709O - Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: Overall survival results from the randomized, double-blind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study

Background

At the first interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study (NCT04221945), pembrolizumab (pembro) + concurrent chemoradiotherapy (CCRT) showed a statistically significant and clinically meaningful improvement in PFS vs placebo (pbo) + CCRT in patients (pts) with high-risk locally advanced cervical cancer (LACC). Based on this study, the US FDA has approved pembro + CCRT for pts with FIGO 2014 Stage III-IVA cervical cancer. We present the OS results from the second interim analysis.

Methods

Eligible pts with newly diagnosed, previously untreated, high-risk LACC (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of lymph node status) were randomized 1:1 to 5 cycles of pembro 200 mg or pbo Q3W + CCRT, then 15 cycles of pembro 400 mg or pbo Q6W. CCRT included 5 cycles (optional 6th dose) of cisplatin 40 mg/m² Q1W + EBRT then brachytherapy. Pts were stratified by planned EBRT type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), stage at screening (IB2-IIB vs III-IVA), and planned total radiotherapy dose (<70 Gy vs ≥70 Gy [EQ2D]). Primary endpoints are PFS per RECIST v1.1 by investigator and OS.

Results

1060 pts were randomized to pembro + CCRT (n=529) or pbo + CCRT (n=531). At this analysis (January 8, 2024, data cutoff), median follow-up was 29.9 mo (range, 12.8-43.0). Pembro + CCRT showed a statistically significant improvement in OS compared with pbo + CCRT. The 36-mo OS rate was 82.6% with pembro + CCRT vs 74.8% with pbo + CCRT; median OS was NR in either group (HR=0.67 [95% CI, 0.50-0.90]; P=0.0040). The benefit of pembro + CCRT was generally consistent in all prespecified subgroups, including FIGO stages IB2-IIB (HR=0.89 [95% CI, 0.55-1.44]) and III-IVA (HR=0.57 [95% CI, 0.39-0.83]). Grade ≥3 TRAE incidence was 69.1% in the pembro + CCRT group and 61.3% in the pbo + CCRT group.

Conclusions

Pembro + CCRT showed a statistically significant and clinically meaningful improvement in OS vs pbo + CCRT in pts with high-risk LACC and had a manageable safety profile. These data provide further support for pembro + CCRT as a new standard of care for this population.

Clinical trial identification

NCT04221945; EudraCT: 2019-003152-37.

Editorial acknowledgement

Medical writing assistance was provided by Christine McCrary Sisk of Merck & Co., Inc., Rahway, NJ, 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, U.S.A.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A.

Disclosure

D. Lorusso: Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: GSK, Clovis Oncology, PharmaMar; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speakers: AstraZeneca, MSD; Financial Interests, Personal, Other, Consultancy: PharmaMar, AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Seagen, Novartis; Financial Interests, Personal, Advisory Board, Invited member of advisory board and invited speaker: Seagen, Immunogen, Genmab; Financial Interests, Personal, Advisory Board, Invited member of advisory board: Oncoinvest, Corcept, Sutro; Financial Interests, Institutional, Funding, Grant for founding academic trials: MSD, Clovis Oncology, GSK, PharmaMar; Financial Interests, Institutional, Coordinating PI, ENGOT trial with institutional support for coordination: Clovis Oncology; Financial Interests, Institutional, Coordinating PI, ENGOT trial with institutional support for coordination: Genmab, MSD; Financial Interests, Institutional, Funding, Clinical trial/contracted research: AstraZeneca, Clovis Oncology, GSK, MSD, Seagen; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Genmab, Immunogen, Incyte, Novartis, Roche; Non-Financial Interests, Principal Investigator, PI of several trials, no compensation received: GSK; Non-Financial Interests, Principal Investigator, PI of several trials. No personal compensation received: AstraZeneca, Genmab; Non-Financial Interests, Principal Investigator, PI in several trials, no personal compensation received: MSD; Non-Financial Interests, Principal Investigator, PI of clinical trial, no personal compensation received: Immunogen, Clovis Oncology, Roche, Incyte, Seagen; Non-Financial Interests, Principal Investigator, PI of several trials, no personal compensation received: Novartis; Non-Financial Interests, Principal Investigator, PI of clinical trials, no personal compensation received: PharmaMar; Non-Financial Interests, Member, Board of Directors: GCIG; Other, Other, Grants for traveling: AstraZeneca, Clovis Oncology, GSK. Y. Xiang: Financial Interests, Institutional, Funding, Funding to the Peking Union Medical College Hospital for MK3475-A18 study conduction: Merck Sharp & Dohme LLC; Financial Interests, Institutional, Principal Investigator, Principal Investigator of MK3475-A18 study in China: Merck Sharp & Dohme LLC; Non-Financial Interests, Personal and Institutional, Advisory Board, Scientific advisory committee member for MK3475-A18 study: Merck Sharp & Dohme LLC. K. Hasegawa: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, Takeda, Chugai, Genmab, Kaken, Eisai, Sanofi, GSK; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Funding, contracted research: MSD, Ono, Daiichi Sankyo, Eisai, Takeda. G. Scambia: Financial Interests, Personal, Invited Speaker, Speaker: Baxter Healthcare, GSK, Intuitive Surgical Inc., AstraZeneca & MSD, Olympus Europa, GSK, AstraZeneca & MSD, Olympus Europa; Financial Interests, Personal, Advisory Board, Trainer: Covidien AG (Medtronic company); Financial Interests, Institutional, Coordinating PI, ‘IsoMSLN’ in Ovarian Cancer and Malignant Pleural Mesothelioma: Kiromic; Financial Interests, Institutional, Coordinating PI, Roll-over study for patients who have completed a previous cancer study with olaparib and who the investigator believes can benefit from continued treatment - ROSY-O: AstraZeneca; Financial Interests, Institutional, Coordinating PI, CATCH-R: Roll-over study to provide continuous access to clinical therapy with rucaparib: Clovis Oncology; Financial Interests, Institutional, Coordinating PI, Phase 3, multicenter, placebo-controlled clinical study comparing chemo-immunotherapy (paclitaxel-carboplatin-oregovomab) versus chemotherapy (paclitaxel-carboplatin-placebo) in patients with advanced epithelial ovarian, tubal cancer of fallopian or peritoneal (FLORA-5): Oncoquest Pharmaceuticals Inc.; Financial Interests, Institutional, Coordinating PI, Phase 2b randomized, open-label, active comparator, parallel-group, multicenter study designed to evaluate the efficacy and safety of three different doses of the P2X3 receptor antagonist (BAY 1817080) versus placebo and Elagolix 150 mg in women with symptomatic endometriosis: Bayer AG; Financial Interests, Institutional, Coordinating PI, Usability of ITE transducers for sending electric fields for tumor treatment (TTFields): Novocure Ltd; Financial Interests, Institutional, Coordinating PI, Phase III, multicentre, open-label extension trial to evaluate long-term safety and efficacy in patients with advanced cancers currently undergoing treatment or in follow-up in a pembrolizumab trial: Merck. P. Ramos Elias: Financial Interests, Personal, Invited Speaker, Guest speaker at educational events: MSD, Asofarma, Novartis, AstraZeneca; Financial Interests, Personal, Advisory Board, Participation as a local expert on advisory board meetings: Bristol Myers Squibb, Asofarma, AstraZeneca; Financial Interests, Personal, Advisory Board, local expert on advisory board meetings: Pfizer; Financial Interests, Personal and Institutional, Local PI, Fees for conducting clinical studies: MSD, Roche Genentech, Zymeworks. A. Acevedo: Financial Interests, Institutional, Principal Investigator: MSD, Bristol Myers Squibb, Amgen, Seagen, Gilead, AstraZeneca. M. Bednarikova: Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK; Financial Interests, Personal, Other, Supporting for attending meetings: Roche; Financial Interests, Personal, Advisory Board: Sanofi Aventis; Financial Interests, Personal, Other, Supporting for attending meeting: Viatris. A.J.P.D.S. Gomes: Financial Interests, Personal, Invited Speaker: Astellas, Bayer, Janssen, AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer, Janssen. F. Contreras Mejia: Financial Interests, Personal, Invited Speaker: MSD, BMS, GSK, Eli-Lilly, AstraZeneca, Novartis; Financial Interests, Personal, Advisory Board: MSD, Janssen, GSK, Eli-Lilly, BMS. A. Reiss: Financial Interests, Personal, Advisory Board: MSD Israel. F. Zagouri: Financial Interests, Personal, Invited Speaker: Roche, Novartis, Gilead, Genesis Pharma, AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck, MSD, Pfizer; Non-Financial Interests, Principal Investigator: Roche, Eli Lilly, Pfizer, MSD. J. Lee: Financial Interests, Personal, Invited Speaker: AstraZeneca, Takeda, MSD, Roche; Financial Interests, Personal, Advisory Board: Eisai, GI Innovation; Financial Interests, Institutional, Local PI: Alkermes, AstraZeneca, BergenBio, Cellid, Clovis Oncology, Eisai, GI Innovation, ImmunoGen, Janssen, Merck, Mersana, MSD, Novartis, OncoQuest, Roche, Seagen, Synthon; Financial Interests, Personal and Institutional, Local PI: BeiGene; Financial Interests, Personal, Steering Committee Member: AstraZeneca, OncoQuest, Seagen, ImmunoGen, MSD; Financial Interests, Institutional, Research Grant: Ono, Takeda. P. Liu: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. K.U. Yamada: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. M. Puglisi: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. S. Pignata: Financial Interests, Personal, Advisory Board: Roche, AZ, MSD, Clovis, GSK, PharmaMar; Financial Interests, Institutional, Funding: Roche, MSD, Pfizer, AZ. L. Duska: Financial Interests, Personal, Advisory Board, Scientific advisory board: Aadi Bioscience; Financial Interests, Personal, Royalties, I write expert content for: UpToDate; Financial Interests, Personal, Other, I serve on the Editorial Board: British Journal of Obstetrics and Gynecology; Financial Interests, Institutional, Research Grant, Merck has provided funding for investigator initiated trials to my institution: Merck; Non-Financial Interests, Advisory Role, Acted as an expert advisor for: Merck. All other authors have declared no conflicts of interest.