Abstract
Although pembrolizumab confers clinical benefit in non-small cell lung cancer (NSCLC), only a subset of patients will respond due to a heterogenous tumor microenvironment. KEYNOTE-495/KeyImPaCT is an ongoing biomarker-directed, adaptively randomized phase 2 study investigating first-line pembrolizumab (200 mg every 3 weeks) + lenvatinib (20 mg daily), anti-CTLA-4 quavonlimab (25 mg every 6 weeks) or anti-LAG-3 favezelimab (200 mg or 800 mg every 3 weeks) in advanced NSCLC. Patients were categorized by T-cell-inflamed gene expression profile (TcellinfGEP) and tumor mutational burden (TMB) status and randomly assigned 1:1:1 to receive pembrolizumab + lenvatinib, pembrolizumab + quavonlimab or pembrolizumab + favezelimab. The primary outcome was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 using pre-specified efficacy thresholds for each biomarker-defined subgroup (>5% (TcellinfGEPlowTMBnon-high (group I)), >20% (TcellinfGEPlowTMBhigh (group II) and TcellinfGEPnon-lowTMBnon-high (group III)) and >45% (TcellinfGEPnon-lowTMBhigh (group IV))). Secondary outcomes were progression-free survival, overall survival and safety. At data cutoff, ORR ranges were 0–12.0% in group I, 27.3–33.3% in group II, 13.6–40.9% in group III and 50.0–60.0% in group IV. ORR with pembrolizumab + lenvatinib in group III met the pre-specified efficacy threshold. The safety profile of each treatment arm was consistent with the known safety profile of each combination. These data demonstrate the feasibility of prospective TcellinfGEP and TMB assessment to study the clinical activity of first-line pembrolizumab-based combination therapies in advanced NSCLC. ClinicalTrials.gov registration: NCT03516981.
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Merck Sharp & Dohme, LLC, a subsidiary of Merck & Co., Inc., is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. Merck Sharp & Dohme is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The Merck Sharp & Dohme data-sharing website (http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of Merck Sharp & Dohme subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with Merck Sharp & Dohme before data access is granted. Data will be made available for request after product approval in the United States and European Union or after product development is discontinued. There are circumstances that may prevent Merck Sharp & Dohme from sharing requested data, including country-specific or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and Merck Sharp & Dohme subject matter experts. After approval of the statistical analysis plan and execution of a data-sharing agreement, Merck Sharp & Dohme will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that are uploaded to an analysis portal so that the requestor can perform the proposed analyses.
References
Bristol Myers Squibb. OPDIVO (nivolumab) injection, for intravenous use (US prescribing information). https://packageinserts.bms.com/pi/pi_opdivo.pdf (2022).
Genentech. TECENTRIQ (atezolizumab) injection, for intravenous use (US prescribing information). https://www.gene.com/download/pdf/tecentriq_prescribing.pdf (2022).
Merck. KEYTRUDA (pembrolizumab) injection, for intravenous use. (US prescribing information). https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf (2023).
Mok, T. S. K. et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 393, 1819–1830 (2019).
Gandhi, L. et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med. 378, 2078–2092 (2018).
Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).
Cristescu, R. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018).
Ayers, M. et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127, 2930–2940 (2017).
Ott, P. A. et al. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J. Clin. Oncol. 37, 318–327 (2019).
Cristescu, R. et al. Transcriptomic determinants of response to pembrolizumab monotherapy across solid tumor types. Clin. Cancer Res. 28, 1680–1689 (2022).
Herbst, R. S. et al. Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials. Ann. Oncol. 30, LBA79 (2019).
Aurora-Garg, D. et al. Large-scale evaluation of concordance of genomic scores in whole exome sequencing and foundation medicine comprehensive genomic platform across cancer types. J. Immunother. Cancer 7, 172 (2019).
Keefer, L. A. et al. Automated next-generation profiling of genomic alterations in human cancers. Nat. Commun. 13, 2830 (2022).
Paz-Ares, L. et al. Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) for metastatic NSCLC: tissue TMB (tTMB) and outcomes in KEYNOTE-021, 189, and 407. Ann. Oncol. 30, LBA80 (2019).
Perets, R. et al. Safety and efficacy of quavonlimab, a novel anti-CTLA-4 antibody (MK-1308), in combination with pembrolizumab in first-line advanced non-small-cell lung cancer. Ann. Oncol. 32, 395–403 (2020).
Taylor, M. H. et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J. Clin. Oncol. 38, 1154–1163 (2020).
Garralda, E. et al. A phase 1 first-in-human study of the anti-LAG-3 antibody MK4280 (favezelimab) plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer. J. Clin. Oncol. 39, 3584–3584 (2021).
Hellmann, M. D. et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med. 381, 2020–2031 (2019).
Hellmann, M. D. et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).
Cristescu, R. et al. Association between tumor mutational burden (TMB) assessed by whole-exome sequencing (WES) and outcomes of pembrolizumab (pembro) monotherapy. Cancer Res. 80, LB-261 (2020).
Herbst, R. S., Morgensztern, D. & Boshoff, C. The biology and management of non-small cell lung cancer. Nature 553, 446–454 (2018).
Wang, M., Herbst, R. S. & Boshoff, C. Toward personalized treatment approaches for non-small-cell lung cancer. Nat. Med. 27, 1345–1356 (2021).
Garralda, E. et al. A first-in-human study of the anti-LAG-3 antibody favezelimab plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer. ESMO Open 6, 100639 (2022).
Acknowledgements
Funding for this research was provided by Merck Sharp & Dohme, LLC, a subsidiary of Merck & Co., Inc. The authors thank M. Ayers and E. J. Dettman at Merck & Co., Inc. for their contributions. Medical writing and/or editorial assistance was provided by M. Aggarwal and H. C. Cappelli of ApotheCom. This assistance was funded by Merck Sharp & Dohme, LLC,a subsidiary of Merck & Co., Inc.
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M.D.H., M.A.G., C.A., D.S.W.T., J.C.-H.Y., E.B.G., A.B., H.M., R.C., L.F., A.S., J.Y. and R.S.H. contributed to the conception, design or planning of the study. W.-S. L., M.D.H., C.A., D.S.W.T., E.F., J.W.Y.C., J.-S.L., E.B.G., G.F., A.L., A.B., A.S., J.Y. and R.S.H. acquired the data. M.G., M.D.H., C.A., D.S.W.T., J.-S.L., A.B., J.K., J.P., R.C., A.S., J.Y. and R.S.H. analyzed the data. M.G., M.D.H., C.A., D.S.W.T., J.C.-H.Y., E.B.G., M.-J.A., A.B., J.K., J.P., R.C., L.F., A.S., J.Y. and R.S.H. interpreted the data. G.A.L., A.B., J.K., J.P. and R.S.H. contributed to the drafting of the manuscript. All authors critically reviewed or revised the manuscript for important intellectual content.
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M.G. reports a speaker role with Guardant Health; a consultant role with Cellularity; and stocks/shares with COTA. M.D.H. reports grants from Bristol Myers Squibb; personal fees from Achilles, Adagene, Adicet, Arcus, AstraZeneca, Blueprint, Bristol Myers Squibb, DaVolterra, Eli Lilly, Genentech/Roche, Genzyme/Sanofi, Janssen, Immunai, Instil Bio, Mana Therapeutics, Merck, Mirati, Natera, Pact Pharma, Shattuck Labs and Regeneron; and equity options from Factorial, Immunai, Shattuck Labs, Arcus and Avail Bio. A patent filed by Memorial Sloan Kettering related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) is pending and licensed by Personal Genome Diagnostics. Subsequent to the completion of this work, M.D.H. began as an employee (and equity holder) at AstraZeneca. M.A.G. reports funding to institution from Amgen, Celgene, Johnson & Johnson, Merck, Novartis, Oncomed and Trizill and personal financial interests in AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Guardant Health, iTeos, Surface and Genzyme/Sanofi. C.A. reports consulting or advisory roles with Genentech, Eli Lilly, Celgene, Merck, AstraZeneca, Blueprint Genetics, Shionogi, Daiichi Sankyo, Regeneron, Sanofi, Eisai, Beigene, Turning Point, Pfizer, Janssen and Boehringer Ingelheim and research funding to institution from Genentech, Roche, Incyte, Macrogenics, Merck Sharp & Dohme and AstraZeneca/MedImmune. D.S.W.T. reports consultancy with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, DKSH, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche and Takeda and grant/research support from ACM Biolabs, Amgen, AstraZeneca and Pfizer. E.F. reports roles on advisory boards for Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Merck Serono, Novartis, Peptomyc, Pfizer, Sanofi and Takeda; speaker roles with Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffman-La Roche, Janssen, Medscape, Merck Sharp & Dohme, Peervoice, Pfizer, Medical Trends, Merck Serono, Sanofi, Takeda and TouchOncology; research funding from Merck KGaA and Fundacion Merck Salud; and independent fees from Grifols. J.C.-H.Y. reports personal fees and other from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono Pharmaceuticals, Pfizer, Roche/Genentech, Takeda Oncology, Yuhan Pharmaceuticals, Johnson & Johnson, Puma Technology, Gilead and GlaxoSmithKline. E.B.G. reports consultant and/or advisor roles for ABL-Bio, AstraZeneca, AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi and Xilio and grand/research support from ABL-Bio, AstraZeneca, Bristol Myers Squibb, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon and Novartis. A.B., J.K., H.M., J.P., R.C. and J.Y. report employment and stock ownership at Merck Sharp & Dohme. H.M. and A.S. were previously employed by and report stock ownership at Merck Sharp & Dohme. L.F. has received research support from Roche/Genentech, AbbVie, Bavarian Nordic, Bristol Myers Squibb, Dendreon, Janssen, Merck and Partner Therapeutics and served on the scientific advisory boards of Actym, Alector, AstraZeneca, Atreca, Bioalta, Bolt, Bristol Myers Squibb, Daiichi Sankyo, Immunogenesis, Innovent, Merck, Merck KGaA, Nutcracker, RAPT, Scribe, Senti, Soteria, Sutro and Roche/Genentech. R.S.H. reports consulting roles with AbbVie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Biodesix, Bolt Biotherapeutics, Bristol Myers Squibb, Cybrexa Therapeutics, eFFECTOR Therapeutics, Eli Lilly, EMD Serono, Genentech/Roche, Genmab, Halozyme Therapeutics, Heat Biologics, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Loxo Oncology, Merck, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Oncternal Therapeutics, Pfizer, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, STCube Pharmaceuticals, Symphogen, Takeda, Tesaro, Tocagen and WindMIL Therapeutics; advisory board roles with AstraZeneca, Bolt Biotherapeutics, Cybrexa Therapeutics, EMD Serono, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Neon Therapeutics, Novartis and STCube Pharmaceuticals; research support from AstraZeneca, Eli Lilly, Genentech/Roche and Merck; and non-executive board membership for Junshi Pharmaceuticals and Immunocore. W.-S.L., J.W.Y.C., J.-S.L., G.F., M.-J.A., A.L. and G.A.L. have no competing interests to report. Funding for this research was provided by Merck Sharp & Dohme. The funder participated in study design, data analysis and interpretation and manuscript writing and maintained the study database. All authors had full access to the data and had final responsibility for the decision to submit the manuscript for publication.
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Extended data
Extended Data Fig. 1
Drug exposure by biomarker subgroup in the pembrolizumab plus lenvatinib (n = 80) (a), pembrolizumab plus quavonlimab (n = 82) (b), pembrolizumab plus favezelimab 200-mg (n = 30) (c), and pembrolizumab plus favezelimab 800-mg (n = 51) (d) treatment arms.
Extended Data Fig. 2 Confirmed ORR per RECIST v1.1 as assessed by single TMB status (N = 243) (a) and PD-L1 statusa (n = 233) (b).
aPD-L1 immunohistochemistry was done centrally or locally; PD-L1 status was missing for 10 patients (two in the pembrolizumab plus lenvatinib arm; five in the pembrolizumab plus quavonlimab arm; one in the pembrolizumab plus favezelimab 200-mg arm; and two in the pembrolizumab plus favezelimab 800-mg arm). ORR, objective response rate; PD-L1, programmed death ligand 1; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1; TMB, tumor mutational burden. Data are presented as percentage values with 95% confidence intervals.
Extended Data Fig. 3 Confirmed ORR per RECIST v1.1 as assessed by dual TMB and PD-L1 statusa (n = 233).
aPD-L1 immunohistochemistry was done centrally or locally; PD-L1 status was missing for 10 patients (two in the pembrolizumab plus lenvatinib arm; five in the pembrolizumab plus quavonlimab arm; one in the pembrolizumab plus favezelimab 200-mg arm; and two in the pembrolizumab plus favezelimab 800-mg arm). ORR, objective response rate; PD-L1, programmed death ligand 1; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1; TMB, tumor mutational burden. Data are presented as percentage values with 95% confidence intervals.
Extended Data Fig. 4 Distribution of TcellinfGEP by PD-L1 status (n = 233).
TcellinfGEP, T-cell–inflamed gene-expression profile; PD-L1, programmed death ligand 1; TPS, tumor proportion score.
Extended Data Fig. 5 Decision algorithm of the Bayesian adaptive design.
The cutoff of −0.16 was used to define TcellinfGEPnon-low and TcellinfGEPlow and the cutoff of 5 mutations/megabase on the Personal Genome Diagnostics Inc. panel (equivalent to 10 mutations/megabase on FoundationOne®CDx) was used to define TMBhigh and TMBnon-high. Group I represents TcellinfGEPlowTMBnon-high, Group II represents TcellinfGEPlowTMBhigh, Group III represents TcellinfGEPnon-lowTMBnon-high, and Group IV represents TcellinfGEPnon-lowTMBhigh. FA, final analysis; IA, interim analysis; ORR, objective response rate; TcellinfGEP, T-cell–inflamed gene-expression profile; TMB, tumor mutational burden.
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Supplementary Table 1 and redacted protocol.
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Gutierrez, M., Lam, WS., Hellmann, M.D. et al. Biomarker-directed, pembrolizumab-based combination therapy in non-small cell lung cancer: phase 2 KEYNOTE-495/KeyImPaCT trial interim results. Nat Med 29, 1718–1727 (2023). https://doi.org/10.1038/s41591-023-02385-6
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DOI: https://doi.org/10.1038/s41591-023-02385-6
