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SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung
H Borghaei1, F de Marinis2, D Dumoulin3
1Hematology and Oncology Department, Fox Chase Cancer Center, Philadelphia, USA.
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.
Insights
Sitravatinib plus nivolumab did not significantly improve overall survival in advanced non-small-cell lung cancer patients who progressed on prior therapy. The combination showed a higher clinical benefit rate but did not meet the primary endpoint in the SAPPHIRE trial.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Checkpoint inhibitor (CPI) therapy is a cornerstone in advanced non-small-cell lung cancer (NSCLC) treatment.
- Primary or acquired resistance limits CPI efficacy in most patients.
- Sitravatinib, a receptor tyrosine kinase inhibitor, modulates the tumor microenvironment to enhance anti-tumor immunity.
Purpose of the Study:
- To evaluate the efficacy and safety of combining sitravatinib with nivolumab (sitra + nivo) versus docetaxel in patients with advanced NSCLC.
- To determine if sitra + nivo can overcome resistance to prior CPI therapy.
Main Methods:
- Phase III SAPPHIRE study randomized 577 patients with advanced nonsquamous NSCLC previously treated with CPI.
- Patients received either sitra + nivo or docetaxel.
- Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), and safety.
Main Results:
- Sitra + nivo did not significantly improve median OS compared to docetaxel (12.2 vs 10.6 months; P=0.144).
- Median PFS was 4.4 months for sitra + nivo and 5.4 months for docetaxel.
- The ORR was similar between groups (15.6% vs 17.2%), but CBR was higher with sitra + nivo (75.5% vs 64.5%; P=0.004).
- Grade ≥3 treatment-related adverse events were less frequent with sitra + nivo (53.0%) compared to docetaxel (66.7%).
Conclusions:
- The combination of sitravatinib and nivolumab did not meet the primary endpoint of significantly improving overall survival in previously treated advanced nonsquamous NSCLC.
- While not statistically significant for OS, the sitra + nivo combination demonstrated a numerically longer median OS and a higher clinical benefit rate.
- The safety profile of sitra + nivo was consistent with previous reports and showed a lower incidence of severe adverse events compared to docetaxel.
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