A phase 1b study of erlotinib and momelotinib for the treatment of EGFR-mutated, tyrosine kinase inhibitor-naive metastatic non-small cell lung cancer

Sukhmani K Padda,Mark Kowalski,Daniel B Huang,Jun Kawashima,Karen L Reckamp,Joel W Neal,Shengchun Kong,Heather A Wakelee,Marianna Koczywas

doi:10.1007/s00280-021-04369-0

Abstract

IntroductionPreclinical 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).MethodsIn 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).ResultsEleven 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.ConclusionsThe 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 identifierNCT02206763.

Highlights

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 tyrosine kinase inhibitors (TKIs)) resistance in EGFR-mutated non-small cell lung cancer (NSCLC)
First- and second-generation EGFR tyrosine kinase inhibitors (TKIs) were routinely used in the frontline setting until the development of third-generation TKI osimertinib [1,2,3,4,5]
The median time since diagnosis of NSCLC was 1.8 months, as patients were permitted to be on erlotinib for up to 45 days prior to enrolling on the study

Summary

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. 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. On-target resistance occurs less frequently with osimertinib, with the EGFR C797S mutation developing in ~ 15%, whereas bypass tracts are more common, including amplification of MET, HER2, and PIK3CA, acquired mutations in the mitogen-activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K) pathway and rare oncogenic fusions [9, 10]. Strategies to prevent and overcome resistance continue to remain important

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