ESMO 2016: Vemurafenib Shows Clinical Benefit in Diverse BRAF V600–Mutated Tumors
Findings from a phase II trial of vemurafenib in previously treated patients with advanced disease and BRAF-mutated tumors indicate that the drug is effective in patients with diverse BRAF V600–mutated tumors but not in patients with BRAF non-V600 mutations. After a mean treatment duration of 1.9 months (range = 0.2–11.0 months), antitumor activity of vemurafenib was found in non–small cell lung cancer (NSCLC), hairy cell leukemia (HCL), and a miscellaneous cohort of BRAF V600–mutated tumors, while non-V600–mutated tumors derived no benefit.
Vemurafenib is approved for BRAF-mutated melanoma and has shown activity in other nonmelanoma tumors that harbor BRAF V600E mutations, which have been reported to be present at low (< 5%) frequency.
Jean-Yves Blay, MD, PhD, medical oncologist at the Centre Léon Bérard, in Lyon, France, presented results from the phase II ACSE study at the 2016 European Society for Medical Oncology (ESMO) Congress in Copenhagen (Abstract 55PD). Dr. Blay explained that this study is part of an effort undertaken by the French National Cancer Institute (INCa) that attempts to avoid off-label use and to allow patients to have safe and controlled access to targeted therapies outside of the labeled indication.
ACSE Trial
The ACSE trial enrolled patients for whom standard treatment for different types of advanced cancers had failed. All patients had a BRAF mutation that was identified using INCa molecular genetic platforms. Of the more than 1,500 patients screened for mutations at 96 centers throughout France, 78 patients with BRAF V600 and BRAF non-V600 mutations were enrolled and treated with vemurafenib at 960 mg twice daily.
The dedicated treatment cohort comprised diverse BRAF V600–positive cancer types including lung, ovarian, bladder, thyroid, and prostate cancers; cholangiocarcinoma; sarcoma/gastrointestinal stromal tumor (GIST); multiple myeloma; chronic lymphocytic leukemia (CLL); and HCL. The specific miscellaneous cohort comprised patients with non-V600 BRAF (exon 11, 15)–mutated tumors or other BRAF alterations.
The efficacy endpoint was objective response rate (ORR), which was evaluated every 8 weeks by RECIST (Responce Evaluation Criteria in Solid Tumors) version 1.1 criteria for solid tumors and by specific criteria for myeloma, CLL, and HCL. Treatment could be halted early when an inefficacy boundary for objective response of 10% that was determined by a Bayesian approach was demonstrated.
The median age of the patients was 67 (range = 18–84) years, and 51% of patients were female. Data from 56 patients were analyzed for response and reported by mutation status and cancer subtype.
Response Demonstrated Across Tumor Types
In the cohort of patients with BRAF V600–positive cancers, 31 patients with NSCLC demonstrated an ORR of 43%; 13 patients achieved partial response, 6 showed stable disease, 7 patients experienced progressive disease, 4 patients died, and the data were missing for 1 patient.
In patients with HCL, 4 of 4 patients having evaluable data showed an ORR of 100%; 2 patients demonstrated a partial response, and 2 patients had stable disease.
The one patient with sarcoma died.
Of the 2 patients with cholangiocarcinoma, one patient also died and one patient demonstrated SD.
Of the 3 patients with thyroid cancer, 1 patient demonstrated stable disease and 2 had progressive disease.
In the miscellaneous cohort, 5 of 6 patients with BRAF V600 mutations had evaluable data: partial response was achieved by 3 of these patients, and 2 patients showed stable disease, resulting in an ORR of 60%. All 6 patients with BRAF non-V600–mutated tumors experienced progressive disease.
The most frequently reported treatment-related adverse events of grade 3 or greater were skin and gastrointestinal toxicities.
Conclusions
The authors concluded that the nationwide screening program for BRAF mutation allowed patients with BRAF-mutated disease to have faster access to treatment in this trial. Although vemurafenib demonstrated important antitumor activity in NSCLC, HCL, and miscellaneous V600 mutation–positive tumors, patients with BRAF non-V600–mutated tumors derived no benefit.
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