Preliminary results from a phase Ib/II, open-label, dose-escalation study of the oral BRAF inhibitor LGX818 in combination with the oral MEK1/2 inhibitor MEK162 in <i>BRAF</i> V600-dependent advanced solid tumors.
Bibliographic record
Abstract
9029 Background: Clinical data indicate that combining a BRAF and a MEK inhibitor (BRAFi, MEKi) may be more effective than BRAFi monotherapy in BRAF-mutant metastatic melanoma and that a MEKi may overcome or delay resistance to a BRAFi. Methods: This ongoing phase 1b/2 study is evaluating the combination of LGX818, a potent, selective BRAF inhibitor, and MEK162, a selective MEK1/2 inhibitor, in BRAFi-naive and -pretreated patients with BRAF-mutant tumors. The objective of the phase 1b part is to determine the maximum tolerated dose and/or recommended phase 2 dose (RP2D) for oral, daily LGX818 + MEK162 in BRAF V600–mutant advanced solid tumors. A Bayesian logistic regression model with overdose control guides the treatment dose escalation. Results: As of January 8, 2013, 20 patients (7 BRAFi-naive melanoma; 9 BRAFi-pretreated melanoma; 2 BRAFi-naive thyroid cancer; 1 BRAFi-naive metastatic colorectal cancer; 1 BRAFi-pretreated colorectal cancer) were treated with LGX818 qd + MEK162 bid at the following dose levels (DLs): 50 mg + 45 mg, 100 mg + 45 mg, 200 mg + 45 mg, and 400 mg + 45 mg. No dose-limiting toxicity has been observed at these DLs. The next DL of 600 mg + 45 mg is under investigation. The single agent RP2Ds for LGX818 and MEK162 are 450 mg and 45 mg, respectively. The most common adverse events (≥ 20%, all grades) suspected to be treatment related were nausea, abdominal pain, and headache. No events of fever, hand-foot-skin reactions, hyperkeratosis, or squamous cell carcinoma were observed. In patients with at least 1 post-baseline CT scan available for investigator-determined response, a complete response was observed in 1/7 (14%) BRAFi-naïve melanoma patients and partial responses were observed in 5/7 (71%) BRAFi-naive melanoma patients, 2/9 (22%) BRAFi-pretreated melanoma patients (starting at 50 mg + 45 mg DL), and 1/2 thyroid cancer patients. Conclusions: Preliminary data from this study indicate that LGX818 + MEK162 can be safely combined with promising clinical benefit. No febrile events or photosensitivity were reported suggesting a distinct safety profile for this BRAFi/MEKi combination vs others. Clinical trial information: NCT01543698.
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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 | 0.001 |
| 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 | 0.001 |
| 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".