D Rodríguez-Abreu1, S F Powell2, M J Hochmair3, S Gadgeel4, E Esteban5, E Felip6, G Speranza7, F De Angelis7, M Dómine8, S Y Cheng9, H G Bischoff10, N Peled11, M Reck12, R Hui13, E B Garon14, M Boyer15, T Kurata16, J Yang17, M C Pietanza17, F Souza17, M C Garassino18. 1. Medical Oncology, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. Electronic address: drodabr@gobiernodecanarias.org. 2. Oncology, Sanford Health, Sioux Falls, USA. 3. Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria. 4. Thoracic Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, USA. 5. Department of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain. 6. Medical Oncology Department, Vall d'Hebron University, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. 7. Centre Integré de Cancérologie de la Montérégie, Hôpital Charles-Le Moyne, Greenfield Park, Canada. 8. Medical Oncology Department, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain. 9. Sunnybrook Health Sciences Centre, Toronto, Canada. 10. Thoraxklinik, Heidelberg, Germany. 11. Department of Oncology, Shaare Zedek Medical Center, Jerusalem, Israel. 12. LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany. 13. Department of Medical Oncology, Westmead Hospital and University of Sydney, Sydney, Australia. 14. Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, USA. 15. Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, Australia. 16. Department of Thoracic Oncology, Kansai Medical University Hospital, Osaka, Japan. 17. Merck & Co., Inc., Kenilworth, USA. 18. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; University of Chicago Medicine & Biological Sciences, Knapp Center for Biomedical Discovery, Chicago, USA.
Abstract
BACKGROUND: In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab. PATIENTS AND METHODS: Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators' choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed-platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS. RESULTS: After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed-platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed-platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed-platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed-platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed-platinum and 66.8% of patients receiving placebo plus pemetrexed-platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off. CONCLUSIONS: Pembrolizumab plus pemetrexed-platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed-platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC.
BACKGROUND: In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab. PATIENTS AND METHODS: Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators' choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed-platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS. RESULTS: After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed-platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed-platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed-platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed-platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed-platinum and 66.8% of patients receiving placebo plus pemetrexed-platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off. CONCLUSIONS: Pembrolizumab plus pemetrexed-platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed-platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC.
Authors: Yu Fujiwara; Nobuyuki Horita; Matthew Harrington; Ho Namkoong; Hirotaka Miyashita; Matthew D Galsky Journal: Cancer Immunol Immunother Date: 2022-04-26 Impact factor: 6.630
Authors: Sarina Piha-Paul; George Simon; Chandra P Belani; Heman Chao; Kim Gaspar; Brenda Lee; Afshin Dowlati Journal: JTO Clin Res Rep Date: 2022-09-16
Authors: M A Siciliano; G Caridà; D Ciliberto; M d'Apolito; C Pelaia; D Caracciolo; C Riillo; P Correale; A Galvano; A Russo; V Barbieri; P Tassone; P Tagliaferri Journal: ESMO Open Date: 2022-04-12