Charles M Rudin1, Mark M Awad2, Alejandro Navarro3, Maya Gottfried4, Solange Peters5, Tibor Csőszi6, Parneet K Cheema7, Delvys Rodriguez-Abreu8, Mirjana Wollner9, James Chih-Hsin Yang10, Julien Mazieres11, Francisco J Orlandi12, Alexander Luft13, Mahmut Gümüş14, Terufumi Kato15, Gregory P Kalemkerian16, Yiwen Luo17, Victoria Ebiana17, M Catherine Pietanza17, Hye Ryun Kim18. 1. Memorial Sloan Kettering Cancer Center, New York, NY. 2. Dana-Farber Cancer Institute, Boston, MA. 3. Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain. 4. Meir Medical Center, Kfar-Saba, Israel. 5. Lausanne University Hospital, Lausanne, Switzerland. 6. Hetényi Géza Kórház Onkológiai Központ, Szolnok, Hungary. 7. William Osler Health System, University of Toronto, Brampton, Ontario, Canada. 8. Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. 9. Rambam Medical Center, Haifa, Israel. 10. National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan. 11. Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier, Toulouse, France. 12. Oncología-Health and Care, Santiago, Chile. 13. Leningrad Regional Clinical Hospital, St Petersburg, Russia. 14. Istanbul Medeniyet University Hospital, Istanbul, Turkey. 15. Kanagawa Cancer Center, Yokohama, Japan. 16. University of Michigan, Ann Arbor, MI. 17. Merck & Co, Kenilworth, NJ. 18. Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
Abstract
PURPOSE:Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC. METHODS:Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg once every 3 weeks or saline placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries were one-sided P = .0048 for PFS and .0128 for OS. RESULTS: Of the 453 participants, 228 were randomly assigned topembrolizumab plus EP and 225 to placebo plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.61 to 0.91; P = .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI, 0.64 to 0.98; P = .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and 74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%. CONCLUSION:Pembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line therapy for patients with ES-SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data support the benefit of pembrolizumab in ES-SCLC.
RCT Entities:
PURPOSE:Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC. METHODS: Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg once every 3 weeks or saline placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries were one-sided P = .0048 for PFS and .0128 for OS. RESULTS: Of the 453 participants, 228 were randomly assigned to pembrolizumab plus EP and 225 to placebo plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.61 to 0.91; P = .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI, 0.64 to 0.98; P = .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and 74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%. CONCLUSION:Pembrolizumab plus EP significantly improved PFS compared with placebo plus EPas first-line therapy for patients with ES-SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data support the benefit of pembrolizumab in ES-SCLC.
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