Response and Resistance Tested With BRAF/MEK Inhibition

Michael A. Davies, MD

Michael A. Davies, MD

Current trends and recent advances have reinforced the superiority of combined inhibition of BRAF/MEK in melanoma treatment, according Michael A. Davies, MD, during a summary of studies in melanoma that he presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting.

“The treatment of melanoma is evolving rapidly,” said Davies, Department of Melanoma Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center in Houston, Texas, in an interview withTargeted Oncology. “In parallel to the recent advances in immunotherapy, there has also been significant progress in the optimization of targeted therapy strategies for melanoma patients withBRAFmutations, which is the most common oncogenic event in this disease. The research presented at ASCO reinforces the superiority of combined inhibition of BRAF and MEK compared to single-agent BRAF-inhibitor therapy in patients with metastatic melanoma and activatingBRAFmutations,” Davies said.

About 45% of cutaneous melanomas have an activating mutation in theBRAFgene, with 90% of these due to single amino acid substitution atBRAF^V600E, making it an ideal target for inhibitor-mediated therapies. After initial setback with the RAF inhibitor sorafenib (Nexavar), sufficient data supported clinical benefit of targetingBRAFmutations with inhibitors, driving approval of single-agent BRAF inhibitors vemurafenib (Zelboraf) in 2011 and dabrafenib (Taflinar) in 2013 by the US Food and Drug Administration (FDA).

Although single-target BRAF inhibitors have been validated, key limiting factors have also been observed, including de novo resistance, acquired resistance, and associated toxicities. A major challenge is the developed resistance to single-agent BRAF inhibitors, mostly by reactivation of MEF pathway. Additionally, common toxicities in secondary malignancies due to paradoxical activation of MEK pathway inhibition have also been observed. A combination therapy approach using BRAF and MEK inhibitors is therefore warranted.

Several inhibitors, such as Genentech’s cobimetinib and vemurafenib, and Array Biopharma’s MEK inhibitor binimetinib and BRAF inhibitor encorafenib, are currently being tested. Two randomized, phase III studies have demonstrated superior response rates and progression-free survival (PFS) with combination therapy versus either single-agent trametinib (Mekinist) or single-agent dabrafenib.

An early phase Ib/II efficacy study, presented by Ryan J. Sullivan, MD, oncologist at the Dana-Farber Cancer Center in Boston, on the combination regimen of binimetinib with encorafenib, showed an impressive 75% response rate (41 of 55) for patients who are BRAF-naïve¹; 100% disease control and a median PFS of 11.3 months were also observed in these patients. However, dramatic differences in treatment outcome based on patient serum lactate dehydrogenase (LDH) levels were observed. While median PFS of 20 months was observed in patients with low serum LDH, the outcome was 7 months in patients with elevated LDH.

Davies concluded that while this is an early-phase study with great response rates and PFS, particularly in the LDH-free population, longer follow-up, randomized studies, and planned triplet combination studies are needed. The study found significant differences in associated toxicities compared with other combination studies.

A second study, presented at the 2015 ASCO meeting by James M.G. Larkin, MD, at The Royal Marsden Hospital in London, England, was a coBRIM update of PFS and biomarker analysis.²Response data with additional follow-up showed migration from partial to complete response with a combined response rate of 16%; the longer follow-up allowed an accurate reading of PFS of over a year. “This is a first benchmark of combination therapy PFS of over a year,” said Davies.

To find better predictors of patient outcomes based on mutagenic profiling, the study included molecular analysis of pretreatment and post-treatment samples; 11% of the samples had mutations in conserved regions as revealed by next-generation sequencing for a panel of oncogenes. However, no correlation in response rates to PFS and mutagenic profiles was observed. “With the high frequency of mutation rate, it is challenging to separate functional and nonfunctional mutations,” said Davies. A deeper look at the data to mine relevant mutations is now required to detect some correlation, he said. Addition of overall survival data later this year will bring investigators closer to an overall assessment of the results.

The third study, a multicenter meta-analysis of BRAF inhibitor-acquired resistance presented by Douglas B. Johnson, MD, MSCI, of Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, looked at outcomes based on frequency, timing of onset, and clinical association.³Clinical and genetic data from three studies were included.^4-6No difference in clinical outcomes with overall survival and no clear correlation between mechanisms of resistance and subsequent responsiveness to combination treatment with BRAF and MEK inhibitors were observed. Most patients with multiple biopsies had distinct mechanisms of resistance showing heterogeneity of resistance.

The key question here is, how much of the lack of correlation can be attributed to intragenic heterogeneity. “While the technical gaps in the study can be filled by a more uniform molecular testing, confirmation of molecular heterogeneity of resistance remains challenging,” said Davies, adding that the shortcomings can be addressed by global approaches to assess resistance.

In summary, Davies concluded that “key challenges remain to identify the melanoma patients who achieve the most durable responses to targeted therapies, and to identify strategies that prevent or overcome resistance to them.”

References

1. Sullivan RJ. A phase Ib/II study of BRAF inhibitor (BRAFi) encorafenib (ENCO) plus MEK inhibitor (MEKi) binimetinib (BINI) in cutaneous melanoma patients naive to BRAFi treatment. 2015 ASCO Annual Meeting; Melanoma/Skin Cancers Oral Abstract Session.
2. Larkin JMG.Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutatedmelanoma.2015 ASCO Annual Meeting;Melanoma/Skin Cancers Oral Abstract Session.
3. Johnson DB. BRAF inhibitor acquired resistance: a multicenter meta-analysis of the spectrum and clinical implications of resistance mechanisms. 2015 ASCO Annual Meeting; Melanoma/Skin Cancers Oral Abstract Session.
4. Rizos H, Menzies AM, Gulietta M, et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact.Clin Cancer Res. 2014;20:1965-1977.
5. Van Allen EM, Wagle N, Sucker A, et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma.Cancer Discov. 2014;4:94-109.
6. Shi H, Hugo W, Kong X, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy.Cancer Discov. 2014;4:80-93.