Momelotinib is a potent inhibitor of JAK1 and JAK2 that demonstrated efficacy in patients with primary and secondary myelofibrosis. This phase 2, open-label, randomized study evaluated the efficacy and safety of oral once-daily momelotinib (100mg and 200mg) for the treatment of polycythemia vera (PV) and essential thrombocythemia (ET). The primary endpoint for PV was overall response rate (ORR), defined as the proportion of patients with hematocrit <45%, white blood cell count <10×10/L, platelet count ≤400×10/L, and resolution of palpable splenomegaly, each lasting ≥4 weeks. The definition of ORR for ET excluded the hematocrit component. A total of 39 patients (28 PV, 11 ET) were enrolled, with 28 patients receiving ≥12 weeks of treatment. The study was terminated due to limited efficacy. Two patients (ORR 5.1%) met the primary efficacy endpoint (both PV 200mg). Predose plasma levels of momelotinib were stable over time. A total of 31 (79.5%) patients experienced momelotinib-related adverse events (AEs), the most frequent being headache (23.1%), dizziness (18.0%), somnolence (15.4%), nausea (15.4%), and fatigue (15.4%). Three patients experienced serious AEs (7.7%), with 1 considered related to momelotinib (dyspnea). Peripheral neuropathy occurred in 7 (17.9%) patients (4 PV, 3 ET).
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 150 mg 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 (100 mg QD, 200 mg QD, and 100 mg twice daily [BID]). The MTD was momelotinib 200 mg QD in combination with erlotinib. Two DLTs of grade 4 neutropenia without fever and grade 3 diarrhea occurred at momelotinib 100 mg 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 9.2 months (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.
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