Pembrolizumab plus weekly paclitaxel in platinum-resistant recurrent ovarian cancer (ENGOT-ov65/KEYNOTE-B96): a multicentre, randomised, double-blind, phase 3 study

Author(s): Nicoletta Colombo, MD PhD^a,*; Prof Emese Zsiros, MD PhD^c,*; Gabriella Parma, MD^b; Eliana Rulli, PhD^d; Alexandra Sebastianelli, MD FRCS^e; Prof Mariusz Bidzinski, MD PhD^f; Carlos Gallardo, MD^g; Emad Matanes, MD^h; Prof Kosei Hasegawa, MD PhDⁱ; Prof Fatih Kose, MD^j; Manuel Magallanes-Maciel, MD^k; Rebecca A Herbertson, DM^l; Sumitra Ananda, MBBS FRACP^m; Prof Judith R Kroep, MD PhDⁿ; Andreia Cristina de Melo, MD PhD^o; Prof Philip R Debruyne, MD PhD^p,q,r; Prof Jae-Weon Kim, MD PhD^s,t; Prof Jalid Sehouli, MD^u; Marc-Edy Pierre, MD^v; Prof Sakari Hietanen, MD^w; Claudio Zamagni, MD^x; Prof Xin Lu, MD PhD^y; Prof Bradley J Monk, MD^z; Robert L Coleman, MD^aa; Xuan Peng, PhD^ab; Karin Yamada, MD MSc^ab; Agata M Bogusz, MD PhD^ab; Thibault De La Motte Rouge, MD PhD^ac; Prof Xiaohua Wu, MD PhD^ad

Source: Volume 407, Issue 10538p1525-1537

Dr. Maen Hussein's Thoughts

Participants (who received one to two previous systemic therapies including at least one platinum regimen and who progressed 6 months or less after the last platinum) regime were randomly assigned 1:1 to intravenous pembrolizumab 400 mg every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle or intravenous placebo every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle; intravenous bevacizumab 10 mg/kg every 2 weeks was permitted per investigator. Overall survival (OS) was significantly improved in the PD-L1 CPS 1 or higher population (median 18·2 months vs 14·0 months; HR 0·76 OS was significantly improved in the overall population (median 17·7 m vs 14·0 m, hazard ratio (HR) 0·82

BACKGROUND

Epithelial ovarian cancer frequently recurs and becomes resistant to platinum chemotherapy. We investigated whether adding pembrolizumab to weekly paclitaxel, with or without bevacizumab, improves progression-free survival and overall survival compared with weekly paclitaxel, with or without bevacizumab, in participants with platinum-resistant recurrent ovarian cancer who had received one to two previous systemic regimens.

METHODS

ENGOT-ov65/KEYNOTE-B96 is a randomised, double-blind, phase 3 study conducted at 187 gynaecologic oncology centres in 25 countries in the Americas, Asia, Europe, and Oceania. Adults (≥18 years) with histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, who received one to two previous systemic therapies including at least one platinum regimen and who progressed 6 months or less after the last platinum regimen, were eligible. Participants were randomly assigned 1:1 to intravenous pembrolizumab 400 mg every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle or intravenous placebo (saline solution) every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle; intravenous bevacizumab 10 mg/kg every 2 weeks was permitted per investigator. Randomisation was stratified by planned bevacizumab use, region, and PD-L1 combined positive score (CPS). The primary endpoint was investigator-assessed progression-free survival per RECIST version 1.1; the key secondary endpoint was overall survival. Results from two interim analyses and the final analysis are included in this Article. This study is registered with ClinicalTrials.gov, NCT05116189, and is now completed.

FINDINGS

Between Dec 13, 2021, and July 3, 2023, 643 female participants were randomly assigned; 322 to pembrolizumab plus paclitaxel and 321 to placebo plus paclitaxel. At the first interim analysis, pembrolizumab plus paclitaxel significantly improved progression-free survival versus placebo plus paclitaxel in both the PD-L1 CPS 1 or higher (median 8·3 months vs 7·2 months; hazard ratio [HR] 0·72; 95% CI 0·58–0·89; p=0·0014 α=0·012]) and overall populations (median 8·3 months vs 6·4 months; HR 0·70, 95% CI 0·58–0·84; p<0·0001, [α=0·0023]), meeting the prespecified criteria for confirmatory efficacy. At the second interim analysis, overall survival was significantly improved in the PD-L1 CPS 1 or higher population (median 18·2 months vs 14·0 months; HR 0·76, 95% CI 0·61–0·94; p=0·0053, [α=0·0083]). At the final analysis, overall survival was significantly improved in the overall population (median 17·7 months vs 14·0 months; HR 0·82, 95% CI 0·69–0·97; p=0·011 [α=0·024]). Grade 3 or worse treatment-related adverse events occurred in 217 (68%) of 320 participants in the pembrolizumab plus paclitaxel group versus 176 (55%) of 318 participants in the placebo plus paclitaxel group. The most common treatment-related adverse events (any grade) included anaemia, peripheral neuropathy, alopecia, fatigue, and nausea. Treatment-related adverse events resulted in death in four participants (1%) in the pembrolizumab plus paclitaxel group (colitis, interstitial lung disease, acute myeloid leukaemia, and intestinal perforation) and in five participants (2%) in the placebo plus paclitaxel group (cardiac failure, intestinal perforation [in two participants], and large-intestine perforation [in two participants]).

INTERPRETATION

Pembrolizumab plus weekly paclitaxel, with or without bevacizumab, significantly improved progression-free survival and overall survival in participants with platinum-resistant recurrent ovarian cancer who had received one to two previous systemic regimens, supporting this regimen as a new treatment option for this population.

FUNDING

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

Author Affiliations

^a Gynecologic Oncology Program, European Institute of Oncology, IRCCS, Milan, Italy; ^b Division of Gynecologic Oncology, European Institute of Oncology, IRCCS, Milan, Italy; ^c Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; ^d Laboratory of Methodology for Clinical Research, Clinical Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; ^e CHU de Québec-Université Laval, QC, Canada; ^f Narodowy Instytut Onkologii im Marii Skłodowskiej-Curie, Warsaw, Poland; ^g Bradford Hill Clinical Research Center and Finis Terrae University, Santiago, Chile; ^h Rambam Health Care Campus, and Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel; ⁱ Saitama Medical University International Medical Center, Hidaka, Saitama, Japan; ^j Başkent University, Ankara, Turkey; ^k Centro Oncologico Internacional, Mexico City, Mexico; ^l University Hospitals Sussex NHS Foundation Trust, Worthing, UK; ^m Epworth Healthcare and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; ⁿ Leiden University Medical Center, Leiden, Netherlands and Dutch Gynaecology Oncology Group; ^o Division of Clinical Research and Technological Development, Brazilian National Cancer Institute, Rio de Janeiro, Brazil; ^p Kortrijk Cancer Centre, az groeninge, Kortrijk, and Belgium and Luxembourg Gynaecological Oncology Group, Leuven, Belgium; ^q Medical Technology Research Centre, School of Allied Health and Social Care, Anglia Ruskin University, Chelmsford, UK; ^r School of Nursing and Midwifery, University of Plymouth, Plymouth, UK; ^s Seoul National University, Seoul, South Korea; ^t Asia-Pacific Gynecologic Oncology Trials Group, Seoul, South Korea; ^u Charite Universitaetsmedizin, Berlin, Germany and North-Eastern German Society of Gynecological Oncology; ^v Gynecology Oncology Unit, Luis Carlos Samiento Angulo Cancer Treatment and Research Center–CTIC, Bogotá, Colombia; ^w Turku University Hospital and NSGO-CTU, Turku, Finland; ^x IRCCS Azienda Ospedaliero–Universitaria di Bologna, Bologna, Italy; ^y; ^Gynecologic Oncology Department, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China; ^z Florida Cancer Specialists and Research Institute, West Palm Beach, FL, USA; ^aa Gynecologic Oncology, Texas Oncology, US Oncology Network Shenandoah, TX, USA; ^ab Merck & Co, Rahway, NJ, USA; ^ac Centre Eugene Marquis, Rennes, and GINECO, Paris, France; ^ad Fudan University Shanghai Cancer Center, Shanghai, China; ^* Contributed equally; ^† ENGOT-ov65/KEYNOTE-B96 investigators are listed in the appendix

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