Ceritinib plus nivolumab in patients with advanced ALK-rearranged non-small-cell lung cancer: results of an open-label, multicenter, phase 1B study: Ceritinib plus nivolumab in ALK-rearranged NSCLC

Abstract Introduction Induction of PD-L1 expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring EML4–ALK rearrangements. We assessed safety and activity of ceritinib plus nivolumab in these patients. Methods In this open-label, phase 1B, multicenter, dose-escalation and expansion study, previously treated (ALK inhibitor [ALKi]/chemotherapy) or treatment-naive patients with stage IIIB/IV ALK-rearranged NSCLC received nivolumab 3 mg/kg intravenously every 2 weeks plus ceritinib (450 mg/300 mg) daily with low-fat meal. Results In total, 36 patients were treated (450 mg cohort [n=14]; 300 mg cohort [n=22]). In the 450 mg cohort, four patients experienced DLTs. In the 300 mg cohort, two patients experienced DLTs. Among ALKi-naive patients, the overall response rate (ORR) was 83% (95% CI 35.9–99.6) in the 450 mg cohort and 60% (95% CI 26.2–87.8) in the 300 mg cohort. Among ALKi-pretreated patients, the ORR was 50% (95% CI 15.7–84.3) in the 450 mg cohort and 25% (5.5–57.2) in the 300 mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 as compared to those who were negative for PD-L1 with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% [95% CI 35.1–87.2] patients had confirmed responses as compared to those with negative PD-L1 staining (31% [95% CI 11.0–58.7]). Most frequently reported grade 3/4 adverse events were increased alanine aminotransferase (ALT) (25%), increased gamma-glutamyl transferase (22%), increased amylase (14%), increased lipase (11%), and maculopapular rash (11%). Incidence of all grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% patients in the 450 mg and 300 mg cohorts, respectively; no grade 4 rash was reported. Conclusion Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.