Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial

• Published in: The Lancet (British edition) Vol. 392; no. 10142; pp. 123 - 133
• Main Authors: Özgüroğlu, Mustafa, Mandalà, Mario, Ryu, Min-Hee, Olesiński, Tomasz, Mansoor, Wasat, Shacham-Shmueli, Einat, Chen, Xinqun, Kang, S Peter, Fuchs, Charles S, Lerzo, Guillermo, Lynam, James, Wong, Mark, Vasey, Paul, Van Laethem, Jean-Luc, Van Cutsem, Eric, Berry, Scott, Vincent, Mark, Muller, Bettina, Rey, Felipe, Zambrano, Angela, Guerra, Joaquin, Krogh, Merete, Yilmaz, Mette, Elme, Anneli, Auvinen, Paivi, Alanko, Tuomo, Moehler, Markus, Kunzmann, Volker, Hoehler, Thomas, Haag, Georg, Castro, Hugo, Aguilar Vasquez, Mynor, Cuffe, Sinead, Geva, Ravit, Hubert, Ayala, Beny, Alex, Giuseppe, Aprile, Passalacqua, Rodolfo, Montesarchio, Vincenzo, Chin, Keisho, Nishina, Tomohiro, Komatsu, Yoshito, Hironaka, Shuichi, Satoh, Taroh, Tamura, Takao, Sugimoto, Naotaoshi, Cho, Haruhiko, Omuro, Yashushi, Kato, Ken, Goto, Masahiro, Hyodo, Ichinosuke, Yoshida, Kazuhiro, Baba, Hideo, Esaki, Taito, Furuse, Junji, Wan Mohammed, Wan Zamaniah, Dominguez Andrade, Adriana, Glenjen, Nils, Kubiatowski, Tomasz, Jacek, Jassem, Wojtukiewicz, Marek, Lazarev, Sergey, Lancukhay, Yuri, Moiseyenko, Vladimir, Kostorov, Vladimir, Shirinkin, Vadim, Sakaeva, Dina, Fadeeva, Natalia, Yong, Wei Peng, Robertson, Barbara, Rapaport, Bernardo, Cohen, Graham, Dreosti, Lydia, Szpak, Waldemar, Roh, Sang-Young, Kim, Yeul Hong, Chung, Hyun Cheol, Longo Munoz, Federico, Cervantes Aguilar, Andres, Garcia Alfonso, Pilar, Feliu Batle, Jaime, Yeh, Kun-Huei, Chen, Jen-Shi, Chao, Yee, Kara, Oguz, Hochhauser, Daniel, Chau, Ian, Shaib, Walid, Philip, Philip, Sharma, Vivek, Sun, Weijing, George, Ben, Bullock, Andrea, Myrick, Samuel, Faruol, Josephine, Siegel, Richard, Becerra, Carlos, Richards, Donald A., Riche, Stephen L.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 14-07-2018; Elsevier B.V; Elsevier Limited
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - mortality; Adenocarcinoma - pathology; Aged; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - therapeutic use; Antimitotic agents; Antineoplastic agents; Apoptosis; Cancer; Cancer therapies; Cell death; Chemotherapy; Clinical trials; Esophageal cancer; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - mortality; Esophageal Neoplasms - pathology; Esophagogastric Junction - pathology; Esophagus; Evidence-based medicine; Female; Gastric cancer; Growth factors; Health care facilities; Humans; Immunotherapy; Infusions, Intravenous; Interactive systems; Ligands; Male; Metastasis; Middle Aged; Monoclonal antibodies; Neoplasm Staging; Oncology; Paclitaxel; Paclitaxel - adverse effects; Paclitaxel - therapeutic use; Patients; PD-L1 protein; Pembrolizumab; Platinum; Product development; Randomization; Response rates; Safety; Stomach Neoplasms - drug therapy; Stomach Neoplasms - pathology; Survival; Survival Rate; Targeted cancer therapy; Treatment Outcome; Tumors; South Korea; Japan; United States > US
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(18)31257-1

Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine.
This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0·0135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498.
Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9·1 months (95% CI 6·2–10·7) with pembrolizumab and 8·3 months (7·6–9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66–1·03; one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4–2·0) with pembrolizumab and 4·1 months (3·1–4·2) with paclitaxel (HR 1·27, 95% CI 1·03–1·57). In the total population, grade 3–5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel.
Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing.
Merck Sharp & Dohme, a subsidiary of Merck & Co.