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.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.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.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.
