Background: At the first interim analysis of the KEYNOTE-671 trial, adding perioperative pembrolizumab to neoadjuvant chemotherapy significantly improved event-free survival in participants with early-stage non-small-cell lung cancer (NSCLC). We report overall survival and health-related quality of life outcomes from the second interim analysis. Methods: KEYNOTE-671 was a global phase 3 trial done at 189 medical centres. Eligible participants (aged ≥18 years) with resectable stage II, IIIA, or IIIB (N2) NSCLC were randomly assigned (1:1) to four cycles of neoadjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) or to four cycles of neoadjuvant placebo (administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant placebo (administered intravenously every 3 weeks). Randomisation was done centrally using an interactive response technology system and was stratified by disease stage, PD-L1 expression, histology, and geographical region in blocks of four. Participants, investigators, and sponsor personnel were masked to treatment assignments; local pharmacists were unmasked to support treatment preparation. The dual primary endpoints were overall survival and event-free survival evaluated in the intention-to-treat population. This study is registered at ClinicalTrials.gov, NCT03425643, and is ongoing but closed to enrolment. Findings: Between May 11, 2018, and Dec 15, 2021, 797 participants were randomly assigned to the pembrolizumab group (n=397) or the placebo group (n=400). Median study follow-up at the second interim analysis was 36·6 months (IQR 27·6–47·8). 36-month overall survival estimates were 71% (95% CI 66–76) in the pembrolizumab group and 64% (58–69) in the placebo group (hazard ratio 0·72 [95% CI 0·56–0·93]; one-sided p=0·0052; threshold, one-sided p=0·0054). Median event-free survival was 47·2 months (95% CI 32·9 to not reached) in the pembrolizumab group and 18·3 months (14·8–22·1) in the placebo group (hazard ratio 0·59 [95% CI 0·48–0·72]). In the as-treated population, grade 3–5 treatment-related adverse events occurred in 179 (45%) of 396 participants in the pembrolizumab group and in 151 (38%) of 399 participants in the placebo group. Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group and three (1%) participants in the placebo group. Interpretation: The significant overall survival benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone coupled with a manageable safety profile support the use of perioperative pembrolizumab in patients with resectable, early-stage NSCLC. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.
Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial / Spicer, J. D.; Garassino, M. C.; Wakelee, H.; Liberman, M.; Kato, T.; Tsuboi, M.; Lee, S. -H.; Chen, K. -N.; Dooms, C.; Majem, M.; Eigendorff, E.; Martinengo, G. L.; Bylicki, O.; Rodriguez-Abreu, D.; Chaft, J. E.; Novello, S.; Yang, J.; Arunachalam, A.; Keller, S. M.; Samkari, A.; Gao, S.; Afanasyev, S.; Ahmed, S.; Alekshun, T.; Alves, G.; Anderson, I.; Araujo, L. H.; Arkhipov, A.; Arora, A.; Bai, J.; Begin, P.; Belonogov, A.; Berard, H.; Berceanu-Ion, R.; Bernabe Caro, R.; Bondarenko, I.; Bonnet, R.; Bosch Barrera, J.; Brocca, C.; Bryl, M.; Bulotta, A.; Calles Blanco, A.; Carcereny, E.; Carvalho, L.; Cebotaru, C.; Chaft, J.; Charu, V.; Chaves, F.; Chen, J.; Chen, H.; Chen, Q.; Chen, K.; Chiang, C. -L.; Chiu, C. -H.; Cicenas, S.; Ciubotaru, E.; Ciuleanu, T.; Ciurescu, I.; Cobb, P.; Coetzee, C.; Collins, D.; Cortinovis, D.; Costas, K.; Costin, D.; Cronemberger, E. H.; Cuevo, R.; Cuffe, S.; De Marchi, P. R. M.; De Paiva Junior, T.; Delmonte, A.; Demedts, I.; Deschepper, K.; Dias, J.; Duchemann, B.; Dutra, C.; Duvivier, H.; Ernani, V.; Faehling, M.; Faria, L.; Fedenko, A.; Fernando, H.; Ferrara, R.; Ferrari, V.; Finley, G.; Fix, P.; Flores, M.; Fourie, S.; Franke, F.; Frohling, K. -P.; Furqan, M.; Gal, C.; Galamaga, R.; Ganea, D.; Ganti, A. K.; Garassino, M.; Gentzler, R.; Gianni, L.; Gilli, M.; Girard, N.; Goranov, B.; Gregorc, V.; Greystoke, A.; Grisanti, S.; Grohe, C.; Guarino, M.; Guimaraes, J. L.; Guisier, F.; Halmos, B.; Hammoud, Z. T.; Han, J. -Y.; Hegmane, A.; Heng, F. Y.; Horinouchi, H.; Horio, Y.; Hu, J.; Huang, H. -C.; Hui, R.; Ikeda, N.; Intagliata, S.; Iordan, I.; Jacobs, C.; Jain, K.; Jain, S.; Jiang, T.; Karaseva, N.; Kaywin, P.; Kazmi, S.; Keresztes, R.; Khan, S.; Kim, J.; Kolesnik, O.; Kolesnik, O.; Kollmeier, J.; Komiya, T.; Koontz, M.; Krasnohrud, Y.; Kristedja, T.; Kryzhanivska, A.; Kuroda, H.; Laktionov, K.; Lambrechts, M.; Lang, S.; Langleben, A.; Lehmann, M.; Levchenko, E.; Levenko, O.; Li, S.; Liao, B. -C.; Lima, I.; Liu, G.; Liu-Dumlao, T.; Lo Russo, G.; Lou, Y. Y.; Lowczak, A.; Luft, A.; Ma, S.; Majem Tarruella, M.; Makles, K.; Martinengo, G.; Martinez Marti, A.; Matias, D.; Mazieres, J.; Mazilu, L.; Mennecier, B.; Migliorino, M. R.; Misleh, J.; Molina, J.; Morbeck, I.; Mueller, A.; Muto, S.; Nadal Alforja, E.; Nesterova, A.; Nishio, W.; Niu, J.; O'Brien, M.; O'Day, S.; Ogliari, F.; Okada, M.; Pang, Y. K.; Paramonov, V.; Pastor, A.; Pawlak, I.; Piantedosi, F.; Pollock, T.; Pope, T.; Puig, J.; Radhi, S.; Rao, S.; Rathnasabapathy, C.; Reck, M.; Reinacher-Schick, A.; Rich, P.; Ritgen, M.; Rittmeyer, A.; Roca, E.; Rodriguez-Abreu, D.; Ruff, P.; Rybkin, I.; Saji, H.; Sakao, Y.; Sangal, A.; Santoro, A.; Sardenberg, R.; Savvides, P.; Scheusan, R.; Schiller, J.; Schumacher, L.; Serke, M.; Shim, B. Y.; Shimizu, J.; Shio, Y.; Sibille, A.; Siegel, R.; Signorelli, D.; Smagina, M.; Sokur, I.; Spicer, J.; Srkalovic, G.; Stampleman, L.; Starodub, A.; Stencel, K.; Sugio, K.; Surmont, V.; Suzuki, H.; Tabacof, J.; Takamochi, K.; Tan, L.; Tanaka, F.; Tatangelo, M.; Tauscher, D.; Teixeira, C.; Thiberville, L.; Trukhin, D.; Tsai, C. -L.; Ungureanu, A.; Ursol, G.; Vanakesa, T.; Vansteenkiste, J.; Varela, M.; Villalona-Calero, M.; Villaruz, L.; Vogel, G.; Voitko, N.; Wang, Q.; Wang, W.; Wang, C. -C.; Wang, S.; Wehler, T.; Weksler, B.; Wermke, M.; Wesseler, C.; Wirtz, H.; Wong, M.; Yan, X.; Yang, Y.; Yu, K. L.; Zasadny, X.; Zemaitis, M.; Zhang, L.; Zhao, G.; Zhao, Q.; Zhu, Y.; Zurawski, B.. - In: THE LANCET. - ISSN 0140-6736. - 404:10459(2024), pp. 1240-1252. [10.1016/S0140-6736(24)01756-2]
Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial
Ferrara R.;Ogliari F.;Santoro A.;
2024-01-01
Abstract
Background: At the first interim analysis of the KEYNOTE-671 trial, adding perioperative pembrolizumab to neoadjuvant chemotherapy significantly improved event-free survival in participants with early-stage non-small-cell lung cancer (NSCLC). We report overall survival and health-related quality of life outcomes from the second interim analysis. Methods: KEYNOTE-671 was a global phase 3 trial done at 189 medical centres. Eligible participants (aged ≥18 years) with resectable stage II, IIIA, or IIIB (N2) NSCLC were randomly assigned (1:1) to four cycles of neoadjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) or to four cycles of neoadjuvant placebo (administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant placebo (administered intravenously every 3 weeks). Randomisation was done centrally using an interactive response technology system and was stratified by disease stage, PD-L1 expression, histology, and geographical region in blocks of four. Participants, investigators, and sponsor personnel were masked to treatment assignments; local pharmacists were unmasked to support treatment preparation. The dual primary endpoints were overall survival and event-free survival evaluated in the intention-to-treat population. This study is registered at ClinicalTrials.gov, NCT03425643, and is ongoing but closed to enrolment. Findings: Between May 11, 2018, and Dec 15, 2021, 797 participants were randomly assigned to the pembrolizumab group (n=397) or the placebo group (n=400). Median study follow-up at the second interim analysis was 36·6 months (IQR 27·6–47·8). 36-month overall survival estimates were 71% (95% CI 66–76) in the pembrolizumab group and 64% (58–69) in the placebo group (hazard ratio 0·72 [95% CI 0·56–0·93]; one-sided p=0·0052; threshold, one-sided p=0·0054). Median event-free survival was 47·2 months (95% CI 32·9 to not reached) in the pembrolizumab group and 18·3 months (14·8–22·1) in the placebo group (hazard ratio 0·59 [95% CI 0·48–0·72]). In the as-treated population, grade 3–5 treatment-related adverse events occurred in 179 (45%) of 396 participants in the pembrolizumab group and in 151 (38%) of 399 participants in the placebo group. Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group and three (1%) participants in the placebo group. Interpretation: The significant overall survival benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone coupled with a manageable safety profile support the use of perioperative pembrolizumab in patients with resectable, early-stage NSCLC. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
