":20.5}]}],"setting":"Previously treated locally advanced or metastatic TNBC: izalontamab brengitecan vs chemotherapy","enrolled":418,"enrolledBasis":"registry"}],"papers":[]},{"era":"2026-2029","title":"Next: residual disease, de-escalation, selection","description":"OptimICE-pCR (omit adjuvant pembrolizumab after pCR), SCARLET (drop anthracycline), ctDNA-guided escalation for RCB II-III, ADCs in the post-neoadjuvant setting, sac-TMT and TROPION-Breast05 first-line readouts, IZABRIGHT-Breast01, TROP2 PET.","status":"emerging","refs":[{"id":"optimice-pcr","kind":"trial","name":"OptimICE-pCR (A012103)","route":"/trials/optimice-pcr/","status":"recruiting","tldr":"Asks whether patients whose cancer completely disappeared before surgery still need a year of immunotherapy afterwards."},{"id":"scarlet-s2212","kind":"trial","name":"SCARLET (SWOG S2212)","route":"/trials/scarlet-s2212/","status":"recruiting","tldr":"Tests whether the anthracycline can be dropped from TNBC pre-surgery treatment without losing effect."},{"id":"tropion-breast05","kind":"trial","name":"TROPION-Breast05","route":"/trials/tropion-breast05/","status":"recruiting","tldr":"Tests whether Dato-DXd plus a PD-L1 blocker beats today's immunotherapy-chemotherapy standard."},{"id":"izabright-breast01","kind":"trial","name":"IZABRIGHT-Breast01","route":"/trials/izabright-breast01/","status":"recruiting","tldr":"IZABRIGHT-Breast01 is the global first-line trial of the EGFR×HER3 bispecific ADC in triple-negative breast cancer."},{"id":"sacituzumab-tirumotecan","kind":"drug","name":"Sacituzumab tirumotecan","route":"/drugs/sacituzumab-tirumotecan/","status":"approved","tldr":"Sacituzumab tirumotecan is Kelun-Biotech's TROP2 ADC, approved in China in 2024 for pretreated triple-negative breast cancer and then EGFR-mutant lung cancer. Merck holds rights outside Greater China and runs the TroFuse programme of more than ten phase 3 trials across breast, lung, endometrial and cervical cancer; in the US it holds a priority voucher but no approval yet."},{"id":"trop2-pet","kind":"technology","name":"TROP2 PET","route":"/technologies/trop2-pet/","status":"phase-1","tldr":"An experimental PET scan that shows whether a tumour carries the TROP2 protein, so doctors could pick the right ADC before giving it."},{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/","status":"established","tldr":"An ultra-sensitive blood test after surgery that detects leftover cancer months before a scan would."}],"trials":[],"papers":[]},{"era":"2029+","title":"Speculative: cure for most, control for the rest","description":"Neoadjuvant ADC + IO replacing anthracyclines; personalised vaccines in the adjuvant setting for high-risk residual disease; payload-switching ADC algorithms guided by PET and ctDNA; mesenchymal-subtype-specific therapy; brain-penetrant ADCs.","status":"speculative","refs":[{"id":"neoantigen-mrna-vaccine","kind":"technology","name":"Personalised neoantigen (mRNA) vaccines","route":"/technologies/neoantigen-mrna-vaccine/","status":"phase-3","tldr":"A vaccine made for one patient, encoding the unique mutations in their own tumour, to train the immune system to hunt it."},{"id":"dual-payload-adc","kind":"technology","name":"Dual-payload ADC","route":"/technologies/dual-payload-adc/","status":"phase-1","tldr":"A dual-payload ADC is an ADC carrying two different poisons at once, so the tumour cannot escape by becoming resistant to one."},{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/","tldr":"How a cancer cell changes shape to migrate and to shrug off drugs. Transcription factors like ZEB1 and SNAIL loosen the cell, switch on pumps that eject chemotherapy, and hide it from the immune system."},{"id":"idea-post-neoadjuvant-adc","kind":"idea","name":"ADC for residual disease after KEYNOTE-522","route":"/ideas/idea-post-neoadjuvant-adc/","tldr":"Patients whose TNBC survives chemo-immunotherapy before surgery have a high relapse risk. Give them an ADC after surgery."}],"trials":[],"papers":[]}],"watch":[]}