ESMO 2016: Vemurafenib Shows Clinical Benefit in Diverse BRAF V600-Mutated Tumours

Patients with BRAF non-V600 mutated tumours show no benefit with vemurafenib

Findings from a phase II trial of vemurafenib in previously treated patients with advanced disease and BRAF mutated tumours indicate the drug is effective in patients with diverse BRAF V600-mutated tumours, but not in patients with BRAF non-V600 mutations. After a treatment duration of mean 1.9 (range: 0.2 to 11.0) months, anti-tumour activity of vemurafenib was found in non-small cell lung cancer (NSCLC), hairy cell leukaemia (HCL) and miscellaneous cohort of BRAF V600 mutated tumours, while non-V600 mutated tumours derived no benefit.

Vemurafenib is approved for BRAF mutated melanoma and has shown activity in other non-melanoma tumours that harbour BRAF-V600E-mutations, which have been reported to be present at low (<5%) frequency.

This study was part of a programme instituted by the French National Cancer Institute

Jean-Yves Blay, Medical Oncology, Centre Léon Bérard, in Lyon, France, presented results from the second ACSE vemurafenib study at the ESMO 2016 Congress in Copenhagen, Denmark on 9 October. Professor 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.

This phase II trial enrolled patients who had failed standard treatment for different types of advanced cancers. All patients had a BRAF mutation that was identified using INCa molecular genetic platforms. Of the more than 1500 patients screened for mutations at 96 centres throughout France, 78 patients with BRAF V600 and BRAF non-V600 mutations were enrolled and treated with vemurafenib at 960 mg BID twice daily.

The dedicated treatment cohort comprised diverse BRAF V600 positive cancer types including lung, ovarian, bladder, thyroid, prostate cancers, cholangiocarcinoma, sarcoma/gastrointestinal stromal tumour (GIST), multiple myeloma, chronic lymphocytic leukemia (CLL), and HCL. The specific miscellaneous cohort comprised patients with non-V600 BRAF (exon 11, 15) mutated tumours or other BRAF alterations.

The efficacy endpoint was objective response rate (ORR), which was evaluated every 8 weeks by RECIST v1.1 criteria for solid tumours and by specific criteria for myeloma, CLL and HCL. Treatment could be halted early when an inefficacy boundary for OR of 10% that was determined by a Bayesian approach was demonstrated.

The median age of the patients was 67 (range: 18 to 84) years and 51% of patients were female. Data from 56 patients were analysed for response and reported by mutation status and cancer subtype.

Response to vemurafenib was demonstrated across diverse cancer types

In the cohort of patients with BRAF V600 positive cancers, 31 patients with NSCLC cancer demonstrated an ORR of 43%; 13 patients achieved partial response (PR), 6 showed stable disease (SD), 7 patients experienced progressive disease (PD), 4 patients died, and the data were missing for one patient. In patients with HCL, 4 of 4 patients having evaluable data showed an ORR of 100%; 2 patients demonstrated PR and 2 patients had SD. 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, one patient demonstrated SD and 2 PD.

In the miscellaneous cohort, 5 of 6 patients with BRAF V-600 mutations had evaluable data: PR was achieved by 3 of these patients and 2 patients showed SD, resulting in an ORR of 60%. All 6 patients with BRAF non V-600 mutated tumours experienced PD.

Caroline Dive who discussed the study findings asked if we have known enough (or use enough) knowledge of the biology? RAF inhibition in colorectal cancer patients with BRAF mutations is not effective. Most BRAF mutants stimulate enhanced B-Raf kinase activity increasing MEK. A few BRAF mutations (D594G, G446E, D287H) reduce MEK and may activate wild type C-Raf driving ERK when treated with vemurafenib. She questioned if these mutants were included in the study. Furthermore she asked if there is worse outcome than expected for non-V600E mutant patients (no benefit reported), was RAS or any upstream regulators of BRAF screened, and impact on outcomes. Headline of ORR in NSCLC of 43% is eye-catching. Key however, is durability of response. Typically imaging is done at 8 weeks, and response confirmed at 12 weeks. Median PFS was 3.9 months, maximum 8 months. If V600 clones are eradicated, does rest of tumour continues to grow? She asked if combination approach is required. In addition, significant toxicity is noted.

Treatment with vemurafenib was well tolerated

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 programme for BRAF mutation allowed patients with BRAF mutated disease to have faster access to treatment in this trial. Although vemurafenib demonstrated important anti-tumour activity in NSCLC, HCL, and miscellaneous V600 mutation positive tumours, patients with BRAF non-V600 mutated tumours derived no benefit.

Reference 

55PD Vemurafenib (VM) in non-melanoma V600 and non-V600 BRAF mutated cancers: First results of the ACSE trial

J.-Y. Blay, J. Mazieres, D. Perol, F. Barlesi, D. Moro-Sibilot, G. Quere, J. Tredaniel, X. Troussard, S. Leboulleux, D. Malka, A. Flechon, C. Linassier, I.L. Ray-Coquard, B. Arnulf, I. Bieche, G. Ferretti, F. Nowak, M. Jimenez, N. Hoog-Labouret, A. Buzyn 

This trial was funded by UNICANCER, Inca and ARC.