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 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 | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| 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".