Simultaneous inhibition of BRAF and MEK improves progression-free survival (PFS) more so than BRAF inhibition alone in patients with advance BRAF V600 mutation-positive melanoma, according to results of a phase III, placebo-controlled trial reported at the European Cancer Congress (ECC 2015), convening in Vienna, Austria, 25 - 29 September 2015. An analysis of genetic alterations shows that the advantage seen with combination treatment is consistent across several mutation types including patients with mutational subclones that might be predicted to induce resistance.
Results from an analysis done at 14.2 month follow-up favoured cobimetinib plus vemurafenib over vemurafenib monotherapy in terms of progression-free survival (PFS), overall response rate (ORR), and the rate of complete response (CR). Median PFS at follow-up was 12.3 months with the combination compared to 7.2 months with sole vemurafenib; hazard ratio [HR] 0.58. The ORR was 70% versus 50%, and the rate of CR were 16% versus 11% with cobimetinib plus vemurafenib versus vemurafenib, respectively.
Cobimetinib is an extremely selective allosteric small molecule inhibitor of MEK and was used with vemurafenib in this study to achieve co-inhibition of BRAF and MEK.
According to Grant McArthur, head of the Cancer Therapeutics Program at the Peter MacCallum Cancer Center in Melbourne, Australia, the most common mechanism of acquired resistance to the BRAF inhibitor vemurafenib is reactivation of cell growth via the MAPK pathway through MEK. Therefore, administering a BRAF inhibitor and MEK inhibitor together in the first-line setting turns off the two individual proteins, increasing pathway inhibition and delaying development of resistance that is observed with BRAF inhibition alone.
Examining impact of baseline tumour heterogeneity
Dr. McArthur presented updated efficacy results and findings from the ongoing coBRIM study, together with an analysis of outcome according to individual mutations present in tumour tissue taken prior to treatment during the Proffered Papers: Melanoma and Skin Cancer session on 27 September.
Findings from the primary coBRIM study (NCT01689519) at a median follow-up of 7.3 months were presented at ESMO 2014 that showed treatment-naive BRAFV600 mutation–positive patients with advanced melanoma receiving cobimetinib plus vemurafenib demonstrated significant improvement in PFS and ORR.
The study reported at the ECC examines the impact of baseline tumour heterogeneity, including BRAFV600 copy number, RAS and other genetic sequence variants that could drive resistance, on clinical outcome following treatment, especially on PFS, at a median follow-up of 14.2 months.
Tumour samples collected prior to treatment from the previously described coBRIM study were analysed by targeted deep-sequencing to a median coverage of 3600×. Variant allele frequency was calculated as a ratio of the variant allele to total read depth at the V600 codon and hotspots in 17 additional oncogenes. Immunohistochemistry was used to assay PTEN loss and Cox proportional hazards modelling was used to determine the association between biomarker parameters and PFS observed until the data cut-off of 16 January 2015.
Benefit from cobimetinib/vemurafenib combination therapy consistent across mutation subgroups
Treatment with cobimetinib/vemurafenib showed clinical benefit that was consistent across every patient subgroup evaluated, including patients with BRAFV600K and BRAFV600E mutation, where median PFS of 12.4 months, HR 0.52 (95% CI 0.27, 1.02) and 10.6 months, HR 0.64 (95% CI 0.49, 0.83), respectively, were observed.
Patients receiving either cobimetinib/vemurafenib or vemurafenib monotherapy with BRAF allelic frequency above the median (>33%) that is an indirect measure of copy number achieved similar median PFS as patients with low allelic frequency.
The presence of co-mutation in oncogene hotspots and tumour suppressor genes known to mediate resistance to BRAF or MEK inhibition, including RAS, RTK, and PTEN, at allele frequencies of >3% (median 8.6%) had no impact on PFS in either arm, with the exception of PIK3CA mutation or PTEN loss.
coBRIM – Addition of cobimetinib to vemurafenib overcomes the negative impact of PTEN loss on progression-free survival.
Credit for image: Grant McArthur
Loss of PTEN expression was associated with shorter PFS in patients receiving vemurafenib monotherapy, as compared to patients with intact PTEN; HR, 1.6 (95% CI 0.96, 2.8). However, loss of PTEN did not affect PFS in patients receiving combination cobimetinib/vemurafenib.
Conclusions
Data from this longer follow-up of the coBRIM study confirms the clinical benefit of cobimetinib/vemurafenib in patients with advanced BRAFV600-mutant melanoma, according to the authors. Both retrospective and exploratory analyses indicate that allelic frequencies of baseline BRAFV600 mutations did not affect combination treatment outcome.
Furthermore, coexisting activating RAS and RTK mutations that can mediate resistance to BRAF and MEK inhibitors also did not affect treatment outcome, suggesting that cobimetinib/vemurafenib is effective in all patients harbouring the BRAFV600 mutation. In addition, cobimetinib/vemurafenib treatment overcame the detrimental effect of PTEN loss.
The data show that genomic heterogeneity at baseline is not necessarily associated with worse clinical outcome.
The authors suggest that the combination of a BRAF and MEK inhibitor will become a new standard treatment for advanced BRAF-mutant melanoma.
Disclosure: The study is sponsored by Hoffmann-La Roche.
Reference
25LBA Impact of baseline genetic heterogeneities on progression-free survival (PFS) in patients (pts) with advanced BRAFV600-mutated melanoma treated with cobimetinib (COBI) + vemurafenib (VEM) in the phase 3 coBRIM study
EMA: Summary of opinion (initial authorisation) cobimetinib
On 24 September 2015, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Cotellic, intended for the treatment of unresectable or metastatic melanoma in combination with vemurafenib. The applicant for this medicinal product is Roche Registration Ltd.
Cotellic will be available as 20 mg film-coated tablets. The active substance of Cotellic is cobimetinib, an antineoplastic agent (ATC code: L01) which blocks the mitogen-activated protein kinase (MAPK) pathway by targeting the kinases MEK1 and MEK2, thereby inhibiting intracellular signalling and decreasing tumour cell proliferation, and delaying the onset of resistance when compared to BRAF inhibitor monotherapy (vemurafenib).
The benefits with Cotellic are its ability to improve progression-free survival in melanoma patients with a BRAFV600 mutation compared with vemurafenib monotherapy. The most common side effects observed with a higher frequency in the Cotellic plus vemurafenib arm were diarrhoea, rash, nausea, pyrexia, photosensitivity reaction, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood creatine phosphokinase, and vomiting.
The full indication is: “Cotellic is indicated for use in combination with vemurafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see sections 4.4 and 5.1).” It is proposed that Cotellic in combination with vemurafenib should only be initiated and supervised by a qualified physician experienced in the use of anticancer medicinal products.
Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.