Keith T. Flaherty, MD, discusses molecular testing issues and the use of combined BRAF/ MEK inhibition in patients with advanced/metastatic melanoma.
Keith T. Flaherty, MD
Keith T. Flaherty, MD, is director of the Termeer Center and Clinical Research at Massachusetts General Hospital Cancer Center, in Boston, Massachusetts. OncologyLive spoke with Flaherty about molecular testing issues and the use of combined BRAF/ MEK inhibition in patients with advanced/metastatic melanoma.At the moment, the only molecular feature in melanoma that is critical to treatment decision making is the presence or absence of a V600 BRAF mutation. Approximately 45% of all patients with advanced melanoma will harbor an activating BRAF mutation at this position. We’ve learned that BRAF mutations arise at a very early point in the development of a melanocytic proliferation. In fact, some studies suggest that as many as 80% of benign nevi have these same V600 BRAF mutations. The best available evidence indicates that BRAF mutations are stably present in all tumor cells in lymph node and visceral metastases, whereas there can be heterogeneity in the primary melanoma.
It is this data that drive the recommended practice of performing BRAF mutation testing in metastatic tumor sites, with previously resected regional lymph nodes (for patients who had stage III disease prior to developing stage IV disease) being a reliable source of tumor material for this testing. At the time of approval of BRAF and MEK inhibitors for the treatment of this population, specific PCR-based methods were developed and approved by the FDA as a basis for identifying candidates for these drugs.In approximately 1% of all melanomas, cKIT mutations have been identified. They are largely confined to acral and mucosal melanomas. Phase II trials have demonstrated that cKIT inhibitors that are FDA approved for treatment of GIST (cKIT mutations are present in 60% of cases) are associated with approximately 20% response rates. This has led to inclusion of cKIT testing and use of these drugs in NCCN guidelines, but none of these agents have been considered for FDA approval.
Beyond V600 BRAF mutations, there are other types of mutations and gene translocations events involving BRAF that are found in approximately 5% of all melanomas.
There are other mutations that we believe can serve a similar function to mutated BRAF. NRAS mutations occur in a mutually exclusive 20% subpopulation of patients with melanoma. Inactivating mutations in NF1 occur in another 12% of cases, but can occur with or without BRAF and NRAS mutations. Presently, testing for non-V600 BRAF mutations or other mutations noted above is helpful for navigating clinical trial options.An important observation from clinical trials establishing the benefit of immune checkpoint antibody therapy is the roughly equal efficacy in patients with or without BRAF mutations. In light of that, patients with V600 BRAF mutations have multiple options for therapy in the metastatic setting, including both immunotherapy and molecularly targeted therapy.
Phase III trials have demonstrated that single- agent BRAF (vemurafenib or dabrafenib) or MEK (trametinib) inhibitor therapy improves response rates, progression and overall survival compared with historically standard chemotherapy. More recently, combined BRAF and MEK inhibition (dabrafenib/trametinib or vemurafenib/ cobimetinib) have demonstrated improved response rates, progression, and overall survival compared with BRAF inhibitor monotherapy. And, toxicities are largely comparable with regard to moderate and severe toxicity rates seen with BRAF-inhibitor monotherapy.
For these reasons, combined BRAF/MEK-inhibitor therapy is considered to be the recommend approach for molecularly targeted therapy. Presently, we lack data that inform the choice between molecularly targeted therapy and immunotherapy. In addition to data showing clear benefit for treatment-naïve patients, there are phase II data that indicate that BRAF inhibitor-based therapy or PD-1 antibody therapy can produce meaningful response rates in patients who have progressed following first-line treatment.There are two bases for adding a MEK inhibitor to a BRAF inhibitor: one related to overcoming resistance and the other to countering a mechanism of toxicity. Analysis of patients’ tumor specimens at the time of progression on single- agent BRAF-inhibitor therapy is typically associated with evidence of reactivation of the BRAF (aka MAP kinase) pathway.
Taken in conjunction with evidence of consistent and profound suppression of the pathway early in the course of therapy, this evidence suggests that BRAF-mutant tumors require the activity to be restored in most cases. A number of molecular drivers of this pathway reactivation have been identified, but none of them have yet been identified in tumor prior to initiation of therapy. Therefore, preclinical and clinical trials were initiated to investigate the potential for a MEK inhibitor to impede some of these resistance mechanisms, as MEK is a molecule downstream of BRAF in the pathway.
With regard to toxicity, proliferative skin lesions are commonly seen in the setting of BRAF inhibitor monotherapy. These can include benign keratoses, papillomas, keratoacanthomas, but also well-differentiated cutaneous squamous cell carcinomas. These observations were made in parallel with laboratory discoveries regarding the ability of BRAF inhibitors (like vemurafenib and dabrafenib) to activate the BRAF/MAP-kinase pathway in some contexts.
A notable example is the pathway and growth-stimulating effects of these drugs in cell-harboring RAS mutations. In the BRAF-inhibitor— treated patient population, the majority of squamous cell carcinomas have HRAS mutations. This evidence supported the use of MEK inhibitors to block these effects, as MEK inhibitors block pathway activity in BRAF- or RAS-mutated cells, and most other cell types.There are no specific clinical or demographic characteristics that preclude consideration of BRAF-inhibitor—based therapy. However, in clinical trials, patients were required to have good performance status and near-normal renal and liver function. That leaves uncertainty with regard to preserved efficacy in patients with poor performance status or with organ dysfunction. Dedicated phase II trials have been initiated in these populations.