Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer

Abstract

Purpose: BRAF V600E mutation is seen in 5% to 8% of patients with metastatic colorectal cancer (CRC) and is associated with poor prognosis. Vemurafenib, an oral BRAF V600 inhibitor, has pronounced activity in patients with metastatic melanoma, but its activity in patients with BRAF V600E-positive metastatic CRC was unknown.

Patients and methods: In this multi-institutional, open-label study, patients with metastatic CRC with BRAF V600 mutations were recruited to an expansion cohort at the previously determined maximum-tolerated dose of 960 mg orally twice a day.

Results: Twenty-one patients were enrolled, of whom 20 had received at least one prior metastatic chemotherapy regimen. Grade 3 toxicities included keratoacanthomas, rash, fatigue, and arthralgia. Of the 21 patients treated, one patient had a confirmed partial response (5%; 95% CI, 1% to 24%) and seven other patients had stable disease by RECIST criteria. Median progression-free survival was 2.1 months. Patterns of concurrent mutations, microsatellite instability status, CpG island methylation status, PTEN loss, EGFR expression, and copy number alterations were not associated with clinical benefit. In contrast to prior expectations, concurrent KRAS and NRAS mutations were detected at low allele frequency in a subset of the patients' tumors (median, 0.21% allele frequency) and were apparent mechanisms of acquired resistance in vemurafenib-sensitive patient-derived xenograft models.

Conclusion: In marked contrast to the results seen in patients with BRAF V600E-mutant melanoma, single-agent vemurafenib did not show meaningful clinical activity in patients with BRAF V600E mutant CRC. Combination strategies are now under development and may be informed by the presence of intratumor heterogeneity of KRAS and NRAS mutations.

Trial registration: ClinicalTrials.gov NCT00405587.

Fig 1.

(A) Waterfall plot of best RECIST response to vemurafenib in evaluable patients. (*) Fifty-nine percent growth from baseline. (†) Patients with notable mixed responses. (B) Progression-free survival. (C) Overall survival.

Fig 2.

Correlation of best overall response rate with molecular characterization. Gray boxes represent samples unable to be analyzed for the specified assay. Numbers in the copy number (CN) alteration boxes represent the number of unique segments with CN alterations. Percentages in the RAS clone box represent mutant allele frequency. (*) Not evaluable for response.

Fig 3.

(A) Rare KRAS-mutant (mut) clones were detected in a validated cohort of BRAF V600E–mutant colorectal cancer tumors by droplet digital polymerase chain reaction (ddPCR). (*) Lower limit of detection for clinical sequencing is approximately 5% to 20% depending on assays used. (†) Lower limit of detection for ddPCR. (B) A patient-derived xenograft model developed resistance to vemurafenib analog PLX4720 provided through ad lib chow at a dose of 417 mg/kg. Gray represents control arm; blue and gold represent PLX4720 treatment arm with acquisition of KRAS G12R and G12D mutations, respectively.

Fig A1.

Development of keratoacanthoma while on therapy. (A) Before initiation of therapy and (B) after 8 weeks of treatment. (C and D) Development of multiple keratoacanthomas requiring treatment discontinuation.

Fig A2.

Mean steady-state concentration-time profile of patients with metastatic colorectal cancer (CRC) compared with patients with melanoma treated with vemurafenib 960 mg twice per day.

Fig A3.

Response by positron emission tomography to vemurafenib. (Top) Baseline scan. (Bottom) After one cycle of vemurafenib.

Fig A4.

(A) Progression-free survival (PFS) for patients with or without identified alterations resulting in PI3K pathway activation (as denoted in Fig 2). (B) PFS for patients with tumors with intact or absent EGFR expression by immunohistochemistry.