LBA32 - Pembrolizumab versus chemotherapy in microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC): 5-year follow-up of the randomized phase III KEYNOTE-177 study

Background

In the phase 3 KEYNOTE-177 (NCT02563002) study, pembrolizumab (pembro) vs chemotherapy (chemo) improved PFS and showed a trend towards improved OS in MSI-H/dMMR mCRC, supporting pembro as first-line therapy. We report efficacy and safety at 5 yrs of follow-up.

Methods

Patients (pts) aged ≥18 y with untreated MSI-H/dMMR mCRC measurable per RECIST v1.1 and an ECOG PS of 0 or 1 were enrolled. Pts were randomly assigned 1:1 to receive pembro 200 mg Q3W or chemo (mFOLFOX6 or FOLFIRI Q2W ± bevacizumab 5 mg/kg Q2W or cetuximab weekly), IV. Pts assigned to chemo could receive ≤35 cycles of pembro after centrally confirmed progressive disease (PD). End points at 5 y were OS, PFS, DOR, and safety.

Results

At data cutoff (July 17, 2023), median follow-up duration was 73.3 mo (6.1 y; range, 64.9-89.2 mo). Of 153 pts assigned to pembro, all pts received treatment and 59 (38.6%) completed 35 cycles of treatment; 143/154 pts assigned to chemo received treatment. A total of 94 (61.4%) pts in the pembro arm and 143 (100%) in the chemo arm discontinued treatment most commonly due to PD (32.7% and 60.8%, respectively). 57 (37.0%) pts in the chemo arm met the crossover criteria and received pembro; 21 (36.8%) completed 35 cycles of pembro. An additional 39 (25.3%) pts who received chemo received a PD-1/L1 inhibitor off-protocol. Median OS (95% CI) was 77.5 mo (6.5 y; 49.2 mo-not reached) with pembro vs 36.7 mo (3.1 y; 27.6-65.3 mo) with chemo (HR 0.73 [95% CI 0.53,0.99]). The 5 y OS rate was 54.8% in the pembro arm and 44.2% in the chemo arm. The 5 y PFS rate was 34.0% and 7.6%, respectively. Median (range) DOR was 75.4 mo (6.3 y; 2.3+ to 80.1+ mo) with pembro vs 10.6 mo (2.8 to 71.5+ mo) with chemo; 85.7% and 33.6% of pts had DOR ≥24 mo, respectively. Treatment-related adverse events (TRAEs) occurred in 79.7% of pts who received pembro and 98.6% who received chemo; grade 3-5 TRAEs occurred in 21.6% and 67.1% of pts, respectively.

Conclusions

After 5 y of follow-up, responses to pembro were more durable than those from chemo, and the trend towards improved OS with pembro persisted despite an effective crossover rate of 62% in pts with MSI-H/dMMR mCRC.

Clinical trial identification

NCT02563002.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Mehak Aggarwal, PharmD and Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

K. Shiu: Financial Interests, Personal, Invited Speaker, Educational Webinars on CRC and UGI cancer management with immunotherapy: BMS; Financial Interests, Personal, Advisory Board, Advisory Board on Regorafenib for chemorefractory mCRC in readiness for NICE application: Bayer; Financial Interests, Personal, Invited Speaker, Educational webinars on Pembrolizumab for MSI-High CRC, as well as OG cancers: MSD; Financial Interests, Personal, Advisory Board, For Pembrolizumab in CRC of OG cancers pre or NICE application or post NICE approval: MSD; Financial Interests, Personal, Invited Speaker, Webinars on updates on management of mCRC: Merck Serono; Financial Interests, Personal, Advisory Board, On Mirati GI Global Advisory Board: Mirati Therapeutics; Financial Interests, Personal, Invited Speaker, To update company on indications/updates in landscape of immunotherapy and vaccines in GI cancers: Nouscom; Financial Interests, Personal, Advisory Board, Advisory on Cancer of Unknown Primary, new indications of molecular profiling usingFoundation Medicine 1: Roche; Financial Interests, Personal, Advisory Board, Advisory Board on Lonsurf for chemorefractory mCRC in readiness for NICE application: Servier; Financial Interests, Institutional, Local PI, For MATTERHORN Trial: AstraZeneca; Financial Interests, Institutional, Coordinating PI, UK Chief Investigator on KEYNOTE 177, KEYNOTE 859, KEYNOTE 811, LEAP 17, MK1308A-008 trials: MSD; Financial Interests, Institutional, Research Grant, Chief Investigator of investigator initiated, MSD funded NEOPRISM-CRC trial: MSD; Financial Interests, Institutional, Local PI, UCLH PI for LEAP 15 and MK4280A-007 trials: MSD; Financial Interests, Institutional, Coordinating PI, UK Chief Investigator for NOUS209-001 trial: Nouscom; Financial Interests, Institutional, Coordinating PI, UK Chief Investigator for CUPSICO trial: Roche; Financial Interests, Personal, Steering Committee Member, Steering Committee Member of CUPISCO trial: Roche; Non-Financial Interests, Member: ASCO, Association of Cancer Physicians UK. T. André: Financial Interests, Personal, Advisory Board, Advosiry Board on February 12, 2021: Astellas pharma; Financial Interests, Personal, Advisory Board, Advisory Board on February 2021: Kaleido Biosciences; Financial Interests, Personal, Invited Speaker, and advisory board 2021: Amgen; Financial Interests, Personal, Invited Speaker, Ivited speaker in a symposuim december 2020: AstraZeneca; Financial Interests, Personal, Advisory Board, and consultant fees and consultant contract 2021 and 2022: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board, Advisory board in Janaury 2020: Clovis; Financial Interests, Personal, Advisory Board, Advisory board in january 2020: Gritstone Oncology; Financial Interests, Personal, Advisory Board, Advisory board 2020: Haliodx; Financial Interests, Personal, Advisory Board, and consultant fees/consultant contract and invited speaker: MSD Oncology; Financial Interests, Personal, Invited Speaker, and other: Pierre Fabre; Financial Interests, Personal, Invited Speaker, in an symposuim in 2020: Roche; Financial Interests, Personal, Invited Speaker, in a meeting in 2019: Ventana; Financial Interests, Personal, Invited Speaker, In a educational meeting in 2019: Sanofi; Financial Interests, Personal, Advisory Board, in a symposuim in 2020: Servier; Financial Interests, Personal, Advisory Board, Consultant with personnal fees and invited speaker: Servier; Financial Interests, Personal, Advisory Board, in 2019: GSK; Financial Interests, Personal, Invited Speaker, in 2020 and 2021: GSK; Financial Interests, Personal, Invited Speaker, Virtual symposuimLecture: 1 MSI-H CRC: Implementation of Immunotherapy in clinical practice (30 minutes) – (this will be pre-recorded)Q&A – Live Q&A – (10 minutes) (on July 2, 2021): MSD Oncology; Financial Interests, Personal, Invited Speaker, June 2022: Sanofi; Financial Interests, Personal, Advisory Board, Contract 2021, 2022, 2023: Merck & Co., Inc; Financial Interests, Personal, Advisory Board, Contrat 2019, 2020, 2021, 2022: BMS; Financial Interests, Personal, Advisory Board, Contract 2021: Gritstone Oncologie; Financial Interests, Personal, Invited Speaker, June 2022 and June 2023 during ESMO GI meeting: Seagen; Financial Interests, Personal, Writing Engagement, Contract of consulting 2021 and 2022 and 2023: MSD Oncology; Financial Interests, Personal, Advisory Board, September 2022: GSK, Seagen; Financial Interests, Personal, Writing Engagement, Contract of consulting 2022 and 2023: GSK; Financial Interests, Personal, Writing Engagement, Contract of consulting 2022: Nordic Pharma; Financial Interests, Personal, Invited Speaker, October 2022: Merk Serono; Financial Interests, Personal, Other, Educationnal in 2022: Roche; Financial Interests, Personal, Other, Contract of consulting 2020, 2021, 2022,2023: Servier; Financial Interests, Personal, Advisory Board, Gilead Sciences Global GI Advisory Board on January 18, 2023: Aptitude Health, Glilead; Financial Interests, Personal, Other, Consultant like member of the SGNTUC-029 Steering Committee (the “Steering Committee”) Services related to the Company’s Study titled “An Open-label Randomized Phase 3 Study of Tucatinib in Combination with Trastuzumab and mFOLFOX6 versus mFOLFOX6 given with or without either Cetuximab or Bevacizumab as First-line Treatment for Subjects with HER2+ Metastatic Colorectal Cancer” (collectively, the “Services”).Including teleconferences and board preparation befor the board (6h)Participation of the Board on September 2022 in Paris, September 10, 2022 MOUNTAINEER-03 Steering Committee Meeting during ESMO: Seagen; Financial Interests, Personal, Other, Consultant like member of the to be a member of the Colorectal Program Scientific Advisory Committee (SAC). In charges for reviewing V940 Pembro on Engagezone (as per your contract in ref).and also an inrtview about Pembrolizumab for MSI/dMMR Metastaic colo-rectal 2023: MSD Oncology; Financial Interests, Personal, Advisory Board, but also formation for the takeda team, and consultant for TakedaContract beetween 1 sept 2023 and 15 october 2024: Takeda; Financial Interests, Personal, Advisory Board, Board Meeting (October 19, 2023): AbbVie; Financial Interests, Institutional, Coordinating PI, PI Garnet study: GSK; Financial Interests, Institutional, Coordinating PI, Keynote 164 and 171 and 811 and C08: MSD; Financial Interests, Institutional, Coordinating PI, BMS CA209-8HW, BMS CA209-142, BMS CA209-577: BMS; Financial Interests, Institutional, Coordinating PI, SPOTLIGHT study: Astellas; Financial Interests, Personal, Steering Committee Member, and international PI (trial chair Solstice study): Servier; Financial Interests, Personal, Steering Committee Member, MOUNTAINEER and MOUNTAINEER-03 study (PI for France) 2022, 2023: Seagen; Financial Interests, Institutional, Local PI, A randomized, open-label, phase 2 study of botensilimab (AGEN1181) AS monotherapy and in combination with balstilimab (AGEN2034) or investigator’s choice standard of care (regorafenib or trifluridine and tipiracil) for the treatment of refractory metastatic colorectal cancer: Agenus; Non-Financial Interests, Member of Board of Directors, Investigator: Gercor group; Non-Financial Interests, Member of Board of Directors, President since october 2022: ARCAD Foundation. T.W. Kim: Financial Interests, Institutional, Research Grant: Genentech. L.H. Jensen: Non-Financial Interests, Institutional, Principal Investigator: 2cureX, BMS, MSD, Roche, Pfizer. C.J.A. Punt: Financial Interests, Institutional, Advisory Board: Nordic Pharma. R. Garcia-Carbonero: Financial Interests, Personal, Advisory Board, Invited Speaker: Novartis, Advanz Pharma, Bayer, BMS, Boehringer, Esteve, Hutchmed, Ipsen, Merck, Midatech Pharma, MSD, PharmaMar, Pierre Fabre, Roche, Servier, Takeda; Financial Interests, Institutional, Research Grant: Pfizer, BMS, MSD. J. Alcaide-Garcia: Financial Interests, Personal, Invited Speaker, Travel/Accommodations/Expenses: Merck, Amgen, Servier; Financial Interests, Personal, Advisory Board, Travel/Accommodations/Expenses: Sanofi, MSD; Financial Interests, Personal, Invited Speaker: Pierre-Fabre. P. Gibbs: Financial Interests, Personal and Institutional, Invited Speaker, Research Grant: MSD, Merck & Co., Inc., Servier; Financial Interests, Institutional, Research Funding: Bayer. C. de la Fouchardiere: Financial Interests, Personal, Advisory Board, Research Grant; Principal Investigator: MSD. F. Rivera: Financial Interests, Personal and Institutional, Advisory Board, Invited Speaker; Research Grant; Funding; Principal Investigator: MSD, Amgen, Roche, BMS, AstraZeneca, Servier, Bayer. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board, Travel/Accommodations/Expenses: Amgen, Bayer, Hoffman La-Roche, Merck Serono, MSD, Pierre Fabre, Sanofi, Servier, Takeda; Financial Interests, Personal, Invited Speaker, Travel/Accommodations/Expenses: Novartis, Organon, Pfizer; Financial Interests, Personal, Training, Travel/Accommodations/Expenses: Seagen; Financial Interests, Personal, Other, Travel/Accommodations/Expenses: Array BioPharma, BMS; Financial Interests, Institutional, Funding: Amgen, Array Biopharma Inc., AstraZeneca, Celgene International SARL, BeiGene, Boehringer Ingelheim, BMS, Debiopharm International SA, Genentech Inc., HalioDX SAS, Hoffman-La Roche, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini; Other, Personal, Other, Volunteer member of the ASCO Annual Meeting. Scientific Program Committee: Developmental Therapeutics – Immunotherapy: American Society of Clinical Oncology (ASCO); Other, Personal, Speaker, Consultant, Advisor: European Society for Medical Oncology (ESMO); Other, Personal, Other, Coordinator of the SEOM + MIR Section of Residents and Young Assistants: Sociedad Española de Oncología Médica (SEOM). D.T. Le: Financial Interests, Personal and Institutional, Advisory Board, Invited Speaker; Research Grant; Funding; Principal Investigator: Merck; Financial Interests, Personal and Institutional, Advisory Board, Research Grant; Funding; Principal Investigator: BMS, Nouscom; Financial Interests, Personal, Advisory Board: G1 Therapeutics, Merus; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board, Principal Investigator: Regeneron; Non-Financial Interests, Institutional, Research Grant, Principal Investigator: Curegenix; Non-Financial Interests, Institutional, Research Grant, Funding; Principal Investigator: Medivir; Financial Interests, Institutional, Research Grant, Principal Investigator: AbbVie. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Consultancy: Sumitomo Corp.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd, Sanofi K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Molecular Health GmbH, Amgen K.K., Pfizer Japan Inc., Genomedia Inc., Sysmex Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eisai Co., Ltd., Roche Diagnostics K.K., FALCO Biosystems Ltd.. Y. Zuo: Financial Interests, Personal, Full or part-time Employment: MSD China. D. Fogelman: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Merck & Co., Inc.. D.E. Adelberg: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Merck & Co., Inc.. L.A. Diaz: Financial Interests, Personal and Institutional, Member of Board of Directors: Quest Diagnostics and Epitope; Financial Interests, Personal, Speaker, Consultant, Advisor: PetDx, Innovatus CP, Se’er, Delfi, Blackstone, Kinnate, Neophore; Financial Interests, Personal, Stocks/Shares: Quest Diagnostics, Epitope, PetDx, Se’er, Delfi, Kinnate, Neophore. All other authors have declared no conflicts of interest.