Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006.

BACKGROUND

Antitumor activity of ipilimumab or BRAF ± MEK inhibitors (BRAFi ± MEKi) following pembrolizumab administration in melanoma is poorly characterized.

PATIENTS AND METHODS

In the phase III KEYNOTE-006 study, patients with unresectable stage III/IV melanoma received pembrolizumab (10 mg/kg) once every 2 or 3 weeks (Q3W) or ipilimumab (3 mg/kg) Q3W. The current post hoc analysis evaluates outcomes with ipilimumab or BRAFi ± MEKi as first subsequent systemic therapy after pembrolizumab administration and includes patients who completed or discontinued pembrolizumab after one or more dose. Pembrolizumab arms were pooled.

RESULTS

At data cut-off (4 December 2017), median follow-up was 46.9 months. Of 555 pembrolizumab-treated patients, first subsequent therapy was ipilimumab for 103 (18.6%) and BRAFi ± MEKi for 59 (10.6%) [33 received BRAFi + MEKi, 26 BRAFi alone; 37 (62.7%) were BRAFi ± MEKi naïve]. In the subsequent ipilimumab group, ORR with previous pembrolizumab was 17.5% [1 complete response (CR); 17 partial response (PR)]; 79.6% had discontinued pembrolizumab due to progressive disease (PD); median overall survival (OS) was 21.5 months. ORR with subsequent ipilimumab was 15.5%; 11/16 responses (8 CRs; 3 PRs) were ongoing. ORR with subsequent ipilimumab was 9.7% for patients with PD as best response to pembrolizumab. Median OS from ipilimumab initiation was 9.8 months. In the subsequent BRAFi ± MEKi group, ORR with previous pembrolizumab was 13.5% (8 PR); 76.3% had discontinued pembrolizumab due to PD; median OS was 17.9 months. ORR with subsequent BRAFi ± MEKi was 30.5%, 7/18 responses (4 CR, 3 PR) were ongoing. Median OS from BRAFi ± MEKi initiation was 12.9 months. ORR for BRAFi ± MEKi-naïve patients who received subsequent BRAFi ± MEKi was 43.2%; 6/16 were ongoing (3 CR, 3 PR).

CONCLUSIONS

Ipilimumab and BRAFi ± MEKi have antitumor activity as first subsequent therapy after pembrolizumab in patients with advanced melanoma.

Informations de copyright

Copyright © 2022 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA, The Author(s). Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Disclosure GVL reports having consultant/advisory roles with Aduro Biotech Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG, Highlight Therapeutics S.L., Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDx B.V., Specialised Therapeutics Australia Pty Ltd, and Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA (MSD). AA reports having received research funding from MSD; having consultant/advisory/speaker roles with Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, and Roche; and receiving personal fees from Amgen and Sanofi. LM reports having a Medical Board role with MSD. PL reports having advisory roles with Amgen, Bristol Myers Squibb, MSD, Nektar, Novartis, and Pierre Fabre; having speaker roles with Bristol Myers Squibb, MSD, Novartis, and Pierre Fabre; having received funding for travel from Bristol Myers Squibb and MSD; and having received research funding from Bristol Myers Squibb. CB reports having received grants paid to his institute from 4SC, AstraZeneca, Bristol Myers Squibb, Genmab, GlaxoSmithKline, Eli Lilly, MSD, Novartis, Pfizer, Roche, Pierre Fabre, and Third Rock Ventures; having received research funding paid to his institute from Bristol Myers Squibb, NanoString and Novartis; and stock ownership in ImmageneBV and Uniti Cars. PM reports having received research grants from Bristol Myers Squibb and MSD; board membership for Bristol Myers Squibb, GlaxoSmithKline, Merck Germany, MSD, Novartis, Pierre Fabre, and Sanofi; and having speaker roles with Bristol Myers Squibb, GlaxoSmithKline, MSD, Novartis, Pierre Fabre, Roche, and Sanofi. JS reports having received personal fees from Bristol Myers Squibb, MSD, and Novartis. JJG reports having advisory roles for Bristol Myers Squibb, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, and Sun Pharma; having speaker roles for MSD, Novartis, and Pierre Fabre; and having received travel funding from Bristol Myers Squibb, MSD, Novartis, and Pierre Fabre. ML reports receiving speaker honoraria from Bristol Myers Squibb, Medison, Novartis, and Roche. MRM reports having received grants paid to his institution from AstraZeneca, GlaxoSmithKline, and Roche; having received funding for study fees paid to his institution from BioLineRx, Bristol Myers Squibb, Immunocore, Millennium, MSD, Novartis, Pfizer, Regeneron, and Replimune; having advisory roles with BioLineRx, Bristol Myers Squibb, Immunocore, Kineta, MSD, Novartis, Replimune, and Silicon Therapeutics; having received personal fees for drug development advice from GlaxoSmithKline; having received funding for travel from MSD; and being a member of an Independent Data Safety Monitoring Committee for MSD. BN reports having received a research grant paid to his institution and personal fees from Novartis and having received personal fees paid to his institution from Bristol Myers Squibb. AR reports having received honoraria for consulting from Amgen, Chugai, Merck, Novartis, Nurix, Sanofi, and Vedanta; being a past or present Scientific Advisory Board member and stock holder for 4C Biomed, Advaxis, Apricity, Arcus, Compugen, CytomX, Five Prime, Highlight, ImaginAb, Isoplexis, Kite-Gilead, Lutris Pharma, MapKure, Merus, PACT Pharma, RAPT, Rgenix, and Tango Therapeutics; and having received research grants paid to his institution from Agilent and Bristol Myers Squibb. EW reports having received personal fees from Novartis. MSC reports having a consulting/advisory role with Amgen, Bristol Myers Squibb, Eisai, IDEAYA, Merck Serono, MSD, Nektar, Novartis, OncoSec, Pierre Fabre, Regeneron, Roche, Sanofi, and QBiotics; and having received honorarium from Bristol Myers Squibb, MSD, and Novartis. CL reports having received grants from Bristol Myers Squibb and Roche; having received funding for travel/accommodation/expenses from Bristol Myers Squibb and MSD; having received honoraria from Bristol Myers Squibb, MSD, Novartis, Amgen, Roche, Pierre-Fabre, Pfizer, and Incyte; having a consultancy role with Bristol Myers Squibb, MSD, Novartis, Amgen, Roche, and Sanofi; receiving speaker bureau fees from Bristol Myers Squibb, Novartis, Amgen, and Roche; having advisory roles with Bristol Myers Squibb, MSD, Novartis, and Roche; serving on advisory boards for Bristol Myers Squibb, MSD, Novartis, Amgen, and Roche; and serving on the Board for Avantis Medical Systems. MS reports having consulting/advisory roles with AbbVie, Adaptimmune, Agenus, Alligator, Apexigen, Array, Boehringer-Ingelheim, Bristol Myers Squibb, Dragonfly, EvolveImmune, Genmab, Genentech/Roche, Genocea, Idera, Immunocore, BioNTech, Innate, Incyte, Jazz Pharmaceuticals, Eli Lilly, Molecular Partners, MSD, Nektar, NewLink Genetics, NextCure, Numab, OncoHost, OncoSec, Pfizer, Pieris, Pierre Fabre, Regeneron, Repertoire, Rubius, Seattle Genetics, Servier, Simcha, Tessa, Trillium, and Verastem; and holding stock/other ownership interests in Actym, Adaptive Biotechnologies, Amphivena, EvolveImmune, Intensity Therapeutics, GlaxoSmithKline, Johnson and Johnson, OncoHost, NextCure, and Repertoire. EJ is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. MAL is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and is a shareholder in Merck & Co., Inc., Kenilworth, NJ, USA. NI is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and is a shareholder in Merck & Co., Inc., Kenilworth, NJ, USA. CR reports having consulting/advisory roles with Amgen, Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi, and AstraZeneca. NS has declared no conflicts of interest. Data sharing Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD) 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. MSD 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 MSD data sharing website (available at: 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 MSD 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 MSD before data access is granted. Data will be made available for request after product approval in the USA and European Union or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country 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 MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD 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 is uploaded to an analysis portal so that the requestor can perform the proposed analyses.