A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed in Patients With Advanced Non-Small Cell Lung Cancer.
J Thorac Oncol
; 12(3): 556-566, 2017 03.
Article
in En
| MEDLINE
| ID: mdl-27876675
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carcinoma, Squamous Cell
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Adenocarcinoma
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Antineoplastic Combined Chemotherapy Protocols
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Carcinoma, Large Cell
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Carcinoma, Non-Small-Cell Lung
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Lung Neoplasms
Type of study:
Clinical_trials
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limits:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Language:
En
Journal:
J Thorac Oncol
Year:
2017
Document type:
Article
Publication country:
EEUU
/
ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
/
USA