Prognosis and survival evaluation in treating high-risk BRAF V600 mutation stage III or IV melanoma with dabrafenib plus trametinib therapy: A meta-analysis of 2,660 patients.

Abstract

e21501 Background: Stage III and IV melanoma is a challenging entity due to its high mortality rate, rapid progression, and therapy resistance. For patients with BRAF V600 mutations, further evidence is needed to validate the effectiveness of combining Dabrafenib and Trametinib. Methods: We conducted a systematic review and meta-analysis of randomized clinical trials (RCTs), non-randomized clinical trials (NRCTs) and observational/real-world (ORW) studies published up to August 22, 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Our review focused on Dabrafenib and Trametinib (D+T) for Stage III or IV melanoma with BRAF V600 mutations. Of 991 manuscripts screened, 16 studies (4 NRCTs, 4 RCTs and 8 ORW) met the inclusion criteria. Three studies evaluated D+T as neoadjuvant therapy, and 13 focused on its use as a standalone targeted therapy for unresectable tumors. Of these, 9 studies did not include a comparator group, while 4 compared D+T to other treatments, including Dabrafenib monotherapy, Pembrolizumab and continuous vs intermittent dosing regimens. The primary outcomes were overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and recurrence-free survival (RFS). Results: Our analysis included 2,660 patients; median age 57.5 years, median treatment duration 31.7 weeks. 88.7% (n=2,360) had stage IV melanoma, 8.9% (n=236) had stage III and 2.4% (n=64) were unreported. As neoadjuvant therapy, the regimen showed an ORR 83.3% (95% CI: 74.5-92%), including 25.4% complete responses and 74.6% partial responses. Among non-responders, 2.4% had stable disease (SD); the rest experienced disease progression or death. The estimated 1- and 2-year OS rates were 100% and 89.7%, respectively. RFS rates at 6 and 12 months were 87.3% and 63.7%. For unresectable tumors treated with D+T, ORR was 62.4% (95% CI: 55.2-69.7%), with 21.4% achieving complete responses and 78.6% partial responses. SD occurred in 18.9%. The 1- and 2-year OS rates were 71.1% and 47.66%, respectively. Median PFS was 11.37 months (95% CI: 9.4-13.3), and median OS was 19.96 months (95% CI: 17.7-22.3). Subgroup analysis showed minimal variation in ORR in patients with unresectable melanoma between clinical trials (65.7%) and ORW studies (60.3%). In comparative analyses, D+T had a significantly higher ORR than Dabrafenib monotherapy (OR: 1.77, 95% CI: 1.25-2.51, p=0.001). Continuous dosing showed no significant advantage over intermittent dosing (OR: 1.78, 95% CI: 0.71-4.44, p=0.22). There was no significant difference in disease progression between D+T and Pembrolizumab (OR: 0.35, 95% CI: 0.12-1.03, p=0.06). Conclusions: Our analysis shows the efficacy of D+T for both resectable and unresectable melanoma harboring the BRAF-V600 mutation, offering notable short-term survival benefits.