Long-term outcomes in patients with advanced melanoma who had initial stable disease with pembrolizumab in KEYNOTE-001 and KEYNOTE-006

Abstract

Objective: Patients with melanoma and early stable disease (SD) with pembrolizumab have unclear prognosis. We present post hoc analyses of long-term outcomes for patients with early SD, partial response (PR) or complete response (CR) with pembrolizumab.

Patients and methods: Patients who received pembrolizumab in the KEYNOTE-001 and KEYNOTE-006 studies and had SD, PR or CR at weeks 12 or 24 were included.

Results: Of 294 patients in the week 12 analysis, 107 (36.4%) had SD at week 12, of whom 7 (6.5%) had a best overall response of CR, 43 (40.2%) had PR and 57 (53.3%) had SD. Forty-eight-month overall survival (OS) rates were 95.2%, 73.0% and 47.7%, respectively, for patients with CR, PR and SD at week 12. Similar results were observed in the 241 patients in the week 24 analysis. Forty-eight-month OS rates were 72.1% for patients with SD at week 12 followed by subsequent response and 75.0% for patients with PR at week 12 followed by no change in response or progression. Thirty-six-month and 48-month OS rates were 11.6% and not reached, respectively, for patients with SD at week 12 followed by progression before week 24.

Conclusions: A substantial proportion of patients (46.7%) with early (week 12) SD with pembrolizumab achieved subsequent PR or CR. Patients with SD at week 12 and subsequent CR/PR had similar survival to those who maintained PR. In contrast, patients with SD at week 12 and subsequent progression had poor survival outcomes. These findings may guide treatment decisions for patients achieving early SD.

Trial registration: Clinicaltrials.gov: NCT01295827 (KEYNOTE-001); NCT01866319 (KEYNOTE-006).

Keywords: Melanoma; PD-1; Pembrolizumab; Programmed death 1.

Conflict of interest statement

Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: O.H. is a consultant advisor for Aduro, Akeso, Amgen, Array, BeiGene, BMS, Genentech, GSK, Immunocore, Incyte, Janssen, Merck, NextCure, Novartis, Sanofi, Regeneron, Seattle Genetics, Tempus and Zelluna. He is a speaker for Array, BMS, Novartis, Pfizer, Sanofi and Regeneron. He has contracted research for his institution from Aduro, Akeso, Amgen, Arcus, Array, BMS, CytomX, Exelixis, Genentech, GSK, Immunocore, Incyte, Io-vance, Merck, Merck Serono, Moderna, NextCure, Novartis, Regeneron, Sanofi, Seattle Genetics, Torque and Zelluna. S.J.D., B.H.M. and E.J. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and S.J.D. owns stock in Merck & Co., Inc., Kenilworth, NJ, USA. A.A. is a consultant advisor for Amgen, BMS, Merck, Novartis, Pierre Fabre, Roche, Sanofi and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. M.S.C. is a consultant advisor for Amgen, BMS, Eisai, IDEAYA, MSD, Merck Serono, Nektar, Novartis, Pierre Fabre, QBiotics, OncoSec, Regeneron, Roche and Sanofi. He has also received honoraria from BMS, MSD and Novartis. T.M. has served on advisory boards for Merck, BMS and OncoSec. A.D. has received grants from BMS, Merck, Pfizer/Array and Xencor. He also served on an advisory board meeting for Xencor. J.J.G. has served on advisory boards for BMS, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi and Sun Pharma. He has also received personal fees from BMS, MSD, Novartis and Pierre Fabre for travel as well as personal fees for serving as a speaker for MSD, Novartis and Pierre Fabre. P.H. has no disclosures to report. F.S.H. is a consultant advisor for Aduro, Bristol Myers Squibb, Eisai, EMD Serono, Genentech/Roche, Idera, Merck, Novartis, Pieris Pharmaceutical, Sanofi and Takeda. He reports grants and royalties paid to his institution by Bristol Myers Squibb and Novartis, as well as personal fees from Gossamer. He also holds equity in Apricity, Bicara, Pionyr and Torque. He has served on advisory boards for Apricity, Bicara, Bioentre, Checkpoint Therapeutics, Compass Therapeutics, Iovance, Pionyr, Surface and Torque. His pending patents include Methods for Treating MICA-Related Disorders (#20100111973; includes royalties), Angiopoietin-2 Biomarkers Predictive of Anti-Immune Checkpoint Response (#20170248603), Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma Using PD-L1 Isoforms (#20160340407), Therapeutic Peptides (#20160046716, #20140004112, #20170022275, #20170008962), Methods of Using Pembrolizumab and Trebananib and Anti-Galectin Antibody Biomarkers Predictive of Anti-Immune Checkpoint and Anti-Angiogenesis Responses (#20170343552). He has been issued patents for Tumor Antigens and Uses Thereof (#7250291), Therapeutic Peptides (#9402905), Vaccine Compositions and Methods for Restoring NKG2D Pathway Function Against Cancers (#10279021) and Antibodies that Bind to MHC Class I Polypeptide-Related Sequence A (#10106611). A.M.J. has received institutional support from MSD. L.M. has no disclosures to report. A.R. is a consultant for Amgen, Chugai, Merck, Novartis, Nurix, Sanofi and Vedanta. He is a current scientific advisory board member and stockholder in 4C Biomed, Apricity, Arcus, Compugen, Highlight, ImaginAb, Isoplexis, Lutris Pharma, MapKure, Merus, PACT Pharma, Rgenix and Tango Therapeutics and is a past scientific advisory board member and stockholder in Advaxis, Cytomx, Five Prime, Kite-Gilead and RAPT. He has also received grants paid to his institution from Agilent and Bristol Myers Squibb. C.R. is a consultant advisor for Amgen, AstraZeneca, BMS, Merck, MSD, Novartis, Pierre Fabre, Roche and Sanofi. J.S. has no disclosures to report. J.S.W. has received grants paid to his institution from Merck. He has been issued a PD-1 biomarker patent with Biodesix unrelated to the submitted work. J.D.W. is a non-compensated consultant for Merck. He is also a consultant for Amgen, Apricity, Arsenal IO, Ascentage Pharma, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chugai, Eli Lilly, Elucida, F Star, Georgiamune, Imvaq, Kyowa Hakko Kirin, Linneaus, Merck, Neon Therapeutics, Polynoma, Psioxus, Recepta, Sellas, Serametrix, Surface Oncology, Syndax, Syntalogic, Takara Bio, Tizona Pharmaceuticals, Trieza, Truvax and Werewolf Therapeutics. He reports equity in Adaptive Biotech, Apricity, Arsenal IO, Belgene, Georgiamune, Imvaq, Linneaus and Tizona Pharmaceuticals. He has received research grants from Bristol Myers Squibb and Sephora. He has licensed patents for xenogeneic DNA vaccines (Merial; includes royalties), a myeloid-derived suppressor cell (MDSC) assay (Serametrix; includes royalties), an anti–PD-1 antibody (Agenus), anti-CTLA4 antibodies (Agenus) and anti-GITR antibodies and method of use thereof (Agenus/Incyte). He has also been issued patents for alphavirus replicon particles expressing Newcastle disease viruses for cancer therapy, phosphatidylserine targeting agents and uses thereof for adoptive T-cell therapies, immunosuppressive follicular help-like T cells modulated by immune checkpoint blockade, identifying and treating subjects at risk for checkpoint blockade therapy–associated colitis, CAR+ T cells targeting differentiation antigens as means to treat cancer, anti-CD40 agonist mAB fused to monophosphoryl lipid A (MPL) for cancer therapy and engineered vaccinia viruses for cancer immunotherapy. G.V.L. is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexel AG, Highlight Therapeutics S.L., Merck Sharp & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V., and Specialised Therapeutics Australia Pty Ltd.

Copyright © 2021 Merck Sharp & Dohme Corp., The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1.

Subsequent response for patients with SD, PR or CR at week 12 in the week 12 analysis population. Response was assessed by independent central review in KEYNOTE-001 and in KEYNOTE-006. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Fig. 2.

Kaplan-Meier estimates of OS (A) by week 12 response in the week 12 analysis population.a (B) by week 24 response in the week 24 analysis population.b CR, complete response; OS, overall survival; PR, partial response; SD, stable disease. aOS rate from week 12. bOS rate from week 24.

Fig. 3.

Kaplan-Meier estimate of OS from week 12 by subsequent response in patients with PR or SD at week 12 in the week 12 analysis population. CR, complete response; OS, overall survival; PR, partial response; SD, stable disease. aAll patients with CR at week 12 for whom data were available continued to have CR at weeks 18 and 24. bPatients had PR at week 12 and no subsequent change in response and no progression at week 18 or 24.