Phase 1B Study of Momelotinib Combined With Trametinib in Metastatic, Kirsten Rat Sarcoma Viral Oncogene Homolog-Mutated Non-Small-Cell Lung Cancer After Platinum-Based Chemotherapy Treatment Failure

Clin Lung Cancer. 2018 Nov;19(6):e853-e859. doi: 10.1016/j.cllc.2018.07.004. Epub 2018 Aug 4.


Introduction: Specific treatment options are lacking for Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated non-small-cell lung cancer (NSCLC) despite treatment advances in other mutation-driven subgroups.

Patients and methods: In this study we evaluated the multitargeted Janus kinase/TANK-binding kinase 1 (TBK1) inhibitor momelotinib combined with the mitogen/extracellular signal-related kinase (MEK)1/MEK2 inhibitor trametinib in patients with platinum-treated, refractory, metastatic, KRAS-mutated NSCLC. Dose escalations (3 + 3 design) were conducted with momelotinib in combination with trametinib 1.0 mg once daily, then with trametinib in combination with the maximum tolerated dose (MTD) of momelotinib. MTD was determined from dose-limiting toxicity (DLT) during patients' first 28-day cycle. Safety was the primary end point, and efficacy parameters, including disease control rate (DCR) at 8 weeks, were secondary end points.

Results: Twenty-one patients were enrolled (median age: 68 years; 14 [66.7%] female). The MTD was momelotinib 150 mg twice daily in combination with trametinib 1.0 mg once daily. DLTs that determined the MTD were increased alanine aminotransferase and fatigue. The most common adverse events of any grade were nausea (n = 14 [66.7%]), diarrhea (n = 11 [52.4%]), and fatigue (n = 11 [52.4%]). The most common Grade ≥3 event was hypoxia (n = 3 [14.3%]). No patients achieved objective response. DCR at 8 weeks was 12 patients (57.1%) (90% confidence interval [CI], 37.2%-75.5%). Median progression-free and overall survival were 3.6 months (90% CI, 2.2-5.6 months) and 7.4 months (90% CI, 4.0-15.3 months), respectively. Maximum momelotinib plasma concentrations were reached 1 to 2 hours after dosing, but were insufficient to achieve significant TBK1 inhibition.

Conclusion: The additional use of momelotinib with trametinib does not improve on the activity of single-agent trametinib in KRAS-mutated NSCLC on the basis of historic data.

Trial registration: NCT02258607.

Keywords: Janus kinase; MEK inhibition; MEK pathway; Metastatic non–small-cell lung cancer; TBK1 inhibition.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzamides / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Female
  • Humans
  • Janus Kinases / antagonists & inhibitors
  • Lung Neoplasms / drug therapy*
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Neoplasm Metastasis
  • Platinum / therapeutic use*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Pyridones / therapeutic use*
  • Pyrimidines / therapeutic use*
  • Pyrimidinones / therapeutic use*
  • Treatment Failure


  • Benzamides
  • KRAS protein, human
  • Pyridones
  • Pyrimidines
  • Pyrimidinones
  • trametinib
  • Platinum
  • N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
  • Janus Kinases
  • MAP Kinase Kinase 1
  • Proto-Oncogene Proteins p21(ras)

Associated data