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

David A. Barbie, Alexander Spira, Karen Kelly, Rita Humeniuk, Jun Kawashima, Shengchun Kong, Marianna Koczywas

Research output: Contribution to journalArticle

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Abstract

We evaluated the multitargeted Janus kinase/TRAF family member associated NF-κβ activator (TANK)-binding kinase 1 (TBK1) inhibitor momelotinib combined with trametinib in 21 patients with Kirsten rat sarcoma viral oncogene homolog-mutated non–small-cell lung cancer. The maximum tolerated dose of momelotinib was 150 mg twice daily (insufficient to achieve significant TBK1 inhibition). No patients achieved objective response and the combination did not improve on the activity of single-agent trametinib on the basis of historic data. 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.

Original languageEnglish (US)
JournalClinical Lung Cancer
DOIs
StateAccepted/In press - Jan 1 2018

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Platinum
Treatment Failure
Oncogenes
Non-Small Cell Lung Carcinoma
Sarcoma
Maximum Tolerated Dose
Drug Therapy
Phosphotransferases
Janus Kinases
Confidence Intervals
Fatigue
MAP Kinase Kinase Kinase 1
trametinib
N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
Alanine Transaminase
Mitogens
Nausea
Disease-Free Survival
Diarrhea
Safety

Keywords

  • Janus kinase
  • MEK inhibition
  • MEK pathway
  • Metastatic non–small-cell lung cancer
  • TBK1 inhibition

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

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. / Barbie, David A.; Spira, Alexander; Kelly, Karen; Humeniuk, Rita; Kawashima, Jun; Kong, Shengchun; Koczywas, Marianna.

In: Clinical Lung Cancer, 01.01.2018.

Research output: Contribution to journalArticle

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title = "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",
abstract = "We evaluated the multitargeted Janus kinase/TRAF family member associated NF-κβ activator (TANK)-binding kinase 1 (TBK1) inhibitor momelotinib combined with trametinib in 21 patients with Kirsten rat sarcoma viral oncogene homolog-mutated non–small-cell lung cancer. The maximum tolerated dose of momelotinib was 150 mg twice daily (insufficient to achieve significant TBK1 inhibition). No patients achieved objective response and the combination did not improve on the activity of single-agent trametinib on the basis of historic data. 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.",
keywords = "Janus kinase, MEK inhibition, MEK pathway, Metastatic non–small-cell lung cancer, TBK1 inhibition",
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T1 - 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

AU - Barbie, David A.

AU - Spira, Alexander

AU - Kelly, Karen

AU - Humeniuk, Rita

AU - Kawashima, Jun

AU - Kong, Shengchun

AU - Koczywas, Marianna

PY - 2018/1/1

Y1 - 2018/1/1

N2 - We evaluated the multitargeted Janus kinase/TRAF family member associated NF-κβ activator (TANK)-binding kinase 1 (TBK1) inhibitor momelotinib combined with trametinib in 21 patients with Kirsten rat sarcoma viral oncogene homolog-mutated non–small-cell lung cancer. The maximum tolerated dose of momelotinib was 150 mg twice daily (insufficient to achieve significant TBK1 inhibition). No patients achieved objective response and the combination did not improve on the activity of single-agent trametinib on the basis of historic data. 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.

AB - We evaluated the multitargeted Janus kinase/TRAF family member associated NF-κβ activator (TANK)-binding kinase 1 (TBK1) inhibitor momelotinib combined with trametinib in 21 patients with Kirsten rat sarcoma viral oncogene homolog-mutated non–small-cell lung cancer. The maximum tolerated dose of momelotinib was 150 mg twice daily (insufficient to achieve significant TBK1 inhibition). No patients achieved objective response and the combination did not improve on the activity of single-agent trametinib on the basis of historic data. 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.

KW - Janus kinase

KW - MEK inhibition

KW - MEK pathway

KW - Metastatic non–small-cell lung cancer

KW - TBK1 inhibition

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