Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer
Leena Gandhi, Delvys Rodríguez-Abreu, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Flávia De Angelis, Manuel Domine, Philip Clingan, Maximilian J Hochmair, Steven F Powell, Susanna Y-S Cheng, Helge G Bischoff, Nir Peled, Francesco Grossi, Ross R Jennens, Martin Reck, Rina Hui, Edward B Garon, Michael Boyer, Belén Rubio-Viqueira, Silvia Novello, Takayasu Kurata, Jhanelle E Gray, John Vida, Ziwen Wei, Jing Yang, Harry Raftopoulos, M Catherine Pietanza, Marina C Garassino, KEYNOTE-189 Investigators, Victoria Bray, Baerin Ben Houghton, George Kannourakis, Ritwik Pandey, Otto Burghuber, Sylvia Hartl, Bernd Lamprecht, Horst Olschewski, Kathrin Philipp-Abbrederis, Michael Reiter, Michael Schumacher, Michael Studnicka, Marc Lambrechts, Sebahat Ocak, Nathalie Aucoin, Vincent Castonguay, Giovanna Speranza, Andrew Robinson, Stephanie Snow, Jens Benn Soerensen, Karin Holmskov Holmskov Hansen, Miroslaw Jan Stelmach, Marjukka Myllarniemi, Satu Tiainen, Delphine Carmier, Benoit Godbert, Francois Goldwasser, Olivier Molnier, Michel Poudenx, Jean Tredaniel, Wolfgang Brueckl, Walburga Engel-Riedel, Christian Gessner, Wolfram Gruening, Monika Heilmann, Jens Kollmeier, Susanne Lang, Wolfgang Schuette, Thomas C Wehler, Richard Bambury, Linda Coate, Sinead Cuffe, Emer Hanrahan, Patrick Morris, Jair Bar, Maya Gottfried, Shmuel Ariad, Irina Lazarev, Ofer Merimsky, Suzannah Nak, Mirjana Wollner, Alona Zer, Vincenzo Adamo, Alessandra Bearz, Gloria Borra, Emilio Bria, Francesco Cognetti, Filippo de Marinis, Cesare Gridelli, Lorenzo Livi, Alessandro Morabito, Hidehito Horinouchi, Naoyuki Nogami, Masayuki Takeda, J G J V Aerts, J M Smit, Chantal Smits-van der Graaf, Dolores Isla, Cristobal Delda Iniesta, Ana Collazo, Jose Fuentes Pradera, Guillermo Lopez Vivanco, Raquel Marse, Noemi Reguart Arasany, Oscar Juan Vidal, Hendrik-Tobias Arkenau, Fiona Blackhall, David Chao, Ekaterini Boleti, Clive Mulatero, Katy Clarke, Siow Ming Lee, Marianne Nicolson, Toby Talbot, Sanjiv Agarwala, Mark Awad, Deepti Behl, William Conkright, Daniel B Costa, Konstantin Dragnev, Michael Krabak, Herbert Duvivier, Justin Gainor, Aqeel A Gillani, Mark Graham, Richard Gralla, Michael J Guarino, Matthew Gubens, Richard Hall, Balazs Halmos, Ralph Hauke, Syed Jafri, Mohammed Kassar, Goetz Kloecker, Michael P Kosty, Corey J Langer, Danko Martincic, Mohammed Masri, Mahsa Mohebtash, Amit Panwalker, Benjamin Parsons, Ravidranath Patel, Julio A Peguero, Maria Quejada, Suman Banner Rao, Igor I Rybkin, Edgardo Santos, Andrew O Schreiber, Nagashree Seetharamu, Deepa Mocherla, Tejvir Singh, Bethany Graham Sleckman, Laura Stampleman, James Stevenson, Joseph Stilwill, Ammar Sukari, William V Walsh, John Wrangle, Stephen H Wrzesinski, Paul Bunn, David Johnson, Robert Pirker, Weichung Joe Shih, Leena Gandhi, Delvys Rodríguez-Abreu, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Flávia De Angelis, Manuel Domine, Philip Clingan, Maximilian J Hochmair, Steven F Powell, Susanna Y-S Cheng, Helge G Bischoff, Nir Peled, Francesco Grossi, Ross R Jennens, Martin Reck, Rina Hui, Edward B Garon, Michael Boyer, Belén Rubio-Viqueira, Silvia Novello, Takayasu Kurata, Jhanelle E Gray, John Vida, Ziwen Wei, Jing Yang, Harry Raftopoulos, M Catherine Pietanza, Marina C Garassino, KEYNOTE-189 Investigators, Victoria Bray, Baerin Ben Houghton, George Kannourakis, Ritwik Pandey, Otto Burghuber, Sylvia Hartl, Bernd Lamprecht, Horst Olschewski, Kathrin Philipp-Abbrederis, Michael Reiter, Michael Schumacher, Michael Studnicka, Marc Lambrechts, Sebahat Ocak, Nathalie Aucoin, Vincent Castonguay, Giovanna Speranza, Andrew Robinson, Stephanie Snow, Jens Benn Soerensen, Karin Holmskov Holmskov Hansen, Miroslaw Jan Stelmach, Marjukka Myllarniemi, Satu Tiainen, Delphine Carmier, Benoit Godbert, Francois Goldwasser, Olivier Molnier, Michel Poudenx, Jean Tredaniel, Wolfgang Brueckl, Walburga Engel-Riedel, Christian Gessner, Wolfram Gruening, Monika Heilmann, Jens Kollmeier, Susanne Lang, Wolfgang Schuette, Thomas C Wehler, Richard Bambury, Linda Coate, Sinead Cuffe, Emer Hanrahan, Patrick Morris, Jair Bar, Maya Gottfried, Shmuel Ariad, Irina Lazarev, Ofer Merimsky, Suzannah Nak, Mirjana Wollner, Alona Zer, Vincenzo Adamo, Alessandra Bearz, Gloria Borra, Emilio Bria, Francesco Cognetti, Filippo de Marinis, Cesare Gridelli, Lorenzo Livi, Alessandro Morabito, Hidehito Horinouchi, Naoyuki Nogami, Masayuki Takeda, J G J V Aerts, J M Smit, Chantal Smits-van der Graaf, Dolores Isla, Cristobal Delda Iniesta, Ana Collazo, Jose Fuentes Pradera, Guillermo Lopez Vivanco, Raquel Marse, Noemi Reguart Arasany, Oscar Juan Vidal, Hendrik-Tobias Arkenau, Fiona Blackhall, David Chao, Ekaterini Boleti, Clive Mulatero, Katy Clarke, Siow Ming Lee, Marianne Nicolson, Toby Talbot, Sanjiv Agarwala, Mark Awad, Deepti Behl, William Conkright, Daniel B Costa, Konstantin Dragnev, Michael Krabak, Herbert Duvivier, Justin Gainor, Aqeel A Gillani, Mark Graham, Richard Gralla, Michael J Guarino, Matthew Gubens, Richard Hall, Balazs Halmos, Ralph Hauke, Syed Jafri, Mohammed Kassar, Goetz Kloecker, Michael P Kosty, Corey J Langer, Danko Martincic, Mohammed Masri, Mahsa Mohebtash, Amit Panwalker, Benjamin Parsons, Ravidranath Patel, Julio A Peguero, Maria Quejada, Suman Banner Rao, Igor I Rybkin, Edgardo Santos, Andrew O Schreiber, Nagashree Seetharamu, Deepa Mocherla, Tejvir Singh, Bethany Graham Sleckman, Laura Stampleman, James Stevenson, Joseph Stilwill, Ammar Sukari, William V Walsh, John Wrangle, Stephen H Wrzesinski, Paul Bunn, David Johnson, Robert Pirker, Weichung Joe Shih
Abstract
Background: First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.
Methods: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review.
Results: After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.
Conclusions: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).
Source: PubMed