Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with pemetrexed for <i>KRAS</i>-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): A phase I/Ib trial.
Bibliographic record
Abstract
8027 Background: Lung cancer patients with mutated KRAS tumors present a treatment challenge. Trametinib + pemetrexed (pem) enhanced growth inhibition and apoptosis compared with either agent alone in lung cancer cell lines with WT or mutated RAS/RAF. Methods: This 2-part, multiarm, phase I/Ib, open-label study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase II dose (RP2D) for trametinib + pem in patients (pts) with advanced solid tumors. In part 2, NSCLC pts were stratified as KRAS WT or mutation unknown (WT) or KRAS-mutant (KRAS) and were treated with trametinib + pem at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Exploratory mutational profiling was done using circulating-free DNA from plasma and available archival tumor tissue. Results: As of January 2013, 42 NSCLC pts (22 WT [82% had ≥ 2 prior therapies], 20 KRAS [55% had ≥ 2 prior therapies]) have been treated at the trametinib + pem RP2D (1.5 mg + 500 mg/m2). Nausea, fatigue, and peripheral edema were the 3 most frequent toxicities. 26% of pts reported grade 3-4 hematologic toxicity. Dose reduction occurred in 15 pts (33%), most often for diarrhea, decreased ejection fraction, and fatigue (all 7%). Preliminary PK suggests no drug-drug interaction. In KRAS pts, the best investigator-assessed response (confirmed + unconfirmed) was 3 partial response (PR; RR = 15%) and 10 stable disease (SD; 50%); additionally, 3 pts had > 20% tumor shrinkage. The disease control rate (DCR) was 65%. Final response and progression-free survival (PFS) data will be reported upon maturity. In WT pts, 3 PR (RR = 14%) and 13 SD (59%) were observed (73% DCR); preliminary median PFS was 5.8 months (95% CI, 2.8-6.7 months). Biomarker analyses, including assessment of KRAS mutation subtype vs efficacy, are ongoing. Conclusions: MEK inhibition with trametinib + pem demonstrates tolerability and clinical activity in both KRAS-mutant and WT NSCLC, exceeding expectations for each drug alone and warranting further study. Clinical trial information: NCT01192165.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".