Pembrolizumab With Dabrafenib and Trametinib Shows Efficacy, But High TRAEs, in Melanoma

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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.
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.
The following article features coverage from the European Society for Medical Oncology (ESMO) 2018 meeting. Click here to read more of Cancer Therapy Advisor's conference coverage.

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.

Reference

  1. 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.

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