Phase I study of the selective BRAF<sup>V600 </sup>inhibitor encorafenib (LGX818) combined with cetuximab and with or without the α-specific PI3K inhibitor BYL719 in patients with advanced <i>BRAF</i>-mutant colorectal cancer.
Bibliographic record
Abstract
3514 Background: In contrast to BRAFV600 mutated (BRAFm) advanced melanoma, BRAFm colorectal carcinoma (CRC) does not respond to BRAF inhibitors due to strong feedback activation of the epidermal growth factor receptor (EGFR) upon BRAF inhibition. However, combining a BRAF and an EGFR inhibitor resulted in strong synergistic activity with complete inhibition of tumor growth in vitro and in vivo. The addition of a phosphatidylinositol 3-kinase (PI3K) inhibitor increased synergy. Methods: This is a phase I study evaluating safety, tolerability and anti-tumor activity of encorafenib (LGX818), a highly selective BRAF V600 inhibitor, the EGFR mAb cetuximab, ± the α-specificPI3K inhibitor BYL719 in patients (pts) with advanced BRAFm/KRAS wild-type CRC. Cohorts of pts were treated with escalating doses of oral encorafenib once daily in combination with IV cetuximab (400 mg/m2 loading dose, 250 mg/m2weekly) (dual arm), or with escalating doses of oral encorafenib and oral BYL719 once daily in combination with cetuximab (triple arm). Results: By November 08, 2013, 18 pts were enrolled across four dual combination dose levels: 100 (n = 2), 200 (n = 4), 400 (n = 9) and 450 mg (n = 3) encorafenib. Three pts were enrolled in the triple arm at 200 mg encorafenib, 100 mg BYL719 and cetuximab. Dose escalation has been completed in the dual arm where a phase 2 dose has been identified; dose finding is ongoing in the triple arm. In the dual arm, 2 dose-limiting toxicities, vomiting grade 3 (400 mg) and QTc prolongation grade 3 (450 mg), were observed, and fatigue (33%) and vomiting (28%) were the most frequently observed treatment-related adverse events. Three partial responses, including one in the triple arm, have been observed and prolonged disease stabilization was frequently achieved including two pts that have remained on treatment for one year. Decrease in carcinoembryonic antigen (CEA) has also been observed. Updated data from the triple arm will be presented. Conclusions: These results indicate that combination treatment of encorafenib and cetuximab ± BYL719 is well tolerated with promising antitumor activity in pts with advanced BRAFm CRC who failed standard treatment. Clinical trial information: NCT01719380.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 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".