Binimetinib and encorafenib for the treatment of advanced solid tumors with non-V600E BRAF mutations (mts): Final results of the investigator-initiated phase II BEAVER trial.
Bibliographic record
Abstract
3104 Background: Oncogenic non-V600E BRAF mts are present in many cancer types. Pre-clinical data indicate that some BRAF non-V600E mts can be targeted with BRAF + MEK inhibitors. The BEAVER trial was designed to test the safety and efficacy of binimetinib and encorafenib (B+E) in patients (pts) with non-V600E BRAF mts. Safety data were previously presented [ https://doi.org/10.1016/j.annonc.2021.08.1053 ]. Here, we present the final analysis of the efficacy and exploratory objectives. Methods: Key eligibility criteria were: pts with advanced solid tumors with non-V600E activating (Class 1 and 2) or inhibitory (Class 3) BRAF mts, and no prior BRAF/MEK inhibitors. Pts received binimetinib (45mg PO BID) and encorafenib (450mg PO daily) on a 28-day cycle until intolerable toxicity or progression. The primary objective is OR rate (ORR) as per RECIST 1.1. Secondary objectives included PFS. Log-rank test was used to assess PFS. Exploratory objectives included: development of patient derived xenograft (PDX) models, and genomic/transcriptomic profiling of tumors. Mice bearing PDXs were treated with inhibitors and tumors were measured by caliper measurement. Whole exome and RNAseq was performed on PDXs. Results: From June 2019 to Nov 2023, 27 pts were screened and 23 pts enrolled; 21 are evaluable for ORR. Tumor types were melanoma, colorectal and pancreaticobiliary (n=6 each), lung (n=2), and breast, uterine, and small bowel cancers (n=1 each).Median age was 59 yrs (range 40-73). Pts had Class 1 (n=1), Class 2 (n=9), and Class 3 (n=13) BRAF mts. Best ORR was 13% (3/23) with one confirmed PR in a pt with ampullary cancer (BRAF D594G) and unconfirmed PRs in 2 melanoma pts (BRAF G469S and K601E), 4 pts had SD as best response. The median PFS was 2.4 months (mo) in the entire cohort. BRAF mt Class was not associated with differences in PFS or ORR. TP53 was the most frequently co-mutated gene (9/23; 39%) and pts with TP53 mts experienced shorter PFS (1.8 vs. 4.0 mo, P=0.008). Pts with melanoma (4.0 mo) experienced longer PFS than pts with pancreaticobiliary (2.6 mo) colorectal (1.8 mo) or other tumor types (1.6 mo); P=0.006. PDX models were established from 9 pts, 8/9 PDXs expressed the same BRAF mt as corresponding pt tumor. Responses to B+E in BRAF mt PDX models correlated with pt tumor measurements (R=-0.63; P=0.046). RNAseq of PDXs identified PTPN11 (Shp2) and CDK4/6 as potential therapeutic targets in B+E-resistant PDXs. Combination therapies with a Shp2 inhibitor or a CDK4/6 inhibitor significantly enhanced B+E-induced tumor growth inhibition in multiple PDX models. Conclusions: B+E has only modest clinical activity in advanced cancers with non-V600E BRAF mts and resistance to B+E develops quickly. Alternative approaches incorporating Shp2 and CDK4/6 inhibitors warrant further investigation in this patient population. Clinical trial information: NCT03839342 .
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 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".