Background

The phase 3 KEYNOTE-585 study (NCT03221426) evaluated neoadjuvant/adjuvant pembrolizumab (pembro) or placebo (pbo) + chemotherapy (chemo) followed by adjuvant pembro vs pbo in locally-advanced, resectable gastric or gastroesophageal junction (G/GEJ) cancer. A separate cohort evaluated pembro + FLOT. We report results of the pre-specified third interim analysis (IA3).

Methods

Patients (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 + docetaxel, oxaliplatin, leucovorin, and 5-FU, Q2W. Primary end points were pathCR rate (BICR), EFS (RECIST 1.1, by investigator), OS (main cohort), and safety (FLOT cohort).

Results

804 pts were randomized to the main (402 pembro; 402 pbo) and 1007 to main + FLOT ([502 pembro; 505 pbo) cohorts. Median follow-up was 47.7 mo and 46.3 mo, respectively. In the main cohort, pathCR significantly improved with pembro + chemo (12.9% [95% CI, 9.8-16.6]) vs pbo + chemo (2.0 [95% CI, 0.9-3.9]); Δ (10.9% [95% CI, 7.5-14.8]; P<0.00001). EFS was longer with pembro vs pbo (median 44.4 vs 25.3 mo; HR 0.81; 95% CI, 0.67-0.99; P=0.0198), but was not significant. OS continues to final analysis. Median OS was 60.7 vs 58.0 mo (HR 0.90; 95% CI, 0.73-1.12) at IA3. Grade ≥3 drug-related AE rates were 65% with pembro + chemo and 63% with pbo + chemo. Outcomes in the main + FLOT cohort are in the Table. Table: LBA74

Outcomes in main + FLOT cohort

Conclusions

Neoadjuvant/adjuvant pembro + chemo followed by adjuvant pembro, significantly improved pathCR rate with no significant improvement in EFS vs placebo + chemo in pts with untreated, locally-advanced resectable G/GEJ cancer.

Clinical trial identification

NCT03221426.

Editorial acknowledgement

Medical writing assistance was provided by Luana Atherly-Henderson employed by the sponsor.

Legal entity responsible for the study

Merck & Co., Inc.

Funding

Merck & Co., Inc.

Disclosure

K. Shitara: Financial Interests, Personal, Advisory Board: Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Novartis, AbbVie, GSK, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Guardant Health Japan Corp, Astellas Pharma Inc.; Financial Interests, Institutional, Research Grant: Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Eisai, Amgen; Financial Interests, Personal, Invited Speaker: Janssen Pharmaceutical K.K.. S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, Amgen, LG biochemical, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Daiichi Sankyo; Financial Interests, Personal, Steering Committee Member: Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Indivumed, AstraZeneca; Financial Interests, Other, Durg supply for clinical trial: Merck; Financial Interests, Institutional, Coordinating PI, Drug supply for clincal trial: MSD; Financial Interests, Institutional, Local PI, drug supply for clinical trial: zy,meworks; Financial Interests, Institutional, Local PI, drug supply for clinical trial: BeiGene; Financial Interests, Coordinating PI, Drug supply for clnical trial: Incyte. L.S. Wyrwicz: Financial Interests, Personal, Advisory Board: BMS, Servier; Financial Interests, Personal and Institutional, Local PI: BMS, MSD, Servier, BeiGene, Roche, AstraZeneca; Financial Interests, Personal, Steering Committee Member: AstraZeneca. T. Oshima: Financial Interests, Personal, Invited Speaker: Taiho, Astellas; Financial Interests, Personal, Writing Engagement: Astellas; Financial Interests, Personal, Other, research grant: Taiho, Kyowa Kirin, Chugai, Nihon kayaku. N. Karaseva: Financial Interests, Institutional, Funding: MSD. M. Osipov: Financial Interests, Institutional, Funding: MSD. 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, Local PI: MSD, Daiichi Sankyo, Ono Pharmaceutical, Astellas Pharma, Amgen. H. Yabusaki: Financial Interests, Institutional, Funding: MSD. S. Afanasyev: Financial Interests, Institutional, Research Funding: MSD. Y. Park: Financial Interests, Institutional, Funding: MSD. S. Al-Batran: Financial Interests, Personal, Advisory Board: Lilly, Bristol-Myers Squibb, MacroGenics, Immutep, MSD Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Bristol-Myers Squibb, Lilly, AIO Studien gGmbH, MCI Deutschland GmbH; Financial Interests, Personal, Other, CEO/founder: Institute of Clinical Cancer Research IKF at Northwest Hospital; Financial Interests, Institutional, Research Grant: Sanofi, Roche, Celgene, Vifor, Medac, Hospira, Lilly, Eurozyto, Immutep, Ipsen, Bristol-Myers Squibb, MSD Sharp & Dohme, AstraZeneca, German Cancer Aid (Krebshilfe), German Research Foundation, Federal Ministry of Education and Research. T. Yoshikawa: Financial Interests, Personal, Other, honoraria: MSD, Ono, BMS, Daiichi Sankyo, Astra-Zeneca, TERUMO, Otsuka, Covidien, Johnson and Johnson, Olympus, Intuitive. P.E. Yanez Weber: Financial Interests, Institutional, Funding: MSD. M. Di Bartolomeo: Financial Interests, Personal, Other, honoraria: MSD, BMS, Novartis, Lilly, Servier; Financial Interests, Personal, Other, Travel: 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, Coordinating PI: 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: GONOFoundation. X. Fang: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.. C. Shih: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA. P. Bhagia: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA. Y. Bang: Financial Interests, Personal, Advisory Role: Astellas, Amgen, Samyang Biopharm, Hanmi, Daewoong.

Background

The global, Phase 3, randomised, double-blind, placebo (P)-controlled MATTERHORN study (NCT04592913) assesses perioperative durvalumab (D) with FLOT in participants (pts) with resectable GC/GEJC. Results of a pre-planned interim analysis (IA) are reported.

Methods

Pts with resectable (>T2 N0-3 M0/T0-4 N1-3 M0) GC/GEJC were randomised 1:1 to D 1500 mg or P every 4 weeks (Q4W) on Day 1 plus FLOT Q2W on Days 1 and 15 for 4 cycles (2 doses of D or P and 4 doses of FLOT pre- and post-operative), followed by D 1500 mg or P on Day 1 Q4W for 10 further cycles. IA was conducted after all randomised pts underwent or were precluded from surgery. Superiority of pCR rate (α=0.1% [2-sided]) by central review (Modified Ryan) was assessed. Surgical and safety outcomes were also assessed.

Results

There were 474 pts randomised to each treatment arm. Baseline characteristics were balanced between arms; 19% of pts in each enrolled in Asia. The majority of pts had GC (68%), cT3 (66%; cT4, 25%) and cLN+ (70%). A statistically significant improvement in pCR was observed with addition of D to FLOT versus P (19% vs 7%; Δ12%; odds ratio [OR], 3.08; p<0.00001; Table). Combined pCR/near-complete pathological response (pnCR) rate was 27% with D vs 14% with P. Surgery rate and R0 resection rate (in pts who underwent surgery) were similar with D (87% and 86%, respectively) vs P (84% and 86%, respectively). Downstaging favoured D vs P (pT0, 21% vs 10%; pN0, 47% vs 33%; by central review). Median D and P exposure was similar. Adverse event rates were similar between arms (Table). Table: LBA73

Conclusions

The addition of D to perioperative FLOT therapy demonstrated a clinically meaningful and statistically significant improvement in pCR in resectable GC/GEJC, with a tolerable safety profile. The MATTERHORN study is ongoing for the primary endpoint of event-free survival.

Clinical trial identification

NCT04592913.

Editorial acknowledgement

The authors thank the study participants, their families, caregivers and study personnel. Medical writing support, under the direction of the authors, was provided by Andrew Briggs, MA, CMC Connect, a division of IPG Health Medical Communications, in accordance with Good Publication Practice (GPP 2022) guidelines.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

Y.Y. Janjigian: Financial Interests, Personal, Invited Speaker: Bristol-Myers Squibb, Merck Serono; Financial Interests, Personal, Advisory Board: RGENIX, Eli Lilly, Daiichi Sankyo, Pfizer, Bayer, Imugene, Merck, Zymeworks Inc., Seagen, Basilea Pharmaceutica, AstraZeneca; Financial Interests, Personal, Other, Consulting: Michael J. Hennessy Associates, Paradigm Medical Communications, Amerisource Bergen, Arcus Biosciences, Geneos Therapeutics, GSK, Imedex, Lynx Health, Mersana Therapeutics, PeerView Institue, Reasearch to Practice, Silverback Therapeutics; Financial Interests, Personal, Stocks/Shares: RGENIX; Financial Interests, Personal and Institutional, Research Grant: NCI, Department of Defense, Cycle for Survival, Fred's Team, RGENIX, Bayer, Genetech/Roche, Bristol-Myers Squibb, Eli Lilly, Merck. S. Al-Batran: Financial Interests, Personal, Advisory Board: Lilly, Bristol-Myers Squibb, MacroGenics, Immutep, MSD Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Bristol-Myers Squibb, Lilly, AIO Studien gGmbH, MCI Deutschland GmbH; Financial Interests, Personal, Other, CEO/founder: Institute of Clinical Cancer Research IKF at Northwest Hospital; Financial Interests, Institutional, Research Grant: Sanofi, Roche, Celgene, Vifor, Medac, Hospira, Lilly, Eurozyto, Immutep, Ipsen, Bristol-Myers Squibb, MSD Sharp & Dohme, AstraZeneca, German Cancer Aid (Krebshilfe), German Research Foundation, Federal Ministry of Education and Research. Z.A. Wainberg: Financial Interests, Personal, Advisory Board, Honoraria: Amgen, Arcus, AstraZeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas; Financial Interests, Institutional, Advisory Board, Advisory/Consultancy: Amgen, Arcus, AstraZeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas; Financial Interests, Personal and Institutional, Research Funding: Amgen, AstraZeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Roche/Genentech, Array/Pfizer. E. Van Cutsem: Financial Interests, Personal, Advisory Board: AbbVie, ALX, Amgen, Array, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, Zymeworks; Financial Interests, Institutional, Research Grant: Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. D. Molena: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca, Johnson & Johnson, Boston Scientific, BMS. K. Muro: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Ono, Chugai; Financial Interests, Personal, Invited Speaker: Eli Lilly, Ono, Daiichi Sankyo, Taiho, Bristol-Myers Squibb, Takeda, Chugai, AstraZeneca, Amgen; Financial Interests, Institutional, Research Grant, Including local PI as role: Astellas, Amgen, Sanofi, Daiichi Sankyo, Taiho, MSD, Pfizer, Merck Biopharma, Eisai, Ono, Novartis; Non-Financial Interests, Principal Investigator: Takeda. L.S. Wyrwicz: Financial Interests, Personal, Advisory Board: BMS, Servier; Financial Interests, Personal and Institutional, Local PI: BMS, MSD, Servier, BeiGene, Roche, AstraZeneca; Financial Interests, Personal, Steering Committee Member: AstraZeneca. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. M. Moehler: Financial Interests, Personal, Advisory Board: BMS, Servier, Amgen, Lilly, BeiGene, Novartis, Taiho, Daiichi, MD, Amgen; Financial Interests, Personal, Invited Speaker: MSD, BMS, Falk foundation, AIO, BeiGene, Amgen; Financial Interests, Institutional, Advisory Board: Bayer, Sanofi; Financial Interests, Personal, Other, Chair: EORTC. M. Garrido: Financial Interests, Personal, Invited Speaker: BMS, novartis, bayer, Pfizer, Merck, Lilly, GBT Biotoscana; Financial Interests, Personal, Advisory Board: MSD, Pfizer, Macrogenic; Financial Interests, Institutional, Invited Speaker: Merck; Financial Interests, Institutional, Research Grant: BMS, Novartis. J.F. Kurland: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. I. Xynos: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. H. Mann: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, TheraMyc, Hutchinson MediPharma International, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex / HMP; Financial Interests, Personal, Invited Speaker, educacional collaboration: MJH Life Sciences; Financial Interests, Personal, Advisory Board: Cardiff Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, HalioDX SAS, Hutchinson Medipharma, MedImmune, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA –Universidad de Navarra; Non-Financial Interests, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Principal Investigator, Clinical Trials & Research: AstraZeneca Pharmaceutics LP, Array Biopharma Inc., BeiGene, Boehringer Ingelheim, Debiopharm International SA, Bristol-Myers Squibb International Corporation, Celgene International SARL, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Menarini, Janssen-Cilag International NV, MedImmune, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc; Non-Financial Interests, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer -EORTC; Non-Financial Interests, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc; Non-Financial Interests, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. All other authors have declared no conflicts of interest.

Background

One-third of patients with oesophageal cancer has a pathologically complete response after neoadjuvant chemoradiotherapy (nCRT) plus oesophagectomy. Active surveillance may be an alternative for patients with clinically complete response (CCR).

Methods

A noninferiority stepped-wedge cluster randomised trial was performed. Patients with CCR (i.e. no residual disease 6 and 12 weeks after nCRT) underwent active surveillance (surgery only when locoregional regrowth was detected) or standard surgery. Primary endpoint was overall survival (OS) from day of CCR. Noninferiority was defined as Hazard Ratio (HR) <1.77 for mortality in active surveillance after two years. Secondary endpoints were operative outcomes, disease-free survival (DFS), distant dissemination rate and quality of life (HRQOL, EORTC QLQ-C30).

Results

Some 198 patients underwent active surveillance and 111 patients underwent standard surgery. Median follow-up was 34 months in active surveillance and 50 months in standard surgery. OS in active surveillance was noninferior to standard surgery (HR 0.88, 95% upper boundary 1.40, p = 0.007). During active surveillance, 69 patients (35%) maintained CCR, 96 patients (48%) developed locoregional regrowths, and 33 patients (17%) developed distant metastases. R1 rate was 2% in both groups and postoperative 90-day mortality was 4% (active surveillance) versus 5% (standard surgery). Median DFS for active surveillance was 35 (95% CI 31 – 41) versus 49 months (95% CI 38 – NA) for standard surgery (HR 1.35, 95% CI 0.89 – 2.03, p = 0.15). At 30 months after nCRT, 43% of patients with active surveillance versus 34% with standard surgery developed distant metastases (OR 1.45, 95% CI 0.85 – 2.48, p = 0.18). HRQOL was statistically significantly better at six (p = 0.002) and nine months (p = 0.007) for active surveillance.

Conclusions

After a follow-up of two years, patients undergoing active surveillance had noninferior OS and improved short-term HRQOL compared to standard surgery. Postponed esophagectomy for locoregional regrowth was safe. Extended follow-up is required to assess long-term efficacy of active surveillance.

Clinical trial identification

NTR6803 8-11-2017.

Legal entity responsible for the study

The authors.

Funding

This study was funded by the Dutch Cancer Society (KWF) and Netherlands Organisation for Health Research and Development (ZonMw).

Disclosure

All authors have declared no conflicts of interest.

Background

In a previous analysis of the phase III KEYNOTE-811 study, pembrolizumab (pembro)/trastuzumab and chemotherapy (chemo) vs placebo (pbo)/trastuzumab and chemo provided an ORR of 74% vs 52% in the first 264 pts. These data led to FDA approval of first-line pembro/trastuzumab and chemo for HER2+ mG/GEJ adenocarcinoma. We present results of a prespecified interim analysis of PFS.

Methods

Eligible patients (pts) aged ≥18 years with treatment-naive unresectable, HER2+ mG/GEJ adenocarcinoma irrespective of PD-L1 status were randomized 1:1 to pembro 200 mg IV Q3W or pbo IV Q3W plus chemo (5-FU and cisplatin [FP] or capecitabine and oxaliplatin [CAPOX] and trastuzumab [SOC]). Randomization was stratified by region, PD-L1 status, and chemo choice. Treatment continued for ≤2 years or until disease progression or intolerable toxicity. Dual primary end points were PFS (RECIST v1.1, BICR) or OS. Data cut-off for this interim analysis was May 25, 2022. Per the DSMC, OS assessment is ongoing.

Results

At data cut-off, 698 pts were randomized (350 to pembro + SOC; 348 to pbo + SOC). Median follow-up was 28.4 mo. In all pts, pembro + SOC vs pbo + SOC significantly improved PFS (median 10.0 vs 8.1 mo; HR 0.72; 95% CI 0.60-0.87; p=0.0002). In pts with PD-L1 CPS ≥1, median PFS was 10.8 vs 7.2 mo (HR 0.70; 95% CI, 0.58-0.85). 24-mo PFS rates were 27% vs 13%. At data cut-off, 75% of required OS events had occurred. OS follow-up is ongoing. ORR was 72.6% vs 59.8% with pembro + SOC vs pbo + SOC (73.2% vs 58.4% [PD-L1 CPS ≥1]); median (range) DOR was 11.2 mo (1.1+ to 40.1+) vs 9.0 mo (1.4+ to 38.3+). Approximately 31% vs 19% of responders had a response duration ≥24 mo. Grade ≥3 drug-related AE rates were 58% vs 51%. Grade 5 drug-related AEs occurred in 4 (1.1%) vs 3 (0.9%) pts, respectively.

Conclusions

First-line pembro plus trastuzumab and chemo provided superior PFS, and improved ORR with durable responses vs pbo plus trastuzumab and chemo in pts with unresectable, HER2+ mG/GEJ adenocarcinoma, notably in pts with PD-L1 CPS ≥1. These efficacy and safety data continue to support use of this regimen in the first-line setting.

Clinical trial identification

NCT03615326.

Editorial acknowledgement

Editorial assistance provided by Luana Atherly-Henderson, an employee of 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

Y.Y. Janjigian: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Merck; Financial Interests, Personal, Advisory Board: RGENIX, Eli Lilly, Daiichi Sankyo, Pfizer, Bayer, Imugene, Merck, Zymeworks Inc., Seagen, Basilea Pharmaceutica, AstraZeneca; Financial Interests, Personal, Other, Consulting: Michael J. Hennessy Associates, Paradigm Medical Communications, Amerisource Bergen, Arcus Biosciences, Geneos Therapeutics, GSK, Imedex, Lynx Health, Mersana Therapeutics, PeerView Institue, Reasearch to Practice, Silverback Therapeutics; Financial Interests, Personal, Stocks/Shares: RGENIX; Financial Interests, Personal and Institutional, Research Grant: NCI, Department of Defense, Cycle for Survival, Fred's Team, RGENIX, Bayer, Genentech/Roche, Bristol Myers Squibb, Eli Lilly, Merck. A. Kawazoe: Financial Interests, Personal, Advisory Board: Zymeworks; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo, Eli Lilly, Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Expert Testimony: Merck & Co. Y. Bai, J. Xu: Financial Interests, Institutional, Research Grant: MSD. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi Sankyo, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Pierre Fabre, GSK, Roche, Astellas; Financial Interests, Institutional, Invited Speaker: Amgen, Merck, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb. J. Metges: Financial Interests, Personal, Research Grant: MSD, Bristol Myers Squibb, Zymeworks, Daisshi, Astellas, Bayer; Financial Interests, Personal, Speaker’s Bureau, honoraria: MSD, Astellas, Bayer; Financial Interests, Personal, Other, travel fees: MSD, Daiishi, Bristol Myers Squibb. P.E. Yanez Weber: Financial Interests, Institutional, Research Grant: MSD. L.S. Wyrwicz: Financial Interests, Personal, Advisory Board: BMS, Servier; Financial Interests, Personal and Institutional, Local PI: BMS, MSD, Servier, BeiGene, Roche, AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca. L. Shen: Financial Interests, Institutional, Funding: Astellas; Financial Interests, Personal, Writing Engagement: Oxford PharmaGenesis; Financial Interests, Personal, Research Grant: Beijing Xiantong Biomedical Technology, Qilu Pharmaceutical, ZaiLab Pharmaceutical (Shanghai), Beihai Kangcheng (Beijing) Medical Technology, Yaojie Ankang (Nanjing) Technology Co., Ltd., Baiji Shenzhou (Beijing) Biotechnology Co., Ltd, Jacobio Pharmaceuticals; Financial Interests, Personal, Speaker, Consultant, Advisor: Mingji Biopharmaceutical, Haichuang Pharmaceutical, Harbour BioMed; Financial Interests, Personal, Speaker’s Bureau: Hutchison Whampoa, Hengrui, ZaiLab, CStone Pharmaceutical; Financial Interests, Personal, Advisory Board: MSD, Merck, Bristol Myers Squibb, BI, Sanofi, Roche, Servier, AstraZeneca. Y.V. Ostapenko: Financial Interests, Institutional, Other, Principal Investigator: Jounce Therapeutics. M. Bilici: Financial Interests, Institutional, Research Grant: MSD. H.C. Chung: Financial Interests, Institutional, Funding: MSD. K. Shitara: Financial Interests, Personal, Advisory Board: Lilly, Bristol Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, MSD, Taiho, Novartis, AbbVie, GSK, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Guardant Health Japan Corp, Astellas Pharma Inc.; Financial Interests, Personal, Invited Speaker: Janssen Pharmaceutical K.K.; Financial Interests, Institutional, Research Grant: Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho, Chugai Pharmaceutical, MSD, Eisai, Amgen. S. Qin: Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Personal and Institutional, Principal Investigator: China. E. Van Cutsem: Financial Interests, Personal, Advisory Board: AbbVie, ALX, Amgen, Array, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, Zymeworks; Financial Interests, Institutional, Research Grant: Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Ikena Oncology, IQVIA, Lilly, Menarini, Merck, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, TheraMyc, Hutchinson MediPharma International, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex/HMP; Financial Interests, Personal, Invited Speaker, educacional collaboration: MJH Life Sciences; Financial Interests, Personal, Advisory Board: Cardiff Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, HalioDX SAS, Hutchinson Medipharma, MedImmune, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer - AECC; Non-Financial Interests, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA –Universidad de Navarra; Non-Financial Interests, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Taiho Pharma USA Inc, Janssen-Cilag International NV, Servier; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Janssen-Cilag International NV, Merus NV, Hutchinson Medipharma, Taiho Pharma USA Inc; Non-Financial Interests, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer-EORTC; Non-Financial Interests, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. K. Li, C. Shih, P. Bhagia: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. 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, Local PI: 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, Local PI, drug supply for clinical trial: Zymeworks; Financial Interests, Institutional, Local PI, drug supply for clinical trial: BeiGene; Financial Interests, Invited Speaker, Drug supply for clinical trial: Incyte.