Phase II study of selumetinib (sel) versus temozolomide (TMZ) in gnaq/Gna11 (Gq/11) mutant (mut) uveal melanoma (UM).
Bibliographic record
Abstract
CRA9003 Background: Gq/11 mutations are early oncogenic events in UM resulting in MAPK pathway activation. We demonstrated decreased viability in UM cell lines harboring Gq/11 mut with sel, a small molecule inhibitor of MEK1/2 (Ambrosini, CCR 2012). Methods: We conducted a 16 center randomized phase II study of hyd-sulfate sel 75 mg BID vs TMZ 150 mg/m 2 daily for 5 days in 28-day cycles (or DTIC 1000 mg/m 2 q21 days) for patients (pts) with metastatic UM with a Q209 Gq/11 mut who have not received prior TMZ/DTIC. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall survival (OS) and response rate (RR). Select pts underwent tumor biopsies at baseline and after 14 (+/- 3 days) of sel. Our statistical plan required ≥80 pts randomized and ≥68 events to detect a PFS hazard ratio of 0.6 (p=0.1). Randomization was stratified by mut (Gq vs G11), M stage and number of prior therapies (tx). Tumor assessment occurred every 4 weeks (wks) for 8 wks and then every 8 wks using RECIST 1.1. Pts receiving TMZ who progressed could receive sel (TMZ→sel). Results: 80 pts were randomized. Sel (n=39): median age 66 (range 32-86), 54% male, 54% G11 mut, median ECOG PS 0 (range 0-1), 97% M1c, median prior tx 0 (range 0-2). TMZ (n=41): median age 60 (range 34-81), 63% male, 58% G11 mut, median ECOG PS 0 (range 0-1), 93% M1c, median prior tx 0 (range 0-2). 11/39 (28%) pts on sel experienced grade (gr) 3 toxicity (tox) manageable with dose modification (5 CPK elevation, 3 LFT elevation, 1 rash, 1 lymphopenia, 1 edema). 1/41 (2%) pt on TMZ experienced gr 3 tox (neutropenia). No gr 4/5 tox occurred. 28 pts on sel underwent paired tumor biopsies with inhibition of pERK and cyclinD1 observed by Western blot at day 14. At interim analysis (9/25/12), 55 pts were evaluable with 45 progression events and 16 deaths. Sel (n=27): median PFS 16 wks (95% CI 8-30.9), RR 11%, median OS 11.8 months (95% CI 4.8-not reached). TMZ (n=28): median PFS 4 wks (95% CI 3.7-15), RR 0%, median OS 4.7 months (95% CI 4.3-14.3). TMZ→sel (n=25): median PFS 8.1 wks (95% CI 7-15), RR 0%. Conclusions: Sel is the first drug to ever show improved clinical activity in UM relative to TMZ. Sustained target inhibition is observed with sel. Final results will be presented. Clinical trial information: NCT01143402.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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 teacher head, 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".