LBA3 - Final analysis of the phase III KEYNOTE-585 study of pembrolizumab plus chemotherapy vs chemotherapy as perioperative therapy in locally-advanced gastric and gastroesophageal junction cancer

Background

At third interim analysis (IA3) of KEYNOTE-585 (NCT03221426), perioperative pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo did not show significant improvement of event-free survival (EFS) in patients (pts) with untreated locally-advanced, resectable G/GEJ cancer, although pathCR rate improved. A separate cohort evaluated pembro + FLOT. We present results of the final analysis (FA) of overall survival.

Methods

Eligible pts with untreated, locally advanced, resectable G/GEJ cancer were randomized 1:1 to neoadjuvant pembro 200 mg IV Q3W or pbo + chemo (cisplatin + capecitabine or cisplatin + 5-FU) for 3 cycles. After surgery, pts received adjuvant pembro or pbo + chemo Q3W for 3 cycles, then adjuvant pembro or pbo Q3W for 11 cycles (main cohort). In the FLOT cohort, pts were randomized 1:1 to pembro or pbo + docetaxel, oxaliplatin, leucovorin, and 5-FU, Q2W. Primary end points were pathCR (BICR), EFS (RECIST 1.1, INV), OS (main cohort), and safety (FLOT cohort). OS was not tested statistically at FA as EFS was not positive at IA3.

Results

804 pts were randomized to the main (402 pembro; 402 pbo) and 1007 to main + FLOT (502 pembro; 505 pbo) cohorts. At data cut-off (Feb 16, 2024), median follow-up was 59.9 mo and 58.6 mo respectively. In the main cohort, the pathCR rate was 13.4% (95% CI, 10.3-17.2) with pembro + chemo vs 2.0% (95% CI, 0.9-3.9) with pbo + chemo (Δ (11.4% [95% CI, 8.0-15.3]). At FA, median EFS was 44.4 vs 25.5 mo (HR 0.81; 95% CI, 0.67-0.99) and median OS was 71.8 vs 55.7 mo (HR 0.86; 95% CI, 0.71-1.06) with pembro + chemo vs pbo + chemo, respectively. Grade ≥3 drug-related AE rates were 65% vs 63%. Outcomes in the main + FLOT cohort are in the table.

Conclusions

Efficacy and safety outcomes with neoadjuvant/adjuvant pembro + chemo followed by adjuvant pembro in pts with untreated, locally advanced resectable G/GEJ cancer at final analysis, were consistent with the prior analysis. Table: LBA3

Outcomes in main + FLOT cohort

^aIn first 987 pts randomized; HR, hazard ratio; NA, not applicable; NR, not reached

Clinical trial identification

MK-3475-585/KEYNOTE-585; NCT03221426; First posted July 18, 2017.

Editorial acknowledgement

Editorial assistance was provided by Luana Atherly-Henderson 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. Shitara: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Takeda, Ono Pharmaceutical, MSD, Novartis, Daiichi Sankyo, Amgen, Guardant Health Japan Corp., Astellas Pharma Inc., Astellas, Bayer, AstraZeneca, Zymeworks Biopharmaceuticals Inc, ALX Oncology Inc.; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Janssen, AstraZeneca, Eli Lilly, Astellas, Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Eisai, Amgen, PRA Health Sciences. S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, Amgen, LG Biochemical, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Daiichi Sankyo, Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Indivumed, AstraZeneca; Financial Interests, Other, Drug supply for clinical trial: Merck; Financial Interests, Institutional, Invited Speaker, Drug supply for clinical trial: MSD; Financial Interests, Institutional, Invited Speaker, drug supply for clinical trial: Zymeworks; Financial Interests, Institutional, Invited Speaker, drug supply for clinical trial: Beijing; Financial Interests, Invited Speaker, Drug supply for clinical trial: Incyte. L.S. Wyrwicz, N. Karaseva, M. Osipov, H. Yabusaki, S. Afanasyev, Y. Park, P.E. Yanez Weber: Financial Interests, Institutional, Funding: MSD. T. Oshima: Financial Interests, Personal, Invited Speaker: Taiho, Astellas; Financial Interests, Personal, Other, research grant: Taiho, Kyowa Kirin, Chugai, Nihon Kayaku. H. Yasui: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Chugai Pharma, Bristol Myers Squibb, Daiichi Sankyo, Terumo, Eli Lilly Japan, Merck Biopharma, Yakult Honsha, Bayer Yakuhin; Financial Interests, Institutional, Invited Speaker: MSD, Daiichi Sankyo, Ono Pharmaceutical, Astellas Pharma, Amgen. S. Al-Batran: Financial Interests, Personal, Funding: MSD, Celgene, Lilly, Sanofi, German Cancer Aid, German Research Foundation, Federal Ministry of Education and Research, Roche, Vifor Pharma, Eurozyto, Immutep, Ipsen, Bristol Myers Squibb, AstraZeneca; Financial Interests, Personal, Stocks/Shares: Institut für Klinische Krebsforschung GmbH, Immutep; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, AstraZeneca/Daiichi Sankyo, Eli Lilly Germany; Financial Interests, Personal, Speaker’s Bureau: Lilly, AIO GmbH, Bristol Myers Squibb, MCI Group. T. Yoshikawa: Financial Interests, Personal, Other, honoraria: MSD, BMS, Ono, Chugai, Daiichi Sankyo, Astellas. M. Di Bartolomeo: Financial Interests, Personal, Other, honoraria: MSD, Bristol Myers Squibb, Novartis, Lilly, Servier; Financial Interests, Personal, Other, travel fees: Daiichi; Financial Interests, Personal, Advisory Board: Novartis. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi Sankyo, Bristol Myers Squibb, Astellas, GSK, Takeda, Bayer; Financial Interests, Personal, Invited Speaker: Pierre Fabre, GSK, Roche, Servier, Amgen, Bristol Myers Squibb, Incyte, Lilly, Merck Serono, MSD; Financial Interests, Institutional, Invited Speaker: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb; Non-Financial Interests, Member of Board of Directors, Italian No-Profit Oncology Research Foundation supporting academic Clinical trials: GONO Foundation. X. Fang, C. Shih, P. Bhagia: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. Y. Bang: Financial Interests, Personal, Advisory Role: Astellas, Amgen, Hanmi, Daewoong, SK BioPharm; Financial Interests, Institutional, Funding: MSD.