Kohei Shitara1, Mustafa Özgüroğlu2, Yung-Jue Bang3, Maria Di Bartolomeo4, Mario Mandalà5, Min-Hee Ryu6, Lorenzo Fornaro7, Tomasz Olesiński8, Christian Caglevic9, Hyun C Chung10, Kei Muro11, Eray Goekkurt12, Wasat Mansoor13, Raymond S McDermott14, Einat Shacham-Shmueli15, Xinqun Chen16, Carlos Mayo16, S Peter Kang16, Atsushi Ohtsu17, Charles S Fuchs18. 1. National Cancer Center Hospital East, Kashiwa, Japan. Electronic address: kshitara@east.ncc.go.jp. 2. Istanbul University, Cerrahpaşa School of Medicine, Istanbul, Turkey. 3. Seoul National University College of Medicine, Seoul, South Korea. 4. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 5. Papa Giovanni XXIII Hospital, Bergamo, Italy. 6. University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea. 7. Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. 8. Maria Skłodowska-Curie Memorial Cancer Center, Warsaw, Poland. 9. Fundación Arturo López Pérez - Clínica Alemana de Santiago, Santiago, Chile. 10. Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. 11. Aichi Cancer Center Hospital, Nagoya, Japan. 12. Hematology Oncology Practice Eppendorf (HOPE), Hamburg, Germany; University Cancer Center Hamburg, Hamburg, Germany. 13. Christie Hospital NHS Foundation Trust, Manchester, UK. 14. Adelaide and Meath Hospital, Dublin, Ireland. 15. Sheba Medical Center, Ramat Gan, Israel. 16. Merck & Co, Kenilworth, NJ, USA. 17. National Cancer Center Hospital East, Kashiwa, Japan. 18. Yale Cancer Center, Smilow Cancer Hospital, New Haven, CT, USA.
Abstract
BACKGROUND: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 aplatinum and fluoropyrimidine. METHODS: 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. FINDINGS: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. INTERPRETATION: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. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
RCT Entities:
BACKGROUND: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. METHODS: 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. FINDINGS: Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1CPS 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. INTERPRETATION:Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
Authors: Tatiana Cunha Pereira; Paulo Rodrigues-Santos; Jani Sofia Almeida; Fábio Rêgo Salgueiro; Ana Raquel Monteiro; Filipa Macedo; Rita Félix Soares; Isabel Domingues; Paula Jacinto; Gabriela Sousa Journal: Med Oncol Date: 2021-03-31 Impact factor: 3.064