Pembrolizumab With Dabrafenib and Trametinib Shows Efficacy, But High TRAEs, in Melanoma
Pembrolizumab plus dabrafenib and trametinib showed a nonsignificant improvement in PFS, but also higher rates of grade 3 to grade 5 TRAEs in advanced melanoma.
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The combination of pembrolizumab plus dabrafenib and trametinib as first-line treatment for BRAF-mutated melanoma showed antitumor activity, but high rates of grade 3-5 treatment-related adverse events, according to results from the phase 2 KEYNOTE-022 trial presented at the ESMO 2018 Congress in Munich, Germany.1
The combination of pembrolizumab plus the BRAF inhibitors dabrafenib and trametinib showed promising antitumor activity in the phase 1 portion of the KEYNOTE-022 trial. This report was of the results from the phase 2 portion.
The double-blind, phase 2 KEYNOTE-022 trial randomly assigned 120 patients with treatment-naïve stage III or IV melanoma harboring a BRAFV600E/Kmutation to receive pembrolizumab plus dabrafenib and trametinib or placebo plus dabrafenib and trametinib. The primary endpoint was progression-free survival (PFS) and the secondary endpoints included objective response rate (ORR), duration of response (DoR), time to response, and overall survival (OS).
The ORR was 63% with pembrolizumab plus dabrafenib and trametinib compared with 72% with the BRAF inhibitors alone, with complete response rates of 18% and 13%, respectively. The median time to response was similar between arms at 2.8 months.
During a median follow-up of 9.6 months, there was a trend toward prolonged PFS with the pembrolizumab combination, but it was not significant based on prespecified parameters that required a hazard ratio (HR) of 0.62 or less. The median PFS with the pembrolizumab combination was 16 months (95% CI, 8.6-21.5 months) compared with 10.3 months (95% CI, 7.0-15.6 months) with dabrafenib plus trametinib alone, resulting in an HR of 0.66 (P = .043). The 12-month PFS was 59% and 45% with the pembrolizumab combination or the BRAF inhibitors alone, respectively.
The median DoR was longer with the pembrolizumab combination at 18.7 months (range, 1.9+ to 22.1 months) compared with 12.5 months (range, 2.1-19.5+ months) with dabrafenib plus trametinib. Responses lasting at least 18 months was more common with pembrolizumab, occurring in 60% of patients compared with 28% of patients receiving only the BRAF inhibitors.
The 12-month OS was 80% with the pembrolizumab combination compared with 73% with dabrafenib plus trametinib.
There were similar rates of any grade treatment-related adverse events (TRAEs), with 95% and 93% reported in the pembrolizumab combination and BRAF inhibitor only arms, respectively. Grade 3 to 5 TRAEs, however, occurred more frequently in the pembrolizumab combination arm at 58% compared with 27% in the dabrafenib plus trametinib arm. The discontinuation rate due to TRAEs was 40% and 20% in the pembrolizumab combination and dabrafenib plus trametinib arms, respectively.
Common grade 3 to 5 TRAEs, which occurred in at least 5% of patients, included pyrexia, elevated ALT and/or AST, increased GGT, rash, and neutropenia. There was a death in the pembrolizumab arm caused by pneumonitis, which was deemed treatment-related.
Immune-related AEs occurred in 43% of patients in the pembrolizumab group compared with 13% of patients in the BRAF inhibitor only group. The most common immune-related AEs were pneumonitis, hypothyroidism, skin disorders, hyperthyroidism, and uveitis.
The authors concluded that the pembrolizumab combination “demonstrated numerically longer PFS and DoR and a higher rate of grade 3-5 TRAEs in patients with treatment-naïve BRAFV600E/K-mutant advanced melanoma.”
Read more of Cancer Therapy Advisor's coverage of the ESMO 2018 meeting by visiting the conference page.
- Ascierto PA, Dummer R, et al. KEYNOTE-022 Part 3: Phase 2 randomized study of 1L dabrafenib (D) and trametinib (T) plus pembrolizumab (Pembro) or placebo (PBO) for BRAF-mutant advanced melanoma. Presented at: ESMO 2018 Congress; Munich, Germany: October 19-23, 2018. Abstract 1244O.