Combination Targeted and Immunotherapy Feasible in Advanced Melanoma

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One of the burning questions about the new agents available to treat melanoma is how best to combine and/or sequence them. A phase 1 study showed the feasibility of combining a BRAF inhibitor and a MEK inhibitor plus a programmed death-1 ligand 1 (PD-L1) inhibitor (MEDI4736). These 3 agents can be safely combined at full doses and elicit clinical activity in both BRAF-mutant and BRAF wild-type advanced melanoma.

“Patients with a BRAF mutation treated with the combination of BRAF and MEK inhibition exhibited the greatest immune activation as well as the greatest clinical activity,� stated lead author Antoni Ribas, MD, PhD, UCLA, Los Angeles, CA.

Previous studies have shown that combined use of da­brafenib and trametinib is efficacious in BRAF-mutant melanoma, and MEK inhibitors have also shown activity in BRAF wild-type melanoma, particularly in NRAS-mutant tumors. Most patients, however, will develop resistance to these agents. The present study was conducted to determine if the addition of an anti–PD-L1 immunotherapy could enhance responses and make them more durable.

“BRAF alone or BRAF/MEK inhibitors induce rapid clinical responses with limited durability. Immunotherapy achieved less frequent objective responses but clinically significant durability, so the hypothesis was to combine these agents in BRAF V600-mutated melanoma,� Dr Ribas told listeners.

Three cohorts of patients with advanced/metastatic melanoma were enrolled as follows: cohort A, 26 patients with BRAF mutation–positive disease; cohort B, 20 patients with wild-type BRAF; and cohort C, 19 patients with wild-type BRAF.

Cohort A received 12 months of MEDI4736 3 or 10 mg/kg every 2 weeks, dabrafenib 150 mg twice daily, and trametinib 2 mg every day. Cohort B received 12 months of MEDI4736 10 mg/kg every 2 weeks plus trametinib 2 mg every day. Cohort C received 12 months of MEDI4736 10 mg/kg every 2 weeks and 6 months of trametinib 2 mg every day. Patients were treated until disease progression. In cohort C only, MEDI4736 could be reintroduced for progressive disease for up to another 12 months.

No patient had received prior BRAF or MEK inhibitor therapy.

Toxicities were consistent with the known safety profiles of all 3 agents. No exacerbation of immune-related adverse events was observed. Dose-limiting toxicities were observed in 2 patients: reversible grade 3 thrombocytopenia in cohort A; reversible grade 3 choroidal effusion in cohort B. Full doses of all agents were tolerable and were chosen for the expansion phase of the study.

Immune activation was observed posttreatment in all cohorts. Cohort A had the most dramatic and consistent CD8 infiltration levels and interferon-gamma levels in plasma.

To date, the overall response rate was 69%, 21%, and 13% in cohorts A, B, and C, respectively. The disease control rate (complete response, partial response, and stable disease) was 100%, 79%, and 80%, respectively. Stable disease for 12 weeks or longer was achieved in 15%, 53%, and 40%, respectively. Ongoing responders were 89%, 100%, and 50%, respectively.

Median duration of response has not yet been reached for cohorts A and B.

Dr Ribas noted that early clinical activity was observed in all cohorts, with the majority of patients having ongoing responses. It is too early to detect differences in concurrent versus sequential dosing of trametinib and MEDI4736, he said. Longer follow-up is needed.

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