For patients with metastatic melanoma with BRAFV600E mutations, treatment with the combination of a BRAF inhibitor (BRAFi) and a MEK inhibitor (MEKi) is a standard of care. While these agents induce high response rates, the majority of responding patients acquire resistance within 15 months of treatment initiation, leading to disease progression. Immunotherapy is an effective subsequent treatment approach, but only a subset of patients experiences long-term benefit, while the majority progress. Preclinical data indicate that epigenetic mechanisms of acquired resistance to BRAF inhibition can be reversed after BRAFi discontinuation. This postulated resistance mechanism provides a rationale for BRAFi rechallenge following a treatment break.
To evaluate this hypothesis, a multi-institution retrospective study analyzed results from 116 patients with metastatic melanoma who had been rechallenged with BRAFi-containing therapy after discontinuation from a prior BRAFi-based therapy due to disease progression (71.6%) or other causes. The median time from first BRAFi treatment cessation was 7.7 months. Immunotherapy was the most commonly administered treatment between first BRAFi and rechallenge (71.5%).
Rechallenge was associated with an overall response rate (ORR) of 42.3%, including a complete response in 2.6% and partial response in 39.7%. In the subgroup of patients who had previously discontinued BRAF inhibition due to disease progression, the ORR was 37.3%. The median progression-free survival (PFS) and overall survival (OS) from rechallenge were 5 months and 9.8 months, respectively. Fewer than 3 metastatic sites and lactate dehydrogenase (LDH) below the upper limit were both positive prognostic factors for response to rechallenge. Duration of response to initial BRAFi treatment was correlated to response to rechallenge. Patients who responded to rechallenge had a median duration of response to first-line BRAFi of 14.8 months, versus 9.7 months for patients who did not respond (P = .014).
The investigators concluded that these results indicate clinically meaningful survival benefit and support rechallenge with BRAFi, with or without MEKi, as a therapeutic option for selected patients with BRAF-mutated metastatic melanoma who progressed on BRAFi and subsequent therapy. Importantly, a potential limitation of this analysis is that the majority of patients had single-agent BRAF inhibition as their initial BRAF therapy, while BRAF plus MEK inhibition was the most common treatment for rechallenge. This reflects changing practice patterns in recent years, but may be a confounding variable when considering the importance of these data. This treatment approach should be investigated further in a prospective clinical trial.
Eur J Cancer. 2018;91:116-124.