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Published on: September 8, 2021
Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma
Antoni Ribas1, Donald Lawrence2, Victoria Atkinson3
1University of California, Los Angeles, Los Angeles, CA, USA. aribas@mednet.ucla.edu.
Abstract:
Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAFV600-mutated melanoma, with a median duration of response of approximately 1 year1-3. Immunotherapy with antibodies to programmed death 1 (PD-1) produces lower response rates but with long response duration. Preclinical models suggest that combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity4-6, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone. We enrolled 15 patients with BRAFV600-mutated metastatic melanoma in a first-in-human clinical trial of dabrafenib, trametinib and pembrolizumab ( NCT02130466 ). Eleven patients (73%) experienced grade 3/4 treatment-related adverse events, the most common being elevation of liver function tests and pyrexia, most of which resolved with drug interruption or discontinuation of either the anti-PD-1 antibody or the targeted therapy combination. Eleven patients (73%; 95% confidence interval = 45-92%) had an objective response, and six (40%; 95% confidence interval = 16-68%) continued with a response at a median follow-up of 27 months (range = 10.3-38.4+ months) for all patients. This study suggests that this triple-combined therapy may benefit a subset of patients with BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.
Insights
Combining BRAF/MEK inhibitors with PD-1 blockade shows promise for BRAF V600-mutated melanoma. This triple therapy achieved a 73% objective response rate, with 40% maintaining response at 27 months, suggesting potential for durable antitumor activity.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- BRAF/MEK inhibitors offer initial responses in BRAF V600-mutated melanoma but lack long-term durability.
- Programmed death 1 (PD-1) blockade yields durable responses but lower initial response rates.
- Preclinical data suggest combination therapy may enhance antitumor activity.
Purpose of the Study:
- To evaluate the safety and efficacy of a triple combination therapy including BRAF inhibitor (dabrafenib), MEK inhibitor (trametinib), and PD-1 inhibitor (pembrolizumab) in patients with BRAF V600-mutated metastatic melanoma.
Main Methods:
- A first-in-human clinical trial (NCT02130466) enrolled 15 patients with BRAF V600-mutated metastatic melanoma.
- Patients received dabrafenib, trametinib, and pembrolizumab.
- Safety and objective response rates were assessed.
Main Results:
- Eleven patients (73%) experienced grade 3/4 treatment-related adverse events, primarily elevated liver function tests and pyrexia, which were manageable.
- Eleven patients (73%) achieved an objective response.
- Six patients (40%) maintained response at a median follow-up of 27 months.
Conclusions:
- The triple combination of dabrafenib, trametinib, and pembrolizumab demonstrated a high objective response rate and potential for long-lasting responses in BRAF V600-mutated metastatic melanoma.
- This combination may offer a beneficial treatment option for patients with limited long-term response to single-agent therapies.
- Further investigation is warranted to confirm these findings in a larger patient cohort.
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