...BRAF mutation-positive (V600 E or K) melanoma for Parts 1, 2 and 3, or for Parts 1, 2, 4 and 5 only BRAF mutation-negative (wild type) melanoma with documented progression of >=1 measurable lesion after prior therapy (if prior therapy was received). The inclusion criterion does not apply to participants with solid tumors in Parts 4 and 5 (dose confirmation only)....

32 treatment-naïve patients with stage IV melanoma harboring a BRAFV600E/K mutated melanoma were enrolled. All patients started with 2 cycles of PEM 200mg (Q3W), followed by randomization to either PEM monotherapy (cohort 1); PEM in combination with either dabrafenib (D) 150 mg BID + trametinib (T) 2mg QD intermittent for 2x1 week (cohort 2), 2x2 weeks (cohort 3) or continuously for 6 weeks (cohort 4). From week 12 and onwards, all cohorts continued PEM for a maximum of in total 2 years....This update from the IMPemBra trial confirms the previous findings indicating that the addition of short-term DT to PEM can induce long-lasting responses upon PEM that appears to be superior compared to PEM monotherapy.

The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab....Patients with treatment-naïve BRAFV600E/K-mutant advanced melanoma started pembrolizumab...ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4….The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy.

Eligible pts were ≥18 y with unresectable stage III/IV BRAFV600E/K-mutant melanoma...At long-term follow-up, first-line pembro + dab + tram continued to show improved PFS, DOR, and OS compared with placebo + dab + tram in pts with BRAFV600E/K-mutant melanoma.

...pts with treatment-naïve BRAFV600E/K mutant advanced melanoma...ORRs were 75% in cohort 1 and 2, and 88% in cohort 3 and 4….After a median follow-up of 43.5 months, the median PFS of pts treated with PEM monotherapy was 10.6 months versus 32.3 months for pts treated with PEM plus D+T (p = 0.19)….IMPemBra demonstrated that short-term addition of intermittent D+T to PEM seems a more feasible, tolerable and an effective alternative for the continuous triple combination.

ORR in parts 1 and 2 was 67% (95% CI, 38-88), which was similar to that reported at an earlier data cut (73% [95% CI, 45-92]); median DOR was 19.4 mo (95% CI, 2.8-NR), median OS was NR (95% CI, 10.3-NR), 48-mo OS rate was 60%, median PFS was 15.2 mo (95% CI, 4.2-NR), and 48-mo PFS rate was 28% (Ribas A et al. Nat Med. 2019;25:936-940). In part 3, median PFS was 17.0 mo (95% CI, 11.3-NR) for pembro + dab + tram vs 9.9 mo (95% CI, 6.7-15.6) for placebo + dab + tram (HR, 0.46; 95% CI, 0.29-0.74) and 24-mo PFS rate was 47% vs 16%, and median OS was 46.3 mo (95% CI, 23.9-NR) vs 26.3 mo (95% CI, 18.2-38.6); and 24-mo OS rate was 63% vs 52%, respectively. ORR was 65% (95% CI, 52-77) for pembro + dab + tram vs 72% (95% CI, 59-83) for placebo + dab + tram; median DOR was 30.2 mo (95% CI, 14.1-NR) vs 12.1 mo (95% CI, 6.0-15.7). At long-term follow-up, first-line pembro + dab + tram continued to show improved PFS, DOR, and OS compared with placebo + dab + tram in pts with BRAFV600E/K-mutant melanoma.

In BRAF V600E/K-mutant advanced melanoma, pembrolizumab plus dabrafenib and trametinib substantially improved PFS, DOR, and OS with a higher incidence of TRAEs….With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%)...

...patients with treatment-naive BRAFV600E/K-mutant, advanced melanoma received the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib together with the PD-1-blocking antibody pembrolizumab (triplet; n = 60)….In summary, triplet therapy with dabrafenib, trametinib and pembrolizumab conferred numerically longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events compared with the doublet therapy of dabrafenib, trametinib and placebo.