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).
Bibliographical noteFunding Information:
Cho BC reports research grants from Novartis, Bayer, AstraZeneca, the MOGAM Biotechnology Research Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, and MSD, a consulting role with Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, and MSD, and stock ownership in TheraCanVac Inc. Kim HR reports research grants from Ono, BMS, and AstraZeneca.
This work was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (grant number 2016R1A2B3016282 to B.C. Cho; grant number 2017M3A9E9072669 to H. R. Kim).
© 2019 Elsevier B.V.
All Science Journal Classification (ASJC) codes
- Pulmonary and Respiratory Medicine
- Cancer Research