Ceritinib plus Nivolumab in Patients with Advanced ALK-Rearranged Non-Small Cell Lung Cancer: Results of an
Enriqueta Felip1, Filippo G de Braud2, Michela Maur3
1Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Introduction:
Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the 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 (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal.
Results:
In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [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% (95% CI: 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 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1-87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0-58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of 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.
Insights
This study found that combining ceritinib and nivolumab shows activity in non-small cell lung cancer (NSCLC) with EML4-ALK rearrangements. Response rates correlated with PD-L1 expression, but toxicity, particularly rash, was more frequent than with single agents.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Constitutive oncogenic signaling can induce programmed death ligand 1 (PD-L1) expression in non-small cell lung cancer (NSCLC) with echinoderm microtubule associated protein like 4 gene (EML4)-echinoderm microtubule associated protein like 4 gene (ALK) rearrangements.
- Assessing combination therapies is crucial for improving outcomes in ALK-rearranged NSCLC.
Purpose of the Study:
- To evaluate the safety and activity of combining ceritinib with nivolumab in patients with ALK-rearranged NSCLC.
- To explore the correlation between PD-L1 expression and treatment response.
Main Methods:
- An open-label, phase 1B, multicenter study involving dose escalation and expansion.
- Patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab (3 mg/kg IV every 2 weeks) plus ceritinib (450 mg or 300 mg daily with a low-fat meal).
- Patients were either treatment-naive or previously treated with an ALK inhibitor (ALKI) or chemotherapy.
Main Results:
- 36 patients were treated; dose-limiting toxicities were observed in both the 450-mg (n=14) and 300-mg (n=22) cohorts.
- Overall response rates (ORR) were higher in ALK inhibitor-naive patients (83% in 450-mg cohort, 60% in 300-mg cohort) compared to ALK inhibitor-pretreated patients (50% and 25%, respectively).
- Higher ORR was observed in PD-L1 positive patients (64% with ≥1% PD-L1) versus PD-L1 negative patients (31%). Grade 3/4 adverse events included elevated liver enzymes and maculopapular rash (64% all-grade).
Conclusions:
- Ceritinib plus nivolumab demonstrates clinical activity in ALK-rearranged NSCLC.
- Treatment response appears to correlate with baseline PD-L1 expression.
- The combination therapy is associated with increased toxicity, particularly rash, compared to monotherapy.
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