SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer

Borghaei, H.; De Marinis, F.; Dumoulin, D.; Reynolds, C.; Theelen, W. S. M. E.; Percent, I.; Gutierrez Calderon, V.; Johnson, M. L.; Madroszyk-Flandin, A.; Garon, E. B.; He, K.; Planchard, D.; Reck, M.; Popat, S.; Herbst, R. S.; Leal, T. A.; Shazer, R. L.; Yan, X.; Harrigan, R.; Peters, S.; Abdel-Karim, I.; Abdelsalam, M.; Addeo, A.; Aguado, C.; Alexander, P.; Alt, J.; Azzi, G.; Balaraman, R.; Biesma, B.; Blackhall, F.; Bohnet, S.; Boleti, E.; Borghaei, H.; Bradbury, P.; Brighenti, M.; Campbell, N.; Campbell, T.; Canon, J. -L.; Cappuzzo, F.; Costa, E. C.; Cavanna, L.; Cetnar, J.; Chella, A.; Chouaid, C.; Christoph, D.; Castan, J. C.; Dakhil, S.; De Castro Carpeno, F. J.; De Marinis, F.; Delmonte, A.; Demedts, I.; Demey, W.; Dits, J.; Del Pilar Diz Tain, M.; Gomez, M. D.; Dorius, T.; Dumoulin, D.; Duruisseaux, M.; Eaton, K.; Gonzalez, E. E.; Evans, D.; Faehling, M.; Farrell, N.; Feinstein, T.; Font, E. F.; Garcia Campelo, M. R.; Garon, E.; Garrido Lopez, M. P.; Germonpre, P.; Gersten, T.; Cao, M. G.; Gopaluni, S.; Greillier, L.; Grossi, F.; Guisier, F.; Gurubhagavatula, S.; Calderon, V. G.; Hakimian, D.; Hall, R.; Hao, D.; Harris, R.; Hashemi, S.; He, K.; Hendriks, L.; Huang, C.; Ibrahim, E.; Jain, S.; Johnson, M.; Jones, B.; Jones, M.; Juan Vidal, O. J.; Juergens, R.; Kaderbhai, C.; Kastelijn, E. A. L.; Keresztes, R.; Kio, E.; Kokowski, K.; Konduri, K.; Kulkarni, S.; Kuon, J.; Kurkjian, C.; Labbe, C.; Lerner, R.; Lim, F.; Madroszyk-Flandin, A.; Marathe, O.; Martincic, D.; Mcclay, E.; Mcintyre, K.; Mekhail, T.; Misino, A.; Molinier, O.; Morabito, A.; Morocz, E.; Muller, V.; Nagy, T.; Nguyen, A. V.; Nidhiry, E.; Okazaki, I.; Ortega-Granados, A. L.; Ostoros, G.; Oubre, D.; Owen, S.; Pachipala, K.; Park, D.; Patel, P.; Percent, I.; Perol, M.; Peters, S.; Piet, B.; Planchard, D.; Polychronis, A.; Aix, S. P.; Pons-Tostivint, E.; Pulla, M. P.; Quantin, X.; Quere, G.; Rafique, N.; Ramaekers, R.; Reck, M.; Reiman, A.; Reinmuth, N.; Reynolds, C.; Rodriguez-Abreu, D.; Romano, G.; Roque, T.; Salzberg, M.; Sanborn, R.; Sandiego, S.; Schaefer, E.; Schreeder, M.; Seetharamu, N.; Seneviratne, L.; Shah, P.; Shunyakov, L.; Slater, D.; Parra, H. S.; Stigt, J.; Stilwill, J.; Su, J.; Surmont, V.; Swink, A.; Szalai, Z.; Talbot, T.; Garcia, A. T.; Theelen, W.; Thompson, J.; Tiseo, M.; Uprety, D.; Uyeki, J.; Van Der Leest, K. C.; Van Ho, A.; Van Putten, J.; Estevez, S. V.; Veatch, A.; Vergnenegre, A.; Ward, P.; Weise, A.; Weiss, M.; Whitehurst, M.; Zai, S.; Zalcman, G.; Zuniga, R.

doi:10.1016/j.annonc.2023.10.004

Background: Checkpoint inhibitor (CPI) therapy revolutionized treatment for advanced non-small-cell lung cancer (NSCLC); however, most patients progress due to primary or acquired resistance. Sitravatinib is a receptor tyrosine kinase inhibitor that can shift the immunosuppressive tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with nivolumab (sitra + nivo) may potentially overcome initial CPI resistance. Patients and methods: In the phase III SAPPHIRE study, patients with advanced non-oncogenic driven, nonsquamous NSCLC who initially benefited from (≥4 months on CPI without progression) and subsequently experienced disease progression on or after CPI combined with or following platinum-based chemotherapy were randomized 1: 1 to sitra (100 mg once daily administered orally) + nivo (240 mg every 2 weeks or 480 mg every 4 weeks administered intravenously) or docetaxel (75 mg/m2 every 3 weeks administered intravenously). The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR; all assessed by blinded independent central review), and safety. Results: A total of 577 patients included randomized: sitra + nivo, n = 284; docetaxel, n = 293 (median follow-up, 17.1 months). Sitra + nivo did not significantly improve OS versus docetaxel [median, 12.2 versus 10.6 months; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.70-1.05; P = 0.144]. The median PFS was 4.4 versus 5.4 months, respectively (HR 1.08, 95% CI 0.89-1.32; P = 0.452). The ORR was 15.6% for sitra + nivo and 17.2% for docetaxel (P = 0.597); CBR was 75.5% and 64.5%, respectively (P = 0.004); median DOR was 7.4 versus 7.1 months, respectively (P = 0.924). Grade ≥3 treatment-related adverse events were observed in 53.0% versus 66.7% of patients receiving sitra + nivo versus docetaxel, respectively. Conclusions: Although median OS was numerically longer with sitra + nivo, the primary endpoint was not met in patients with previously treated advanced nonsquamous NSCLC. The safety profiles demonstrated were consistent with previous reports.

SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer / Borghaei, H.; De Marinis, F.; Dumoulin, D.; Reynolds, C.; Theelen, W. S. M. E.; Percent, I.; Gutierrez Calderon, V.; Johnson, M. L.; Madroszyk-Flandin, A.; Garon, E. B.; He, K.; Planchard, D.; Reck, M.; Popat, S.; Herbst, R. S.; Leal, T. A.; Shazer, R. L.; Yan, X.; Harrigan, R.; Peters, S.; Abdel-Karim, I.; Abdelsalam, M.; Addeo, A.; Aguado, C.; Alexander, P.; Alt, J.; Azzi, G.; Balaraman, R.; Biesma, B.; Blackhall, F.; Bohnet, S.; Boleti, E.; Borghaei, H.; Bradbury, P.; Brighenti, M.; Campbell, N.; Campbell, T.; Canon, J. -L.; Cappuzzo, F.; Costa, E. C.; Cavanna, L.; Cetnar, J.; Chella, A.; Chouaid, C.; Christoph, D.; Castan, J. C.; Dakhil, S.; De Castro Carpeno, F. J.; De Marinis, F.; Delmonte, A.; Demedts, I.; Demey, W.; Dits, J.; Del Pilar Diz Tain, M.; Gomez, M. D.; Dorius, T.; Dumoulin, D.; Duruisseaux, M.; Eaton, K.; Gonzalez, E. E.; Evans, D.; Faehling, M.; Farrell, N.; Feinstein, T.; Font, E. F.; Garcia Campelo, M. R.; Garon, E.; Garrido Lopez, M. P.; Germonpre, P.; Gersten, T.; Cao, M. G.; Gopaluni, S.; Greillier, L.; Grossi, F.; Guisier, F.; Gurubhagavatula, S.; Calderon, V. G.; Hakimian, D.; Hall, R.; Hao, D.; Harris, R.; Hashemi, S.; He, K.; Hendriks, L.; Huang, C.; Ibrahim, E.; Jain, S.; Johnson, M.; Jones, B.; Jones, M.; Juan Vidal, O. J.; Juergens, R.; Kaderbhai, C.; Kastelijn, E. A. L.; Keresztes, R.; Kio, E.; Kokowski, K.; Konduri, K.; Kulkarni, S.; Kuon, J.; Kurkjian, C.; Labbe, C.; Lerner, R.; Lim, F.; Madroszyk-Flandin, A.; Marathe, O.; Martincic, D.; Mcclay, E.; Mcintyre, K.; Mekhail, T.; Misino, A.; Molinier, O.; Morabito, A.; Morocz, E.; Muller, V.; Nagy, T.; Nguyen, A. V.; Nidhiry, E.; Okazaki, I.; Ortega-Granados, A. L.; Ostoros, G.; Oubre, D.; Owen, S.; Pachipala, K.; Park, D.; Patel, P.; Percent, I.; Perol, M.; Peters, S.; Piet, B.; Planchard, D.; Polychronis, A.; Aix, S. P.; Pons-Tostivint, E.; Pulla, M. P.; Quantin, X.; Quere, G.; Rafique, N.; Ramaekers, R.; Reck, M.; Reiman, A.; Reinmuth, N.; Reynolds, C.; Rodriguez-Abreu, D.; Romano, G.; Roque, T.; Salzberg, M.; Sanborn, R.; Sandiego, S.; Schaefer, E.; Schreeder, M.; Seetharamu, N.; Seneviratne, L.; Shah, P.; Shunyakov, L.; Slater, D.; Parra, H. S.; Stigt, J.; Stilwill, J.; Su, J.; Surmont, V.; Swink, A.; Szalai, Z.; Talbot, T.; Garcia, A. T.; Theelen, W.; Thompson, J.; Tiseo, M.; Uprety, D.; Uyeki, J.; Van Der Leest, K. C.; Van Ho, A.; Van Putten, J.; Estevez, S. V.; Veatch, A.; Vergnenegre, A.; Ward, P.; Weise, A.; Weiss, M.; Whitehurst, M.; Zai, S.; Zalcman, G.; Zuniga, R.. - In: ANNALS OF ONCOLOGY. - ISSN 0923-7534. - 35:1(2024), pp. 66-76. [10.1016/j.annonc.2023.10.004]