A phase 1b study of erlotinib and momelotinib for the treatment of EGFR-mutated, tyrosine kinase inhibitor-naive metastatic non-small cell lung cancer. Cancer chemotherapy and pharmacology Padda, S. K., Reckamp, K. L., Koczywas, M., Neal, J. W., Kawashima, J., Kong, S., Huang, D. B., Kowalski, M., Wakelee, H. A. 2021


INTRODUCTION: Preclinical evidence suggests the feedforward cytokine loop of interleukin-6/Janus kinases (JAK)/STAT3 plays a role in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance in EGFR-mutated non-small cell lung cancer (NSCLC).METHODS: In this phase 1b study, the JAK1/2 and TANK-binding kinase 1 (TBK1) inhibitor momelotinib was evaluated in combination with erlotinib in patients with EGFR TKI-naive, EGFR-mutated NSCLC. After erlotinib lead-in (50, 75, 100, or 150mg oral daily [QD]), momelotinib was combined and dose escalated in a 3+3 study design. The primary endpoint of maximum tolerated dose (MTD) of momelotinib was determined based on the incidence of dose-limiting toxicities (DLTs) during the first 28-day cycle. Secondary endpoints included efficacy and pharmacokinetics (PK).RESULTS: Eleven patients were enrolled across 3 dose levels of momelotinib (100mg QD, 200mg QD, and 100mg twice daily [BID]). The MTD was momelotinib 200mg QD in combination with erlotinib. Two DLTs of grade 4 neutropenia without fever and grade 3 diarrhea occurred at momelotinib 100mg BID. Most common treatment-emergent adverse events included diarrhea, dry skin, fatigue, and decreased appetite; the vast majority being grades 1-2. The overall response rate was 54.5% (90% CI 27.1-80.0; all partial) and median progression-free survival was 9.2months (90% CI 6.2-12.4). Momelotinib did not affect the PK of erlotinib.CONCLUSIONS: The JAK1/2 and TBK1 inhibitor momelotinib in combination with erlotinib did not appear to enhance benefit over the historical data of erlotinib monotherapy in patients with EGFR-mutated NSCLC. CLINICALTRIALS.GOV IDENTIFIER: NCT02206763.

View details for DOI 10.1007/s00280-021-04369-0

View details for PubMedID 34773474