# No one can predict who responds to immunotherapy

Source: https://onco.cc/bottlenecks/b-immunotherapy-response/  
OnCo record `b-immunotherapy-response` (Bottleneck). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Checkpoint drugs cure some patients and do nothing for most. We still cannot tell the two apart before treating.

## Summary

PD-L1 immunohistochemistry, tumour mutational burden and mismatch-repair deficiency are the approved selection biomarkers for checkpoint inhibitors, and all are imperfect: PD-L1-negative patients respond, PD-L1-high patients progress, TMB thresholds vary by tumour type and assay, and only dMMR/MSI-high is a strong discriminator. As a result checkpoint inhibitors are given to nearly half of US patients with cancer while an estimated one in eight benefits, at a cost of tens of billions of dollars and a burden of immune-related adverse events in non-responders. Better predictors will need to integrate the tumour (antigenicity, interferon signalling, antigen presentation), the microenvironment (T-cell infiltration, myeloid state), the host (HLA genotype, microbiome) and early on-treatment dynamics (ctDNA clearance, CD8 PET, radiomics). The regulatory and reimbursement systems also need to accept biomarkers that deselect patients, which no sponsor is motivated to develop.

## Fields

- Kind: Bottleneck
- Last checked: 2026-09-08
- Stage: biology
- Severity: major
- Metrics: US patients with cancer eligible for checkpoint inhibitors vs estimated responders (2018): 43.6% eligible, 12.5% respond (Haslam & Prasad, JAMA Network Open 2019); Objective response rate to pembrolizumab vs chemotherapy in untreated NSCLC selected by PD-L1 TPS 50% or more (KEYNOTE-024): even the best-selected group has a majority of non-responders: 44.8% vs 27.8% (Reck et al., NEJM 2016)
- Causes: Response depends on several partly independent axes (antigenicity, T-cell infiltration, antigen presentation, host factors) that no single marker captures.; PD-L1 expression is heterogeneous, dynamic and measured with several non-interchangeable assays and cut-offs.; TMB is a proxy for neoantigen load that ignores immunogenicity and antigen presentation.; Sponsors are not rewarded for developing biomarkers that shrink the eligible population.; Early on-treatment signals (ctDNA, imaging) are rarely used to stop ineffective therapy.

## Sources

- Haslam & Prasad (JAMA Network Open 2019): https://doi.org/10.1001/jamanetworkopen.2019.2535
- Cristescu et al., Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy (Science 2018): https://doi.org/10.1126/science.aar3593
- Hirsch et al., Blueprint PD-L1 IHC assay comparison project (JTO 2017): https://doi.org/10.1016/j.jtho.2016.11.2228

## Connected records

- ideas: [A single calibrated tumour mutational burden across all sequencing panels](https://onco.cc/ideas/idea-tr2-tmb-calibration-standard/), [Antibodies that see mutant KRAS and p53 fragments displayed on the cell surface](https://onco.cc/ideas/idea-bio1-pmhc-bispecifics-public-drivers/), [Capture diet, fibre and antibiotic exposure in every immunotherapy pivotal trial](https://onco.cc/ideas/idea-nl-diet-covariates-io-trials/), [CD8 PET to stop or switch immunotherapy early](https://onco.cc/ideas/idea-cd8-pet-io/), [Check whether a tumour can still show itself to the immune system](https://onco.cc/ideas/idea-bio2-antigen-presentation-triage/), [Clear the suppressive neutrophils out of pancreatic tumours first](https://onco.cc/ideas/idea-bio2-cxcr2-neutrophil-blockade/), [De-acidify the tumour so T cells can work in it](https://onco.cc/ideas/idea-bio2-lactate-acid-axis/), [Grow immune command posts inside tumours](https://onco.cc/ideas/idea-bio2-tertiary-lymphoid-induction/), [Grow tumour organoids together with the patient's own immune cells](https://onco.cc/ideas/idea-bio1-organoid-immune-coculture/), [Humanised mice with an immune system matched to the tumour donor](https://onco.cc/ideas/idea-bio1-immune-matched-humanised-mice/), [Make every cold tumour hot: a coordinated programme to reprogramme immune-excluded tumours](https://onco.cc/ideas/idea-moon-cold-to-hot-programme/), [Map which tumour clones sit next to which immune cells before choosing therapy](https://onco.cc/ideas/idea-bio1-spatial-clone-immune-map/), [One digital PD-L1 scale that maps across all the competing assays](https://onco.cc/ideas/idea-tr2-pdl1-digital-calibration/), [Patient-level multimodal foundation models for treatment selection](https://onco.cc/ideas/idea-multimodal-foundation-model/), [Personalised cancer vaccines at commodity cost through fully automated manufacturing](https://onco.cc/ideas/idea-moon-neoantigen-vaccines-at-scale/), [Pick the radiation dose that switches the immune alarm on, not off](https://onco.cc/ideas/idea-bio2-radiotherapy-sting-fractionation/), [Pool every immunotherapy trial's biomarker data into one commons](https://onco.cc/ideas/idea-bio2-io-biomarker-data-commons/), [Predict immune side-effects before they happen and pre-empt them](https://onco.cc/ideas/idea-moon-irae-prediction-and-prevention/), [Protect the gut flora of patients about to start immunotherapy](https://onco.cc/ideas/idea-bio2-antibiotic-stewardship-io/), [Randomise a cheap antihistamine alongside immunotherapy](https://onco.cc/ideas/idea-reg-antihistamine-plus-io-trial/), [Randomised trials to test whether biomarker-negative patients really do not benefit](https://onco.cc/ideas/idea-tr2-biomarker-negative-arms/), [Reprogramme suppressive macrophages instead of trying to delete them](https://onco.cc/ideas/idea-bio2-trem2-myeloid-reprogramming/), [Select microsatellite stable patients for immunotherapy by a measured immune biomarker, not by how many treatments they have already failed](https://onco.cc/ideas/idea-crc-mss-immunotherapy-by-biomarker-not-by-line/), [Select patients for cell therapy by whether their tumour holds reactive T cells](https://onco.cc/ideas/idea-bio2-til-reactivity-selection/), [Standards for spatial and multiplex tissue biomarkers before they reach the clinic](https://onco.cc/ideas/idea-tr2-spatial-biomarker-standards/), [Take faecal transplant plus immunotherapy to a definitive trial](https://onco.cc/ideas/idea-bio2-fmt-plus-checkpoint-phase3/), [Test a high-fibre diet as an immunotherapy adjunct](https://onco.cc/ideas/idea-bio2-fibre-diet-io-trial/), [Test protein and resistance training during immunotherapy](https://onco.cc/ideas/idea-bio2-protein-plus-training-during-io/), [Time immunotherapy to the moment targeted drugs make tumours visible](https://onco.cc/ideas/idea-bio1-immunopeptidome-timing/), [Treat immunotherapy side-effects without wiping out the response](https://onco.cc/ideas/idea-bio2-steroid-sparing-irae/), [Turn one tumour into a vaccine to treat all the others](https://onco.cc/ideas/idea-bio2-in-situ-vaccination-solid/), [Turn the map of immune cells inside a tumour into a standardised test](https://onco.cc/ideas/idea-bio2-spatial-signature-cdx/), [Unmask hidden antigens with a short epigenetic course before immunotherapy](https://onco.cc/ideas/idea-bio2-epigenetic-priming-cold-tumours/), [Use a blood test at six weeks to decide whether to keep going](https://onco.cc/ideas/idea-bio2-ctdna-six-week-io-switch/), [Use a hypoxia scan to pick patients for adenosine-pathway drugs](https://onco.cc/ideas/idea-bio2-hypoxia-guided-adenosine/), [Use pre-surgery immunotherapy windows as the field's biomarker engine](https://onco.cc/ideas/idea-bio2-neoadjuvant-biomarker-engine/), [Vaccinate against the resistance mutation before it takes over](https://onco.cc/ideas/idea-bio1-resistance-mutation-vaccine/), [Vaccines aimed only at mutations shared by every tumour cell](https://onco.cc/ideas/idea-bio1-clonal-neoantigen-vaccines/), [Watch the immune system's response in the blood three weeks in](https://onco.cc/ideas/idea-bio2-tcr-repertoire-early-readout/)
- roadmaps: [Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation](https://onco.cc/roadmaps/colorectal-roadmap/), [Immunotherapy roadmap: Coley's toxins → checkpoint inhibitors → engineered immunity](https://onco.cc/roadmaps/immunotherapy-roadmap/), [Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/), [Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question](https://onco.cc/roadmaps/pancreatic-roadmap/), [Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch](https://onco.cc/roadmaps/prostate-roadmap/), [Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem](https://onco.cc/roadmaps/tnbc-roadmap/)
- cancers: [Bladder & urothelial cancer](https://onco.cc/cancers/urothelial/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/), [Head and neck squamous cell carcinoma](https://onco.cc/cancers/head-and-neck/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Melanoma](https://onco.cc/cancers/melanoma/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Dietary fibre and the gut microbiome for immunotherapy response](https://onco.cc/technologies/dietary-fibre-microbiome-io/), [Digital pathology & AI](https://onco.cc/technologies/digital-pathology-ai/), [Faecal microbiota transplantation for PD-1 non-responders](https://onco.cc/technologies/fmt-checkpoint-nonresponders/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Immuno-PET](https://onco.cc/technologies/immuno-pet/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Pathology & radiology foundation models](https://onco.cc/technologies/pathology-foundation-model/), [Probiotics, antibiotics and stewardship around immunotherapy](https://onco.cc/technologies/probiotics-antibiotic-stewardship-io/)
- targets: [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/)
- drugs: [Atezolizumab](https://onco.cc/drugs/atezolizumab/), [Durvalumab](https://onco.cc/drugs/durvalumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- companies: [Foundation Medicine (Roche)](https://onco.cc/companies/foundation-medicine/), [Owkin](https://onco.cc/companies/owkin/), [Paige AI](https://onco.cc/companies/paige/), [Tempus AI](https://onco.cc/companies/tempus/)
- terms: [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Combined positive score (CPS)](https://onco.cc/terms/cps/), [Gut microbiome diversity and composition](https://onco.cc/terms/gut-microbiome-diversity/), [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [Immune-related adverse events (irAEs)](https://onco.cc/terms/irae/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/), [Tumour proportion score (TPS)](https://onco.cc/terms/tps/), [Tumour-infiltrating lymphocytes (TILs)](https://onco.cc/terms/tils/)
- trials: [CheckMate 067](https://onco.cc/trials/checkmate-067/), [FMT plus pembrolizumab in anti-PD-1-refractory melanoma (Pittsburgh)](https://onco.cc/trials/fmt-pd1-refractory-melanoma-pitt/), [KEYNOTE-024 & KEYNOTE-189](https://onco.cc/trials/keynote-024-189/), [KEYNOTE-048](https://onco.cc/trials/keynote-048/), [KEYNOTE-177](https://onco.cc/trials/keynote-177/), [MIMic-01: healthy-donor FMT plus anti-PD-1, first-line melanoma](https://onco.cc/trials/mimic-01/)
- key papers: [Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010)](https://onco.cc/key-papers/paper-felip-impower010-adjuvant-atezolizumab-lancet-2021/), [ADRIATIC: durvalumab after chemoradiotherapy for limited-stage small-cell lung cancer](https://onco.cc/key-papers/paper-adriatic-nejm-2024/), [Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC](https://onco.cc/key-papers/paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020/), [Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial](https://onco.cc/key-papers/paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024/), [C-144-01: lifileucel, tumour-infiltrating lymphocytes grown from a patient's own tumour, in melanoma after checkpoint inhibitors have failed](https://onco.cc/key-papers/paper-c-144-01-lifileucel-melanoma-jco-2021/), [Cercek 2022: six months of dostarlimab alone made rectal cancer disappear in every patient with mismatch-repair deficiency](https://onco.cc/key-papers/paper-cercek-dostarlimab-rectal-nejm-2022/), [CheckMate 067 at ten years: nivolumab plus ipilimumab produces long-term survival in half of patients with advanced melanoma](https://onco.cc/key-papers/paper-checkmate-067-10-year-nejm-2025/), [CheckMate 649: nivolumab plus chemotherapy as first treatment for advanced gastric, gastro-oesophageal junction and oesophageal adenocarcinoma](https://onco.cc/key-papers/paper-checkmate-649-lancet-2021/), [CheckMate 816: three cycles of nivolumab plus chemotherapy before lung cancer surgery](https://onco.cc/key-papers/paper-checkmate-816-nejm-2022/), [Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer](https://onco.cc/key-papers/paper-burstein-tnbc-genomic-subtypes-ccr-2015/), [Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN)](https://onco.cc/key-papers/paper-paz-ares-caspian-durvalumab-es-sclc-lancet-2019/), [Estimation of the Percentage of US Patients With Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs](https://onco.cc/key-papers/paper-haslam-jama-netw-open/), [Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer](https://onco.cc/key-papers/paper-spigel-pacific-five-year-survival-jco-2022/), [HARMONi-2: ivonescimab, a PD-1 x VEGF bispecific, beats pembrolizumab head-to-head in PD-L1-positive lung cancer](https://onco.cc/key-papers/paper-harmoni-2-lancet-2025/), [Hodi 2010: ipilimumab, the first checkpoint inhibitor, extends survival in metastatic melanoma](https://onco.cc/key-papers/paper-hodi-ipilimumab-melanoma-nejm-2010/), [IMbrave150: atezolizumab plus bevacizumab replaces sorafenib as first treatment for advanced liver cancer](https://onco.cc/key-papers/paper-imbrave150-nejm-2020/), [Iwai and Honjo: tumours use PD-L1 to escape T cells, and blocking it restores attack](https://onco.cc/key-papers/paper-iwai-pdl1-tumour-escape-pnas-2002/), [KEYNOTE-048: pembrolizumab, alone or with chemotherapy, as first treatment for recurrent or metastatic head and neck cancer](https://onco.cc/key-papers/paper-keynote-048-lancet-2019/), [KEYNOTE-177: pembrolizumab instead of chemotherapy as first treatment for mismatch-repair-deficient metastatic colorectal cancer](https://onco.cc/key-papers/paper-keynote-177-nejm-2020/), [KEYNOTE-189: pembrolizumab plus chemotherapy as first treatment for non-squamous lung cancer without a driver mutation](https://onco.cc/key-papers/paper-keynote-189-nejm-2018/), [KEYNOTE-199: pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer](https://onco.cc/key-papers/paper-antonarakis-keynote-199-pembrolizumab-jco-2020/), [KEYNOTE-522: adding pembrolizumab before and after surgery in early triple-negative breast cancer](https://onco.cc/key-papers/paper-keynote-522-nejm-2022/), [KEYNOTE-942: a personalised mRNA cancer vaccine plus pembrolizumab after melanoma surgery](https://onco.cc/key-papers/paper-keynote-942-lancet-2024/), [KEYNOTE-A18: pembrolizumab with chemoradiotherapy for locally advanced cervical cancer (overall survival)](https://onco.cc/key-papers/paper-keynote-a18-os-lancet-2024/), [KEYNOTE-A18: pembrolizumab with chemoradiotherapy for locally advanced cervical cancer (progression-free survival)](https://onco.cc/key-papers/paper-keynote-a18-pfs-lancet-2024/), [Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ](https://onco.cc/key-papers/paper-le-mmr-deficiency-pd1-nejm-2015/), [Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval](https://onco.cc/key-papers/paper-le-mmr-deficiency-science-2017/), [Leach, Krummel and Allison: releasing the CTLA-4 brake makes mice reject tumours](https://onco.cc/key-papers/paper-leach-allison-ctla4-blockade-science-1996/), [NIAGARA: durvalumab before and after cystectomy for muscle-invasive bladder cancer](https://onco.cc/key-papers/paper-niagara-nejm-2024/), [NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients](https://onco.cc/key-papers/paper-niche-2-nejm-2024/), [PACIFIC: a year of durvalumab after chemoradiotherapy for stage III lung cancer](https://onco.cc/key-papers/paper-pacific-nejm-2017/), [Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy](https://onco.cc/key-papers/paper-cristescu-science/), [PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project](https://onco.cc/key-papers/paper-hirsch-j-thorac-oncol/), [Perioperative durvalumab for resectable non-small-cell lung cancer](https://onco.cc/key-papers/paper-heymach-aegean-perioperative-durvalumab-nejm-2023/), [Perioperative nivolumab and chemotherapy in stage III non-small-cell lung cancer](https://onco.cc/key-papers/paper-provencio-nadim-ii-perioperative-nivolumab-stage-iii-nejm-2023/), [Population-Specific Immunogenomic Alterations in Gallbladder Cancer and Prognostic Significance](https://onco.cc/key-papers/paper-zhu-population-specific-immunogenomics-gallbladder-cancer-mod-pathol-2025/), [Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours](https://onco.cc/key-papers/paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019/), [RELATIVITY-047: relatlimab plus nivolumab, the first LAG-3 checkpoint combination, in untreated advanced melanoma](https://onco.cc/key-papers/paper-relativity-047-nejm-2022/), [RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer](https://onco.cc/key-papers/paper-sethna-rna-neoantigen-vaccine-long-lived-t-cells-nature-2025/), [Rojas 2023: a personalised mRNA vaccine trained T cells against each patient's pancreatic cancer, and those who responded stayed cancer-free longer](https://onco.cc/key-papers/paper-rojas-mrna-neoantigen-vaccine-pancreatic-nature-2023/), [RUBY: dostarlimab with chemotherapy for advanced or recurrent endometrial cancer](https://onco.cc/key-papers/paper-ruby-nejm-2023/), [The mutational landscape of lethal castration-resistant prostate cancer](https://onco.cc/key-papers/paper-grasso-mutational-landscape-lethal-crpc-nature-2012/), [Topalian 2012: the first large trial of a PD-1 antibody shows durable responses across melanoma, lung and kidney cancer](https://onco.cc/key-papers/paper-topalian-anti-pd1-nejm-2012/)
- people: [Michael Bloomberg](https://onco.cc/people/michael-bloomberg/), [Sean Parker](https://onco.cc/people/sean-parker/), [Sharon Belvin](https://onco.cc/people/sharon-belvin/), [Tasuku Honjo](https://onco.cc/people/tasuku-honjo/)
- institutions: [Centre hospitalier de l'Université de Montréal (CHUM)](https://onco.cc/institutions/chum/), [Parker Institute for Cancer Immunotherapy](https://onco.cc/institutions/parker-institute/), [Society for Immunotherapy of Cancer](https://onco.cc/institutions/sitc/), [UVA Comprehensive Cancer Center](https://onco.cc/institutions/uva-cancer-center/)
- pathways: [Cold tumours: immune deserts and exclusion](https://onco.cc/pathways/immune-desert-exclusion/), [T-cell exhaustion](https://onco.cc/pathways/t-cell-exhaustion/)

---
JSON: https://onco.cc/api/v1/entities/b-immunotherapy-response.json