{"entity":{"id":"pdl1-high-nsclc","kind":"cancer","name":"PD-L1-high non-small-cell lung cancer without a driver mutation","aka":["PD-L1 50 percent or more NSCLC","PD-L1-high lung cancer","Driver-negative PD-L1-high non-small-cell lung cancer","Immunotherapy-eligible lung cancer"],"tldr":"Lung cancers that carry a lot of PD-L1 and no targetable mutation can be treated with an immunotherapy antibody alone instead of chemotherapy. Pembrolizumab keeps about a third of patients alive at five years, roughly double what chemotherapy achieved, and adding chemotherapy is reserved for those who need a fast response.","summary":"PD-L1 on tumour cells switches off the T cells that would attack them, and the level of expression, measured by immunohistochemistry as the tumour proportion score, was the first biomarker for checkpoint inhibitors in lung cancer. KEYNOTE-024 (2016) randomised 305 patients with untreated advanced non-small-cell lung cancer, PD-L1 of 50 percent or more and no EGFR or ALK alteration to pembrolizumab or platinum chemotherapy: progression-free survival was 10.3 versus 6.0 months, median overall survival 26.3 versus 13.4 months, and 31.9 percent of pembrolizumab patients were alive at five years against 16.3 percent, despite most of the chemotherapy arm crossing over. The FDA approved first-line pembrolizumab monotherapy in October 2016, the first time a checkpoint inhibitor replaced chemotherapy first line in a common cancer.\n\nKEYNOTE-042 (2019) extended monotherapy to PD-L1 of 1 percent or more but showed the gain came from the high expressers; IMpower110 (atezolizumab, 2020) and EMPOWER-Lung 1 (cemiplimab, 2021) reproduced the result with other PD-1 and PD-L1 antibodies, and nivolumab plus ipilimumab (CheckMate 227) offered a chemotherapy-free doublet. For patients with bulky or symptomatic disease pembrolizumab plus platinum doublet (KEYNOTE-189 for non-squamous, KEYNOTE-407 for squamous) gives higher response rates and is the alternative, with no randomised evidence that it prolongs survival over monotherapy in this group. Squamous and non-squamous tumours are treated alike when PD-L1 is high, apart from the chemotherapy partner.\n\nThe next generation is trying to beat pembrolizumab directly. Ivonescimab, a PD-1 and VEGF bispecific antibody, beat pembrolizumab on progression-free survival in PD-L1-positive patients in the Chinese HARMONi-2 trial (11.1 versus 5.8 months, hazard ratio 0.51), and HARMONi-3 is the global confirmation with chemotherapy; TROP2 antibody-drug conjugates with pembrolizumab (TROPION-Lung08) and TIGIT antibodies have been tested with mixed results. Open questions are who can stop immunotherapy after two years, how to treat the half of patients who progress within a year, and whether PD-L1 will be replaced by better predictors.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/PD-L1","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/PD-L1"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":[],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","bispecific-antibody","adc","companion-diagnostic"],"targets":["pd1","pdl1","ctla4","vegf","trop2"],"drugs":["pembrolizumab","cemiplimab","atezolizumab","nivolumab","ipilimumab","ivonescimab","carboplatin","pemetrexed","paclitaxel","docetaxel","ramucirumab","ventana-pd-l1-sp142"],"companies":["merck","regeneron","sanofi","roche-genentech","bms","akeso","summit-therapeutics"],"institutions":[],"pathways":["pd1-checkpoint","nsclc-signalling"],"terms":["tps","pd-l1-testing","immuno-oncology","immune-checkpoint","maintenance-therapy"],"trials":["keynote-024-189","keynote-042","empower-lung-1","harmoni-2","harmoni-3","nct05215340","tropion-lung01","nct05502237","lung-map-s1800a"],"people":["martin-reck","roy-herbst","tony-mok","julie-brahmer","solange-peters"],"bottlenecks":[],"keyPapers":["paper-keynote-024-nejm-2016","paper-keynote-189-nejm-2018","paper-keynote-001-pembrolizumab-nsclc-nejm-2015","paper-harmoni-2-lancet-2025"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"About a quarter to a third of advanced non-small-cell lung cancers express PD-L1 on 50 percent or more of tumour cells, and most of these lack an EGFR, ALK or other targetable driver; they occur mainly in current or former smokers with adenocarcinoma or squamous histology.","subtypes":["PD-L1-high adenocarcinoma without a driver (pembrolizumab, cemiplimab or atezolizumab alone, or with platinum-pemetrexed)","PD-L1-high squamous cell carcinoma (monotherapy or with carboplatin-paclitaxel)","PD-L1-high disease with STK11 or KEAP1 co-mutation (poorer immunotherapy response)","PD-L1-high disease with bulky or symptomatic tumour (chemoimmunotherapy for a faster response)"],"biomarkers":["PD-L1 tumour proportion score by immunohistochemistry (22C3, SP263, SP142) on tissue","Absence of EGFR, ALK, ROS1, RET, BRAF, MET, HER2, KRAS G12C and NTRK alterations on a broad panel","STK11 and KEAP1 co-mutations (prognostic)","Tumour mutational burden (of limited use)","Thyroid function, liver enzymes, cortisol and glucose for immune-related adverse events"],"standardOfCare":[{"setting":"Advanced, first line, PD-L1 50 percent or more","approach":"Pembrolizumab alone (KEYNOTE-024, KEYNOTE-042), cemiplimab alone (EMPOWER-Lung 1) or atezolizumab alone; pembrolizumab plus platinum doublet for bulky or symptomatic disease; nivolumab plus ipilimumab as a chemotherapy-free alternative.","refs":["pembrolizumab","keynote-024-189","keynote-042","cemiplimab","empower-lung-1","atezolizumab","nivolumab","ipilimumab","tps","pd-l1-testing"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, first line, PD-L1 1 to 49 percent","approach":"Pembrolizumab plus platinum doublet (KEYNOTE-189, KEYNOTE-407); monotherapy is not recommended below 50 percent.","refs":["pembrolizumab","keynote-024-189","carboplatin","pemetrexed","paclitaxel","pd1-plus-chemo-pdl1-low"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, after progression on immunotherapy","approach":"Platinum doublet if not yet given; docetaxel with or without ramucirumab; clinical trials of antibody-drug conjugates and bispecifics.","refs":["docetaxel","ramucirumab","carboplatin","pemetrexed","tropion-lung01"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Duration and stopping","approach":"Two years of immunotherapy for patients in response, with retreatment at relapse; management of immune-related adverse events by organ.","refs":["pembrolizumab","checkpoint-inhibitor","immuno-oncology"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Pembrolizumab alone: five-year survival 31.9 percent versus 16.3 percent with chemotherapy in KEYNOTE-024.","Three antibodies (pembrolizumab, cemiplimab, atezolizumab) approved as monotherapy in PD-L1-high disease.","Ivonescimab beat pembrolizumab on progression-free survival in HARMONi-2; global confirmation awaited.","Two-year fixed duration with retreatment at relapse."],"history":[{"year":2015,"title":"KEYNOTE-001: PD-L1 expression predicts pembrolizumab response in lung cancer","refs":["pembrolizumab","paper-keynote-001-pembrolizumab-nsclc-nejm-2015","tps"]},{"year":2016,"title":"KEYNOTE-024: pembrolizumab alone beats chemotherapy in PD-L1-high disease; first-line approval","refs":["keynote-024-189","pembrolizumab","martin-reck","paper-keynote-024-nejm-2016"]},{"year":2018,"title":"KEYNOTE-189 and KEYNOTE-407: pembrolizumab plus chemotherapy for all PD-L1 levels","refs":["keynote-024-189","pembrolizumab","paper-keynote-189-nejm-2018"]},{"year":2019,"title":"KEYNOTE-042: monotherapy label widened to PD-L1 of 1 percent or more, benefit concentrated at 50 percent or more","refs":["keynote-042","pembrolizumab","tony-mok"]},{"year":2021,"title":"EMPOWER-Lung 1: cemiplimab approved in PD-L1-high disease","refs":["empower-lung-1","cemiplimab"]},{"year":2024,"title":"HARMONi-2: ivonescimab beats pembrolizumab on progression-free survival in China","refs":["harmoni-2","ivonescimab","paper-harmoni-2-lancet-2025","akeso"]}],"pipeline":["harmoni-3","ivonescimab","nct05215340","tropion-lung01","datopotamab-deruxtecan","nct05502237","sacituzumab-tirumotecan","idea-bio2-ctdna-six-week-io-switch"],"openProblems":["Half of PD-L1-high patients progress within a year and have no predictor to identify them in advance.","Whether adding chemotherapy to a checkpoint inhibitor prolongs survival in PD-L1-high disease has never been tested in a randomised trial.","The two-year stopping rule rests on trial design rather than evidence, and the safe minimum duration is unknown.","Ivonescimab's advantage over pembrolizumab has been shown only in China and only on progression-free survival so far."],"parent":"nsclc"},"route":"/cancers/pdl1-high-nsclc/","neighbours":{"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"bispecific-antibody","kind":"technology","name":"Bispecific antibodies","route":"/technologies/bispecific-antibody/"},{"id":"companion-diagnostic","kind":"technology","name":"Companion diagnostics","route":"/technologies/companion-diagnostic/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"}],"target":[{"id":"ctla4","kind":"target","name":"CTLA-4","route":"/targets/ctla4/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"},{"id":"trop2","kind":"target","name":"TROP2","route":"/targets/trop2/"},{"id":"vegf","kind":"target","name":"VEGF / VEGFR","route":"/targets/vegf/"}],"drug":[{"id":"atezolizumab","kind":"drug","name":"Atezolizumab","route":"/drugs/atezolizumab/"},{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"cemiplimab","kind":"drug","name":"Cemiplimab","route":"/drugs/cemiplimab/"},{"id":"datopotamab-deruxtecan","kind":"drug","name":"Datopotamab deruxtecan","route":"/drugs/datopotamab-deruxtecan/"},{"id":"docetaxel","kind":"drug","name":"Docetaxel","route":"/drugs/docetaxel/"},{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/"},{"id":"ivonescimab","kind":"drug","name":"Ivonescimab","route":"/drugs/ivonescimab/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"paclitaxel","kind":"drug","name":"Paclitaxel / nab-paclitaxel","route":"/drugs/paclitaxel/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"pemetrexed","kind":"drug","name":"Pemetrexed","route":"/drugs/pemetrexed/"},{"id":"ramucirumab","kind":"drug","name":"Ramucirumab","route":"/drugs/ramucirumab/"},{"id":"sacituzumab-tirumotecan","kind":"drug","name":"Sacituzumab tirumotecan","route":"/drugs/sacituzumab-tirumotecan/"},{"id":"ventana-pd-l1-sp142","kind":"drug","name":"VENTANA PD-L1 (SP142) Assay","route":"/drugs/ventana-pd-l1-sp142/"}],"company":[{"id":"akeso","kind":"company","name":"Akeso","route":"/companies/akeso/"},{"id":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/"},{"id":"merck","kind":"company","name":"Merck & Co. (MSD)","route":"/companies/merck/"},{"id":"regeneron","kind":"company","name":"Regeneron","route":"/companies/regeneron/"},{"id":"roche-genentech","kind":"company","name":"Roche / Genentech","route":"/companies/roche-genentech/"},{"id":"sanofi","kind":"company","name":"Sanofi","route":"/companies/sanofi/"},{"id":"summit-therapeutics","kind":"company","name":"Summit Therapeutics","route":"/companies/summit-therapeutics/"}],"pathway":[{"id":"nsclc-signalling","kind":"pathway","name":"Non-small cell lung cancer (KEGG map)","route":"/pathways/nsclc-signalling/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"}],"term":[{"id":"immune-checkpoint","kind":"term","name":"Immune checkpoint","route":"/terms/immune-checkpoint/"},{"id":"immuno-oncology","kind":"term","name":"Immuno-oncology (IO) and checkpoint blockade","route":"/terms/immuno-oncology/"},{"id":"maintenance-therapy","kind":"term","name":"Maintenance therapy","route":"/terms/maintenance-therapy/"},{"id":"pd-l1-testing","kind":"term","name":"PD-L1 expression testing (22C3, SP142, SP263)","route":"/terms/pd-l1-testing/"},{"id":"tps","kind":"term","name":"Tumour proportion score (TPS)","route":"/terms/tps/"}],"trial":[{"id":"nct06698042","kind":"trial","name":"A Clinical Study of Pembrolizumab (+) Berahyaluronidase Alfa (MK-3475A) to Treat Newly-diagnosed Metastatic Non-small Cell Lung Cancer (MK-3475A-F84)","route":"/trials/nct06698042/"},{"id":"nct06868277","kind":"trial","name":"A Global Phase III Study of Rilvegostomig or Pembrolizumab Monotherapy for First-Line Treatment of PD-L1-high Metastatic Non-small Cell Lung Cancer","route":"/trials/nct06868277/"},{"id":"nct05047250","kind":"trial","name":"A Study of Atezolizumab in High PD-L1 Expression, Chemotherapy-Naïve Patients With Stage IV Non-Squamous or Squamous Non-Small Cell Lung Cancer","route":"/trials/nct05047250/"},{"id":"nct06472076","kind":"trial","name":"A Study of Belrestotug Plus Dostarlimab Compared With Placebo Plus Pembrolizumab in Previously Untreated Participants With Programmed Death Ligand 1 (PD-L1) High Non-small-cell Lung Cancer (NSCLC)","route":"/trials/nct06472076/"},{"id":"nct06644768","kind":"trial","name":"A Study of Valemetostat Tosylate Plus Pembrolizumab Versus Pembrolizumab Alone in First-Line NSCLC Without Actionable Genomic Alterations","route":"/trials/nct06644768/"},{"id":"nct07361510","kind":"trial","name":"A Study to Evaluate the Efficacy of Pumitamig Versus Pembrolizumab in Participants With Previously Untreated Advanced Non-Small Cell Lung Cancer and P","route":"/trials/nct07361510/"},{"id":"nct05785767","kind":"trial","name":"A Study to Learn if a Combination of Fianlimab and Cemiplimab Versus Cemiplimab Alone is More Effective for Adult Participants With Advanced Non-Small","route":"/trials/nct05785767/"},{"id":"nct05557591","kind":"trial","name":"A Trial to Learn How the Cancer Vaccine BNT116 in Combination With Cemiplimab Works and How Safe the Combination is in Adults With Advanced Non-small ","route":"/trials/nct05557591/"},{"id":"nct06767514","kind":"trial","name":"Clinical Study of Ivonescimab for First-line Treatment of Metastatic NSCLC Patients With High PD-L1","route":"/trials/nct06767514/"},{"id":"empower-lung-1","kind":"trial","name":"EMPOWER-Lung 1","route":"/trials/empower-lung-1/"},{"id":"harmoni-2","kind":"trial","name":"HARMONi-2","route":"/trials/harmoni-2/"},{"id":"harmoni-3","kind":"trial","name":"HARMONi-3","route":"/trials/harmoni-3/"},{"id":"keynote-024-189","kind":"trial","name":"KEYNOTE-024 & KEYNOTE-189","route":"/trials/keynote-024-189/"},{"id":"keynote-042","kind":"trial","name":"KEYNOTE-042","route":"/trials/keynote-042/"},{"id":"lung-map-s1800a","kind":"trial","name":"Lung-MAP S1800A: ramucirumab plus pembrolizumab","route":"/trials/lung-map-s1800a/"},{"id":"nct06162572","kind":"trial","name":"Phase 1b/2 Platform Study of Select Immunotherapy Combinations in Participants With Advanced Non-small Cell Lung Cancer (NSCLC)","route":"/trials/nct06162572/"},{"id":"nct06357533","kind":"trial","name":"Phase III, Open-label, Study of First-line Dato-DXd in Combination With Rilvegostomig for Advanced Non-squamous NSCLC With High PD-L1 Expression (TC ≥","route":"/trials/nct06357533/"},{"id":"nct06170788","kind":"trial","name":"Sacituzumab Tirumotecan (MK-2870) in Combination With Pembrolizumab Versus Pembrolizumab Alone in Metastatic Non-small Cell Lung Cancer (NSCLC) With P","route":"/trials/nct06170788/"},{"id":"nct04736173","kind":"trial","name":"Study Evaluating Effectiveness and Safety of Zimberelimab and Domvanalimab in Lung Cancer","route":"/trials/nct04736173/"},{"id":"nct05215340","kind":"trial","name":"Study of Dato-DXd Plus Pembrolizumab vs Pembrolizumab Alone in the First-line Treatment of Subjects With Advanced or Metastatic NSCLC Without Actionab","route":"/trials/nct05215340/"},{"id":"nct03003962","kind":"trial","name":"Study of Durvalumab Alone or Chemotherapy for Patients With Advanced Non Small-Cell Lung Cancer (PEARL)","route":"/trials/nct03003962/"},{"id":"nct05609968","kind":"trial","name":"Study of Pembrolizumab (MK-3475) Monotherapy Versus Sacituzumab Govitecan in Combination With Pembrolizumab for Participants With Metastatic Non-small Cell Lung Cancer (NSCLC) With Programmed Cell Death Ligand 1 (PD-L1) Tumor Proportion Score (TPS) ≥50% (MK-3475-D46)","route":"/trials/nct05609968/"},{"id":"nct06758401","kind":"trial","name":"This is a Study to Learn About How the Combination of the Study Medicines Sigvotatug Vedotin Plus Pembrolizumab Works in People With Non-small Cell Lu","route":"/trials/nct06758401/"},{"id":"tropion-lung01","kind":"trial","name":"TROPION-Lung01","route":"/trials/tropion-lung01/"},{"id":"nct05502237","kind":"trial","name":"Zimberelimab and Domvanalimab in Combination With Chemotherapy Versus Pembrolizumab With Chemotherapy in Patients With Untreated Metastatic Non-Small Cell Lung Cancer","route":"/trials/nct05502237/"}],"person":[{"id":"julie-brahmer","kind":"person","name":"Julie R. Brahmer","route":"/people/julie-brahmer/"},{"id":"martin-reck","kind":"person","name":"Martin Reck","route":"/people/martin-reck/"},{"id":"roy-herbst","kind":"person","name":"Roy S. Herbst","route":"/people/roy-herbst/"},{"id":"solange-peters","kind":"person","name":"Solange Peters","route":"/people/solange-peters/"},{"id":"tony-mok","kind":"person","name":"Tony S. K. Mok","route":"/people/tony-mok/"}],"paper":[{"id":"paper-harmoni-2-lancet-2025","kind":"paper","name":"HARMONi-2: ivonescimab, a PD-1 x VEGF bispecific, beats pembrolizumab head-to-head in PD-L1-positive lung cancer","route":"/key-papers/paper-harmoni-2-lancet-2025/"},{"id":"paper-keynote-001-pembrolizumab-nsclc-nejm-2015","kind":"paper","name":"KEYNOTE-001 (Garon 2015): pembrolizumab in non-small-cell lung cancer and the 50% PD-L1 cut-off","route":"/key-papers/paper-keynote-001-pembrolizumab-nsclc-nejm-2015/"},{"id":"paper-keynote-024-nejm-2016","kind":"paper","name":"KEYNOTE-024: pembrolizumab alone beats chemotherapy in PD-L1-high lung cancer","route":"/key-papers/paper-keynote-024-nejm-2016/"},{"id":"paper-keynote-189-nejm-2018","kind":"paper","name":"KEYNOTE-189: pembrolizumab plus chemotherapy as first treatment for non-squamous lung cancer without a driver mutation","route":"/key-papers/paper-keynote-189-nejm-2018/"}],"idea":[{"id":"idea-bio2-ctdna-six-week-io-switch","kind":"idea","name":"Use a blood test at six weeks to decide whether to keep going","route":"/ideas/idea-bio2-ctdna-six-week-io-switch/"}],"pairing":[{"id":"pd1-plus-chemo-pdl1-low","kind":"pairing","name":"PD-1 blockade + chemotherapy in PD-L1-low NSCLC","route":"/pairings/pd1-plus-chemo-pdl1-low/"}],"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}]}}