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A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed in Patients With Advanced Non-Small Cell Lung
David R Gandara1, Natasha Leighl2, Jean-Pierre Delord3
1Division of Hematology and Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, California.
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.
Insights
Trametinib combined with chemotherapy showed tolerable safety and clinical activity in non-small cell lung cancer (NSCLC) patients. This combination demonstrated improved overall response rates compared to chemotherapy alone, particularly in patients with KRAS mutations.
Area of Science:
- Oncology
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) remains a significant health challenge.
- KRAS mutations are common in NSCLC and are associated with poorer prognoses.
- Targeting MEK, a downstream effector of KRAS, offers a potential therapeutic strategy.
Purpose of the Study:
- To evaluate the safety, tolerability, pharmacokinetics, and efficacy of trametinib in combination with chemotherapy in NSCLC patients.
- To assess the overall response rate (ORR) of trametinib plus docetaxel or pemetrexed in NSCLC patients with and without KRAS mutations.
Main Methods:
- Phase 1b study evaluating trametinib (2.0 mg or 1.5 mg daily) combined with docetaxel (75 mg/m² every 3 weeks) or pemetrexed (500 mg/m² every 3 weeks).
- Expansion cohorts included patients with metastatic NSCLC, known KRAS mutation status, and limited prior treatment.
- Primary endpoint was overall response rate (ORR).
Main Results:
- Trametinib plus docetaxel achieved a 21% ORR (10/47 patients), with higher response in KRAS-mutant (24%) versus wild-type (18%) NSCLC.
- Trametinib plus pemetrexed resulted in a 14% ORR (6/42 patients), with higher response in KRAS-mutant (17%) versus wild-type (11%) NSCLC.
- Adverse events, including diarrhea, nausea, and fatigue, were manageable.
Conclusions:
- Trametinib in combination with docetaxel or pemetrexed demonstrated tolerable safety and clinical activity in NSCLC.
- The combination regimens showed improved ORRs compared to historical data for docetaxel or pemetrexed alone, especially in KRAS-mutated NSCLC.
- These findings support further investigation of trametinib-based chemotherapy combinations in NSCLC treatment.
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