David R Gandara1, Natasha Leighl2, Jean-Pierre Delord3, Fabrice Barlesi4, Jaafar Bennouna5, Gerald Zalcman6, Jeffrey R Infante7, Karen L Reckamp8, Karen Kelly9, Frances A Shepherd2, Julien Mazieres10, Filip Janku11, Olivia S Gardner12, Bijoyesh Mookerjee13, Yuehui Wu14, Donna S Cox14, Dan Schramek14, Vijay Peddareddigari14, Yuan Liu15, Anthony M D'Amelio13, George Blumenschein16. 1. Division of Hematology and Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, California. Electronic address: david.gandara@ucdmc.ucdavis.edu. 2. Princess Margaret Cancer Centre, Toronto, Ontario, Canada. 3. Institut Claudius Regaud, Toulouse, France. 4. Aix Marseille University-Assistance Publique Hôpitaux de Marseille, Centre d'Essais Précoces en Cancérologie de Marseille, Marseille, France. 5. Institut de Cancerologie de l'Ouest, Nantes, France. 6. Caen University Hospital-Clinical Research Hospital, Caen, France. 7. Sarah Cannon Research Institute/Tennessee Oncology, Professional Limited Liability Company, Nashville, Tennessee. 8. Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California. 9. Division of Hematology and Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, California. 10. Hôpital Larrey Centre Hospitalier Universitaire Toulouse, Toulouse, France. 11. Department of Investigational Cancer Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 12. GlaxoSmithKline, Morrisville, North Carolina. 13. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey. 14. GlaxoSmithKline, Collegeville, Pennsylvania. 15. Novartis Pharmaceuticals Corporation, Wayne, Pennsylvania. 16. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Abstract
OBJECTIVES: This two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated the safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations. METHODS: Phase 1b evaluated trametinib plus docetaxel with growth factor support (trametinib, 2.0 mg once daily, and docetaxel, 75 mg/m2 every 3 weeks) or pemetrexed (trametinib, 1.5 mg once daily, and pemetrexed, 500 mg/m2 every 3 weeks). Eligibility criteria for the expansion cohorts included metastatic NSCLC with measurable disease, known KRAS mutation status, Eastern Cooperative Oncology Group performance status of 1 or lower, and no more than two prior regimens. RESULTS: The primary end point of overall response rate (ORR) was met for both combinations. A confirmed partial response (PR) was observed in 10 of the 47 patients with NSCLC who received trametinib plus docetaxel (21%). The ORR was 18% (four PRs in 22 patients) in those with KRAS wild-type NSCLC versus 24% (six PRs in 25 patients) in those with KRAS-mutant NSCLC. Of the 42 patients with NSCLC treated with trametinib plus pemetrexed, six (14%) had a PR; the ORR was 17% (four of 23) in patients with KRAS-mutated NSCLC versus 11% (two of 19) in KRAS wild-type NSCLC. Adverse events-most commonly diarrhea, nausea, and fatigue-were manageable. CONCLUSIONS: Trametinib-plus-chemotherapy combinations were tolerable. Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS-mutated NSCLC and meeting prespecified criteria was observed.
OBJECTIVES: This two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated the safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations. METHODS: Phase 1b evaluated trametinib plus docetaxel with growth factor support (trametinib, 2.0 mg once daily, and docetaxel, 75 mg/m2 every 3 weeks) or pemetrexed (trametinib, 1.5 mg once daily, and pemetrexed, 500 mg/m2 every 3 weeks). Eligibility criteria for the expansion cohorts included metastatic NSCLC with measurable disease, known KRAS mutation status, Eastern Cooperative Oncology Group performance status of 1 or lower, and no more than two prior regimens. RESULTS: The primary end point of overall response rate (ORR) was met for both combinations. A confirmed partial response (PR) was observed in 10 of the 47 patients with NSCLC who received trametinib plus docetaxel (21%). The ORR was 18% (four PRs in 22 patients) in those with KRAS wild-type NSCLC versus 24% (six PRs in 25 patients) in those with KRAS-mutant NSCLC. Of the 42 patients with NSCLC treated with trametinib plus pemetrexed, six (14%) had a PR; the ORR was 17% (four of 23) in patients with KRAS-mutated NSCLC versus 11% (two of 19) in KRAS wild-type NSCLC. Adverse events-most commonly diarrhea, nausea, and fatigue-were manageable. CONCLUSIONS:Trametinib-plus-chemotherapy combinations were tolerable. Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS-mutated NSCLC and meeting prespecified criteria was observed.
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Authors: J-C Soria; A Fülöp; C Maciel; J R Fischer; G Girotto; S Lago; E Smit; G Ostoros; W E E Eberhardt; P Lishkovska; S Lovick; G Mariani; A McKeown; E Kilgour; P Smith; K Bowen; A Kohlmann; D J Carlile; P A Jänne Journal: Ann Oncol Date: 2017-12-01 Impact factor: 32.976
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