COMBI-MB: A phase II study of combination dabrafenib (D) and trametinib (T) in patients (pts) with <i>BRAF</i> V600–mutant (mut) melanoma brain metastases (MBM).
Bibliographic record
Abstract
9506 Background: CNS metastases are common and associated with very poor prognosis in pts with metastatic melanoma (MM). In the phase II BREAK-MB trial, D had clinical activity in BRAF V600–mut MBM. D + T has shown superiority over D alone in pts with BRAF V600–mut mm without MBM; however, efficacy of this regimen on MBM has not been characterized. Here, we report results from a phase II trial of D + T in BRAFV600–mut MBM (COMBI-MB; NCT02039947). Methods: This open-label, phase II study evaluated D 150 mg BID + T 2 mg QD in 4 MBM cohorts: (A) BRAFV600E, asymptomatic MBM, no prior local treatment (Tx); (B) BRAFV600E, asymptomatic MBM, prior local Tx; (C) BRAFV600D/K/R, asymptomatic MBM, with or without prior local Tx; and (D) BRAFV600D/E/K/R, symptomatic MBM, with or without prior local Tx. The primary objective was intracranial response rate (IRR) in cohort A (null hypothesis, IRR ≤ 35%). Secondary endpoints included IRR in cohorts B, C, and D; extracranial (ERR) and overall (ORR) response rates; intracranial (IDCR), extracranial (EDCR), and overall (ODCR) disease control rates; duration of IR, ER, and OR; PFS; OS; and safety. Results: 125 pts were enrolled (A, n = 76; B, n = 16; C, n = 16; D, n = 17). In cohort A, median age was 52, 53% were male, and 37% had LDH > ULN. At data cutoff (28 Nov 2016; median f/u, 9.0 mo), in cohort A, investigator-assessed IRR was 58% (IDCR, 78%), ERR was 55% (EDCR, 80%), and ORR was 58% (ODCR, 80%). Median duration of IR, ER, and OR was 6.5 mo (95% CI, 4.9-10.3), 10.2 mo (95% CI, 6.5-13.0), and 6.5 mo (95% CI, 4.9-10.3), respectively. Median PFS was 5.6 mo (95% CI, 5.3-7.4). Independent review supported these results. 6-mo OS was 79%; with 31 pts (41%) still in f/u, preliminary median OS was 10.8 mo (95% CI, 8.7-19.6). Efficacy in cohorts B, C, and D will be reported. AEs across cohorts (any, 98%; grade 3/4, 48%) were consistent with prior D + T studies; 10% of pts (8% in cohort A) discontinued due to AEs. Conclusions: In this first report of a phase II trial evaluating a BRAF and MEK inhibitor combination in BRAFV600–mut MBM, the primary endpoint was met. Promising IRR and IDCR were seen with D + T, but responses appear less durable than reported for mm without MBMs. No unexpected safety issues were observed. Clinical trial information: NCT02039947.
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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 | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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".