| General information |
| Database: | DB00048 |
| Objective: | BRAF V600 mutations occur in 515% of metastatic CRC and predict poor prognosis. Although highly effective in BRAF mutant melanoma, BRAF inhibitor monotherapy has shown poor efficacy in BRAF mutant CRC. Preclinical data suggest that improved MAPK pathway suppression with combined inhibition of BRAF and MEK may improve efficacy. |
| Authors: | Ryan Bruce Corcoran, et al |
| Title: | Phase 12 trial of the BRAF inhibitor dabrafenib (D) plus MEK inhibitor trametinib (T) in BRAF V600 mutant colorectal cancer (CRC): Updated efficacy and biomarker analysis. |
| Journal: | J Clin Oncol |
| Year: | 2014 |
| PMID: | http://meeting.ascopubs.org/cgi/content/abstract/32/15_suppl/3517 |
| Trial Design |
| Clinical Trial Id: | IND No: 113, 557. |
| Agent: | dabrafenib
|
| Target: | BRaf protooncogene serine/threonineprotein kinase
|
| Cancer Type: | colorectal cancer |
| Cancer Subtype: | BRAF V600 mutant advanced colorectal cancer |
| Therapy Type: | com |
| Therapeutic Combination Type: | 1 |
| Therapeutic Combination Content: | BRAF inhibitor dabrafenib (D)+ MEK inhibitor trametinib (T) |
| Study Type: | a phase III trial |
| Key Patients Feature: | patients (pts) with BRAFV600 mutant stage IV CRC |
| Biomarker: | BRAF V600 mutant; |
| Biomark Analysis: | Mutational analysis of 15 subjects has been completed to date. The pt with CR and 2 of 3 evaluable pts with PR had PIK3CA mutation. Neither PTEN loss nor MSI correlated with efficacy. |
| Control Group Info: | single arm |
| Treatment Info: | patients were treated with D (150mg BID) and T (2mg QD), 17 of whom were enrolled in a pharmacodynamic cohort with tumor biopsies pretreatment and after 2 weeks of therapy. Archival tissues were analyzed for microsatellite instability (MSI), PTEN loss, and 487gene sequencing (Illumina). |
| Primary End Point: | efficacy and biomarker analysis. |
| Secondary End Point: | NA |
| Patients Number: | 43 |
| Trial Results |
| DLT_MTD: | not mentioned |
| Objective Response Rate: | 5 (12%) achieved partial response (PR) or better (with or without confirmation), including 1 (2%) pt with complete response (CR) ongoing >22 months. |
| Disease Control Rate: | An additional 22 (51%) pts achieved stable disease (SD) at first restaging, of which 11 (26%) pts had a minor response (10% to 30% tumor reduction). 10 (23%) pts remained on study >6 months. |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | NA |
| Conclusions: | The combination of D + T has activity in a subset of BRAF V600 mutant CRC pts, with several PRs and a durable CR. MAPK signaling was inhibited in all pts evaluated, but to a lesser degree than observed in BRAF mutant melanoma with D as a single agent. PIK3CA mutations they were identified in responding patients and thus do not preclude response to this regimen, but a definitive correlation bettheyen PIK3CA mutations and efficacy cannot be established given the limited pt sample. Biomarker refinement and additional therapeutic combinations may improve clinical activity. |