PFS End Point Missed With Spartalizuamb, Dabrafenib, and Trametinib in Melanoma

The primary end point of investigator-assessed progression-free survival (PFS) was missed in part 3 of the randomized, Phase 3 COMBI-i study of spartalizumab in combination with dabrafenib (Tafinlar) and trametinib (Mekinist) in patients with untreated BRAF V600-mutant unresectable or metastatic melanoma, according to results presented at the 2020 ESMO Virtual Congress.

Even though overall survival was not formally tested, a hazard ratio of 0.785 was observed in favor of the spartalizumab plus dabrafenib and trametinib combination, while the median overall survival had not been reached in either arm.

“Part 3 of COMBI-i did not meet the primary endpoint, and the triplet of spartalizumab, dabrafenib and trametinib did not significantly improved investigator-assessed progression-free survival compared with the doublet of dabrafenib and trametinib with placebo,” explained study author Paul Nathan, MBBS, PhD, FRCP, of the Mount Vernon Cancer Centre.

Investigator-assessed PFS for the spartalizumab combination was 16.2 months (12.7-23.9 months, 0.820 HR) compared to 12.0 months for the placebo combination (10.2-15.4 months). The objective overall response rate was similar for both arms, with a 68.5% response rate for the spartalizumab combination and a 64.2% response rate for the placebo arm.

As for overall survival, preliminary data saw a hazard ratio of 0.785, but could not be formally tested until the primary endpoint of investigator-assessed PFS is met with statistical significance.

The randomized, double blind, placebo-controlled, phase 3 COMBI-i study enrolled 532 patients with previously untreated BRAF V600 mutation-positive unresectable or metastatic melanoma. Patients were randomized into 2 groups for the trial: the spartalizumab with dabrafenib and trametinib arm or the placebo with dabrafenib and trametinib arm.

“We did see differences in the number of dose modifications and discontinuations between pateints receiving treatment on the triplet arm compared to the doublet, reflecting the increased toxicity of this combination,” Nathan said in his ESMO presentation.

Close to 40% (n=106) of patients in the spartalizumab group experienced serious adverse events related to treatment compared with just 20% (53) of patients in the placebo group. Grade 3 or higher adverse events were found in 23.2% (n=62) of patients in the spartalizumab arm versus 11% (n=29) of patients in the placebo arm.

Moreover, adverse events leading to discontinuation of treatment occurred in 31.8% of patients in the spartalizumab group compared to 14.4% of patients receiving the placebo combination.

Specifically, the researchers noted an increase of adverse events for the spartalizumab combination patients including pyrexia (71.5%), diarrhea (34.5%), chills (31.1%), and asparate aminotransferase increase (26.6%) compared to the placebo combination group.

Preclinical activity for the trial suggested the potential for a combination of the anti-PD-1 antibody with dabrafenib and trametinib to enhance antitumor activity compared with dabrafenib and trametinib alone.

“Additional analyses are ongoing and planned to better understand these results,” explained Nathan. “Further overall survival follow-up may well provide additional insights.”

_Reference

_{Nathan PD, Dummer R, Long GV, et al. Spartalizumab plus dabrafenib and trametinib (Sparta-DabTram) in patients (pts) with previously untreated BRAF V600–mutant unresectable or metastatic melanoma: results from the randomized part 3 of the Phase III COMBI-i trial. Presented at: 2020 ESMO Virtual Congress; September 19, 2020. Abstract LBA43.}