P2.03-043 A Phase 1b Study of Erlotinib and Momelotinib for TKI-Naïve EGFR-Mutated Metastatic Non-Small Cell Lung Cancer

In this study (NCT02206763), momelotinib, an inhibitor of Janus kinases 1 and 2, was administered in combination with erlotinib, a tyrosine kinase inhibitor (TKI) in patients with TKI-naïve epidermal growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer (NSCLC), to determine the maximum tolerated dose and safety of momelotinib in combination with erlotinib. As previously reported, dose limiting toxicities (DLTs) of grade 3 diarrhea (n=1) and grade 4 neutropenia (n=1) without fever were seen at dose level (DL) 2B and trial enrollment was halted. Here, we report the final results. Patients received oral erlotinib 150 mg QD (including 11-31 day run-in). Momelotinib was administered orally in a standard 3+3 dose-escalation design: DL1, momelotinib 100 mg QD; DL2A, 200 mg QD; and DL2B, 100 mg BID. DLTs were evaluated in the first 28 days. Plasma samples were collected for PK/PD analyzes. Eleven patients enrolled: 3 in DL1, 3 in DL2A, and 5 in DL2B. The median duration of exposure to momelotinib was 40 weeks (range 2.4-63.1) and median number of cycles was 10 (range 0.6-15.8). Treatment was discontinued for progressive disease (n=7), adverse event (n=3), and patient decision (n=1). The objective response rate was 54.5% (90% CI: 27.1%–80.0%) and all responses (n=6) were partial responses; 4 patients had stable disease and 1 patient had progressive disease. The median duration of response was 7.1 (90% CI: 4.4–9.6) months. The median progression-free survival was 9.2 (90% CI: 6.2–12.4) months. The estimated median overall survival was not reached. The most common treatment-emergent adverse events (TEAEs) were decreased appetite, dry skin, and fatigue (7 patients each) and diarrhea (6 patients). In addition to the patient with grade 4 neutropenia (DLT), decreased neutrophil count was recorded in 4 additional patients (grade 1-2 [n=3], grade 3 [n=1]); median time to first neutrophil abnormality was 0.5 (range 0.5–3.7) months. Momelotinib-related TEAEs of interest (one patient each) included grade 1 sensory peripheral neuropathy, grade 1 paresthesia, and reactivation of hepatitis B. There was one momelotinib-related serious adverse event, grade 3 pneumonitis. There was no PK interaction between momelotinib and erlotinib. The combination of momelotinib and erlotinib had more toxicity than expected at DL2B. Neutropenia was common. Although the small number of patients in this phase 1 study limits our ability to make a definitive conclusion regarding efficacy, the response rate and progression-free survival was similar to previous reports with erlotinib alone.