Meaningful Response Possible with Third-Line Targeted Therapy Rechallenge for Patients with BRAF-Mutation–Positive Advanced Melanoma

In a poster presentation delivered at the 2020 American Society of Clinical Oncology Virtual Scientific Program, investigators, led by Victoria Atkinson, MD, Medical Oncologist and Associate Investigator, Melanoma, Centre of Research Excellence for the Study of Naevi, Princess Alexandra Hospital, The University of Queensland, Brisbane, Australia, conclude from their study that “targeted therapy rechallenge should be considered a viable option for palliation in patients with advanced BRAF-mutant melanoma who have progressed on first- and second-line therapy.”

As third-line following first-line targeted therapy and second-line immunotherapy, rechallenge with third-line targeted therapy induced a response in 27%.

Patients with advanced melanoma who progress on first-line targeted therapy and second-line immunotherapy have limited treatment options. The researchers therefore explored the safety and efficacy of retreatment with third-line targeted therapy using data collected and pooled from 6 centers in Australia from 2009 to 2018. A total of 90 patients with BRAF V600-mutation–positive melanoma who had first-line therapy with a BRAF/MEK inhibitor, second-line immunotherapy, were rechallenged with a BRAF/MEK inhibitor. Approximately three-fourths (78%) had BRAF V600E-mutation–positive cancer, 14% had V600K, 6% had V600R, and 1% had V600M.

First-line targeted therapy was a BRAF/MEK inhibitor combination in 80%, predominantly dabrafenib (Tafinlar) plus trametinib (Mekinist). The response to first-line therapy was a complete response in 20%, partial response in 41%, stable disease in 17%, and progressive disease in 13%. Median duration of therapy was 7.2 months; 70% stopped for progressive disease, 9% for toxicity, and 16% had a planned switch to immunotherapy.

Second-line immunotherapy was a PD-1 inhibitor alone in 46%, a PD-1 inhibitor plus a CTLA-4 inhibitor in 33%, and a CTLA-4 inhibitor alone in 14%. Median duration on immunotherapy was 67 days; 81% ceased for progressive disease and 14% for toxicity. The best response to second-line immunotherapy was a complete response in 3%, a partial response in 10%, stable disease in 10%, and progressive disease in 70%.

Of the patients who had a planned switch to immunotherapy before progression on first-line targeted therapy, 1 patient had stable disease as best response to second-line immunotherapy.

At the time of targeted therapy rechallenge in the third line, 54% had American Joint Committee on Cancer stage IVD disease, 34% had stage IVC, and 51% had elevated lactate dehydrogenase. As third line, 49% were rechallenged with dabrafenib plus trametinib, 33% with vemurafenib (Zelboraf) plus cobimetinib (Cotellic), and 11% with encorafenib (Braftovi) plus binimetinib (Mektovi).

The investigators surmised, “Rechallenge with targeted therapy demonstrated clinically meaningful palliation for this cohort of patients with a best objective response rate of 27% and little toxicity, although the duration of response was modest at a median of 81 days.”


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