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|Ref Type||Journal Article|
|Authors||Gandara DR, Leighl N, Delord JP, Barlesi F, Bennouna J, Zalcman G, Infante JR, Reckamp KL, Kelly K, Shepherd FA, Mazieres J, Janku F, Gardner OS, Mookerjee B, Wu Y, Cox DS, Schramek D, Peddareddigari V, Liu Y, D'Amelio AM, Blumenschein G|
|Title||A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed in Patients With Advanced Non-Small Cell Lung Cancer.|
|Journal||Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer|
|Abstract Text||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.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.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.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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||lung non-small cell carcinoma||not applicable||Docetaxel + Trametinib||Phase I||Actionable||In a Phase I/Ib trial, treatment with the combination of Mekinist (trametinib) and Taxotere (docetaxel) resulted in an overall response rate (ORR) of 21% (10/47, all partial responses) and stable disease in 43% (20/47) of patients with non-small cell lung cancer (PMID: 27876675).||27876675|
|Unknown unknown||lung squamous cell carcinoma||not applicable||Docetaxel + Trametinib||Phase I||Actionable||In a Phase I/Ib trial, treatment with the combination of Mekinist (trametinib) and Taxotere (docetaxel) resulted in partial response in 1 patient and stable disease in 3 patients within the subset of 5 evaluable patients with squamous non-small cell lung cancer patients (PMID: 27876675).||27876675|
|Unknown unknown||lung non-small cell carcinoma||not applicable||Pemetrexed Disodium + Trametinib||Phase I||Actionable||In a Phase I/Ib trial, treatment with the combination of Mekinist (trametinib) and Alimta (pemetrexed) resulted in an overall response rate of 14% (6/42, all partial responses) and stable disease in 55% (23/42) of patients with non-small cell lung cancer (PMID: 27876675).||27876675|