A phase Ib study of the combination of afatinib and ruxolitinib in EGFR mutant NSCLC with progression on EGFR-TKIs

Objectives: We evaluated the safety and efficacy of the combination therapy of afatinib, an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), and ruxolitinib, a JAK1/2 selective inhibitor, in patients with EGFR mutant NSCLC progressing on at least one kind of EGFR-TKI. Materials and Methods: In this phase Ib open-label study, we used a 3 + 3 dose-escalation design. Patients with histologically diagnosed EGFR-mutant stage IV NSCLC and documented disease progression on EGFR-TKI therapies were enrolled. Afatinib only was administered on day 1 through day 8 (run-in period), then ruxolitinib was administered concurrently with afatinib until disease progression. The primary endpoints were to determine the dose-limiting toxicity (DLT) and a recommended phase II dose of the combination regimen. We also included a dose confirmation cohort for the highest dose, and an expansion cohort for T790 M mutation. Results: As of October 2017, 30 patients participated in the study, of which 20 had T790 M mutations. Because no DLT was observed in nine patients at the highest dose level (50 mg afatinib once daily plus 25 mg ruxolitinib twice daily), nine patients with T790 M mutations were enrolled in a dose-expansion cohort. Frequent adverse events included diarrhea (G3 in 3 of 22 cases), anemia (G3 in 1 of 26 cases), paronychia (G1/2 in 14 cases), acneiform rash (G1 in 13 cases), and oral mucositis (G1/2 in 12 cases). Objective response rate was 23.3% (no complete response [CR]and 7 partial responses [PR]) and disease control rate was 93.3% (no CR, 7 PR and 21 stable diseases). The median progression-free survival was 4.9 months (95% CI, 2.4–7.5). Conclusion: The combination of afatinib and ruxolitinib was tolerated by patients, with modest clinical activity observed in NSCLC with acquired resistance to EGFR-TKIs (NCT02145637).