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Published on: February 27, 2019
BRAF inhibitor rechallenge in patients with advanced BRAF V600-mutant melanoma
Jennifer Roux1, Cecile Pages, Diane Malouf
1Departments of aDermatology bPathology cPharmacology, Hôpital Saint Louis, APHP dINSERM U976, Université Paris 7 Diderot, Paris, France.
Abstract:
In around 50% of melanomas, the BRAF V600 mutation, resulting in an activation of the MAP kinase pathway, is detected. BRAF inhibitors have shown remarkable activity on the disease. However, efficacy is short-lived in most cases, with a median disease-free survival of 6 months. This short duration of response could be explained by the acquisition of resistance mechanisms. Some cancers show sensitivity to the reintroduction of previously active drugs after disease progression. We carried out a retrospective monocentric study on patients with BRAF V600-mutated melanoma who were rechallenged with BRAF inhibitors that were previously beneficial, but in whom the disease had progressed. Nine patients were included. Five patients showed a subsequent partial response, two showed a dissociated response leading to clinical improvement, and two showed no radiological nor clinical response. Eight patients who received rechallenge BRAF inhibitor had received an intercurrent treatment with ipilimumab. These cases suggest that intermittent treatment with BRAF inhibitors could provide clinical benefit and that sequential therapies should be further evaluated in clinical trials.
Insights
Rechallenging melanoma patients with BRAF inhibitors after progression may offer clinical benefit. Intermittent BRAF inhibitor therapy and sequential treatments warrant further clinical trial evaluation for BRAF V600-mutated cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- BRAF V600 mutations drive MAP kinase pathway activation in approximately 50% of melanomas.
- BRAF inhibitors demonstrate initial efficacy but are limited by acquired resistance, leading to short median disease-free survival (6 months).
Purpose of the Study:
- To investigate the efficacy of reintroducing BRAF inhibitors in patients with BRAF V600-mutated melanoma following disease progression.
- To explore the potential of intermittent BRAF inhibitor treatment and sequential therapies.
Main Methods:
- Retrospective monocentric study including nine patients with BRAF V600-mutated melanoma.
- Patients were rechallenged with previously effective BRAF inhibitors after disease progression.
- Analysis of radiological and clinical responses.
Main Results:
- Five out of nine patients achieved a partial response upon BRAF inhibitor rechallenge.
- Two patients exhibited a dissociated response with clinical improvement.
- Eight patients received ipilimumab between BRAF inhibitor treatments.
Conclusions:
- Intermittent BRAF inhibitor treatment may provide clinical benefit in BRAF V600-mutated melanoma.
- Sequential therapy strategies, including BRAF inhibitor rechallenge, require further investigation in clinical trials.
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