Time’s Up for Anti-PD-1/L1 Plus Targeted Therapy in BRAF Melanoma

Adding an immune checkpoint inhibitor (ICI) to targeted therapy did not improve outcomes in BRAF-mutant unresectable or metastatic melanoma, according to a randomized trial.

Median progression-free survival (PFS) increased from 12.0 months with dabrafenib (Tafinlar) and trametinib (Mekinist) to 16.2 months with the addition of spartalizumab but the difference did not meet predefined requirements for statistical significance. Objective response rates (ORRs) favored the triplet combination (69% vs 64%) but also did not achieve statistical significance.

Substantially more patients in the arm receiving the investigational PD-1 antibody had grade ≥3 adverse events, reported Reinhard Dummer, MD, of the University of Zurich, and coauthors in the Journal of Clinical Oncology.

“Protocol assumptions and lower relative dose intensities of dabrafenib and trametinib in the sparta-DabTram arm because of increased toxicity may have contributed to this result,” the authors stated. “Although OS [overall survival] cannot be formally tested because the primary endpoint was not met, patients remain in follow-up and future exploratory OS analyses are planned. However, the results of this primary analysis do not support routine first-line use of sparta-DabTram in patients with BRAF^V600-mutant metastatic melanoma.”

The study marks the third randomized trial to investigate the addition of a PD-1/L1 inhibitor to targeted agents in unresectable/metastatic melanoma, according to Margaret K. Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center, and Paul B. Chapman, MD, of Weill Cornell Medical College, both in New York City, writing in an accompanying editorial.

One trial showed a modest improvement in investigator-assessed PFS — but not by independent review — with the addition of atezolizumab (Tecentriq) to RAF/MEK inhibitors (RAFi/MEKi), supporting FDA approval of the triplet. A randomized trial of dabrafenib-trametinib with or without pembrolizumab (Keytruda) showed no improvement in PFS with the ICI.

“We believe that there are sufficient data now to be confident that the addition of anti-PD-1 or anti-PD-L1 antibodies to combination RAFi plus MEKi is not associated with a significant clinical benefit and should not be studied further in melanoma,” they wrote.

“Moreover, there is some evidence of harm, as the additional toxicity of triplet combination limited the delivery of combination RAFi and MEKi therapy in [the current study],” they continued. “Focus should turn instead to optimizing doses and schedules of combination RAFi plus MEKi and checkpoint inhibitors, developing treatment strategies to overcome resistance to these therapies, and determining how best to sequence combination RAFi and MEKi therapy and checkpoint inhibitors.”

A compelling rationale has existed for combining ICIs with RAFi/MEKi regimens. RAFi/MEKi regimens achieve high response rates but relatively short response duration, Callahan and Chapman pointed out. In contrast, PD-1/L1 inhibitors are associated with fewer but more durable responses. Additionally, RAFi and MEKi have mostly nonoverlapping toxicities with PD-1/L1 inhibitors.

On the other hand, preclinical data suggested MEK inhibition might suppress T-cell function. Other evidence suggested that a RAFi/MEKi doublet might inhibit dendritic cell maturation and T-cell activation. The first clinical trials evaluating an ICI (ipilimumab, Yervoy) plus RAFi/MEKi were stopped early because of hepatotoxicity in one case and gastrointestinal toxicity in the other.

Dummer and coauthors reported findings from the global COMBI-i trial. Investigators in 29 countries randomized adults with untreated, unresectable/metastatic BRAF^V600–mutant melanoma to receive dabrafenib plus trametinib in combination with either spartalizumab or placebo. The primary endpoint was investigator-assessed PFS, and key secondary endpoints included OS and ORR.

Data analysis included 532 randomized patients, and the treatment groups had no major differences in baseline characteristics. About 90% of the patients had BRAF^V600E mutation, half the patients had PD-L1 expression ≥1%, and about a third of the patients had high tumor mutation burden (≥10 mut/Mb).

After a median follow-up of 27.2 months, the data showed a trend in favor of the spartalizumab arm for the primary endpoint, but the difference did not achieve statistical significance (HR 0.82, 95% CI 0.66-1.03). Landmark analyses showed 12-month PFS rates of 58% with spartalizumab and 50% with placebo. The estimated 24-month PFS was 44% with spartalizumab and 36% with placebo.

Median OS had yet to be reached in either treatment arm. The estimated 24-month OS was 68% with spartalizumab and 62% with placebo.

Median duration of response (DOR) had yet to be reached in the spartalizumab group versus 20.7 months for the placebo group. Estimated 24-month DOR was 55% and 48%, respectively.

In discussing the results, the authors referenced the prior combination trials of atezolizumab and pembrolizumab and said, “collectively, these studies suggest only a modest efficacy benefit with checkpoint inhibitor plus targeted therapy combination compared with targeted therapy alone.”