- BRAF mutations:
- Have been found in approximately 50% of invasive cutaneous melanomas
- The BRAF gene:
- Encodes for production of B-RAF:
- A protein involved in cell signaling and growth
- Encodes for production of B-RAF:
- BRIM-3:
- Was a randomized, open-label, multicenter, phase III study
- It compared a BRAF inhibitor, PLX4032 (vemurafenib), to dacarbazine:
- For treatment of previously untreated, unresectable, stage IIIC or stage IV melanoma in patients harboring a BRAF mutation
- The inhibitor targets the common V600E BRAF mutation
- Interim analysis of 675 patients revealed:
- Superiority in OS and PFS for vemurafenib
- The response rate of patients on vemurafenib:
- Was 48.4% compared to 5.5% for patients receiving dacarbazine
- While such a response rate for single modality therapy was essentially unprecedented in the treatment of metastatic melanoma:
- Enthusiasm was tempered, at least to some extent, by the observation that disease recurrence was observed in the majority of patients 6 to 8 months following initiation of therapy
- Also important was the observation that up to 25% of patients who received vemurafenib developed squamous carcinoma of the skin:
- Often in the form of keratoacanthomas
- Dabrafenib, another agent targeting BRAF V600 mutant melanoma:
- Demonstrated similarly high OR rates in a phase III trial
- Together, these findings provided the basis for approval of each of these agents as monotherapy in 2011 and 2013, respectively
- MEK, a kinase downstream of RAF in the MAPK pathway, has been targeted in a similar fashion:
- MEK inhibitors demonstrated benefit as monotherapy in patients with BRAF-mutant metastatic melanoma:
- Leading to the FDA approval of trametinib in 2013
- Of note, MEK inhibitors are rarely used as monotherapy for patients with BRAF-mutant metastatic melanoma
- MEK inhibitors demonstrated benefit as monotherapy in patients with BRAF-mutant metastatic melanoma:
- Numerous studies have elucidated acquired mechanisms of therapeutic resistance to BRAF-targeted therapy, and insights gained have led to treatment strategies to enhance responses to therapy:
- An outcome of this is the use of combined BRAF and MEK inhibition:
- Based on the observation that most BRAF-mutant melanomas demonstrate MAPK pathway reactivation at the time of therapeutic resistance
- This combination was tested in clinical trials in patients with BRAF-mutant melanoma:
- Results demonstrated that treatment with combined BRAF and MEK inhibition (e.g., dabrafenib plus trametinib vs. dabrafenib monotherapy):
- Was associated with:
- A higher overall response (76% vs. 54%), and with a longer PFS (9.4 months vs. 5.8 months) than with BRAF inhibitor monotherapy
- Was associated with:
- In January 2014, the FDA granted accelerated approval to combined dabrafenib and trametinib for use in combination in patients with unresectable or metastatic BRAF-mutant melanoma
- Results demonstrated that treatment with combined BRAF and MEK inhibition (e.g., dabrafenib plus trametinib vs. dabrafenib monotherapy):
- The following year, the FDA also approved the BRAF / MEK inhibitor combination of vemurafenib and cobimetinib (coBRIM study), and in 2018, encorafenib and binimetinib were added to the armamentarium (COLUMBUS trial)
- Importantly, neither BRAF inhibitor nor MEK inhibitor monotherapy is currently deployed in the current melanoma treatment landscape
- It should also be noted that BRAF inhibitors have been shown to paradoxically stimulate growth in patients with wild-type BRAF status
- The COMBI-MB clinical trial enrolled patients with melanoma brain metastases to receive dabrafenib and trametinib:
- Across four patient cohorts, intracranial response ranged from 44% to 59%, although duration of response was relatively short:
- As such, many medical oncologists prefer to use immunotherapy for brain metastases even in BRAF positive patients given the short duration of benefit with targeted therapy
- Across four patient cohorts, intracranial response ranged from 44% to 59%, although duration of response was relatively short:
- An outcome of this is the use of combined BRAF and MEK inhibition:
Rodrigo Arrangoiz MS, MD, FACS, FSSO 