Combining BRAF Inhibition, Anti-PD-1 No Help in BRAF-Mutant Melanoma

Wen-Jen Hwu, MD

Patients withBRAF-mutant melanoma obtained no survival benefit from combined treatment of anti-BRAF therapy and an immune checkpoint inhibitor, a retrospective analysis showed.¹

Median progression-free survival (PFS) was 6.0 to 6.5 months in BRAF-inhibitor naive patients who received a PD-1/PD-L1 inhibitor alone or with a BRAF inhibitor. Patients with prior exposure to a BRAF inhibitor had a median PFS of 8.0 months with anti—PD-1 therapy and 4.5 months with combined treatment. Median overall survival was 10.5 to 12 months with a PD-1/PD-L1 inhibitor alone or in combination with a BRAF inhibitor, regardless of prior BRAF inhibitor exposure status.

“BRAF inhibitor-refractory patients derived no additional benefit with anti-PD therapy in combination with BRAF inhibition,” Wen-Jen Hwu, MD, of MD Anderson Cancer Center in Houston, and colleagues concluded in a poster presentation at the 2016 ASCO Annual Meeting in Chicago. “Clinical findings are similar with either anti-PD alone or in combination with BRAF inhibition in terms of objective response rate (ORR), disease control rate (DCR), and overall survival (OS).

“This finding is in contrast with the recommendation of continuing BRAF inhibition beyond disease progression by most experts and may be explained by the observation that BRAF inhibitor resistance may decrease melanoma antigen expression and T-cell infiltration. The numerically superior PFS with anti-PD alone is difficult to explain and may be due to small sample size and/or selection bias.”

Anti—PD-1 therapy and BRAF inhibition have demonstrated efficacy in patients withBRAFV600-mutant metastatic melanoma. In the KEYNOTE-001 trial, treatment with pembrolizumab led to an ORR of 50% in patients with no prior exposure to a BRAF inhibitor.²In the CheckMate-067 study, first-line treatment with nivolumab resulted in an ORR of 30% in patients withBRAF-mutant melanoma.³

Combined BRAF/MEK inhibition with dabrafenib and trametinib led to an objective response rate of 76% and median PFS of 9.4 months in patients withBRAF-mutant metastatic melanoma.⁴

Whether combining BRAF inhibitors and anti—PD-1 agents or using them in sequence enhances benefits has remained unclear. Dr. Hwu and colleagues sought to inform the issue by reviewing their single-center clinical experience.

Investigators reviewed records of 457 patients with metastatic melanoma treated with anti—PD-1 therapy from November 2009 through December 2015. The review showed that 129 patients hadBRAF-mutant disease, 89 (69%) of whom had received a BRAF inhibitor.

Dr. Hwu and colleagues separated the patients with BRAF-mutant disease into 4 treatment categories on the basis of prior BRAF-inhibitor exposure (naïve or treated) and use of anti-PD-1 therapy alone or in combination with a BRAF inhibitor. ORR, disease control rate, PFS, and OS were calculated for the 4 treatment groups and compared.

Of the 40 patients with no prior exposure to a BRAF inhibitor, 20 received anti—PD-1 therapy alone and 20 received both anti–PD-1 and BRAF-inhibitor therapy. Of the 89 patients previously treated with a BRAF inhibitor, 49 received only an anti–PD-1 agent, whereas 40 were treated with an anti–PD-1 agent and a BRAF inhibitor.

Patients with no prior BRAF-inhibitor exposure and treatment with anti—PD-1 monotherapy had an ORR of 45% (9 of 20 patients), complete response (CR) of 5% (1 of 20), DCR of 90% (18 of 20), median PFS of 6.5 months, and median OS of 11.0 months. The results for patients who received both anti–PD-1 therapy and a BRAF inhibitor were 60% ORR (12 of 20 patients), 10% CR (2 of 20), 90% DCR (18 of 20), 6.0 months median PFS, and 10.5 months median OS.

For the 89 patients with prior exposure to a BRAF inhibitor, treatment with an anti-PD-1 agent alone resulted in an ORR of 33% (16 of 49 patients), CR of 18% (9 of 49), DCR of 65% (32 of 49), median PFS of 8.0 months, and median OS of 12.0 months. Corresponding figures for patients who received an anti-PD-1 and BRAF inhibition were 30% ORR (12 of 40 patients), 10% CR (4 of 40), 72% DCR (29 of 40), 4.5 months median PFS, and 11.0 months median OS.

One notable difference existed in comparisons of patients treated with monotherapy or a combination.

“BRAF inhibitor-naïve patients had improved objective response rates with the combination of anti-PD and BRAF inhibitor therapy without significant differences in disease control rate, progression-free survival, and overall survival,” the investigators noted. “This finding is suggestive of the additive antitumor effect of combining a BRAF inhibitor and a MEK inhibitor with immunotherapy, as demonstrated in an animal model.”

The small numbers of patients in the individual treatment categories precluded attempts to discern differences in outcomes by performance status, baseline lactate dehydrogenase values, orBRAFV600 genotype, they added.

Barcena E, Trinh V, McIntyre SE, et al. Responses in patients with BRAF V600-mutant metastatic melanoma receiving anti-PD1/PDL1 therapy alone or combined with BRAF inhibitors.J Clin Oncol34, 2016 (suppl; abst 9546).

Ribas A, Hamid O, Daud A, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma.JAMA.April 19, 2016;315(15):1600-1609.

Larkin J, Lao CD, Urba WJ, et al. Efficacy and safety of nivolumab in patients with BRAF V600 mutant and BRAF wild-type advanced melanoma: A pooled analysis of 4 clinical trials.JAMA Oncol.2015;1(4):433-440.

Long GV, Weber JS, Infante JR, et al. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib.J Clin Oncol.March 10, 2016;34(8)871-878.