Summary

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• Zelboraf (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test and for the treatment of patients with Erdheim Chester Disease with BRAF V600 mutation.
• This summary is based on the review of 14 systematic review(s)/meta-analysis(es). ^[1-14]
• In patients with advanced melanoma, Ipilimumab/Nivolumab and Relatlimab/Nivolumab demonstrated no significant differences in progression-free survival (PFS) and the overall response rate (ORR) (HR = 0.99, 95% CI 0.75-1.31; RR = 0.99, 95% CI 0.78-1.27).
• PD-(L)1/BRAF/MEK inhibitors (triplet combinations) showed superior PFS (HR = 0.56, 95% CI 0.37-0.84) and ORR (RR = 3.07, 95% CI 1.61-5.85) compared to Ipilimumab/Nivolumab in the treatment of advanced melanoma.
• In BRAF-V600 mutation-positive patients, Dabrafenib + Trametinib demonstrated favorable PFS and OS compared to monotherapies (Dabrafenib, Vemurafenib) and was comparable to other combination therapies (Encorafenib + Binimetinib and Cobimetinib + Vemurafenib).
• For adjuvant therapy in Stage III BRAF-mutant melanoma, Dabrafenib + Trametinib provided a significant recurrence-free survival (RFS) benefit (HR = 0.49, 95% CI 0.40-0.59), while Nivolumab/Ipilimumab offered the highest RFS benefit in Stage IV melanoma (HR = 0.23, 97.5% CI 0.12-0.45).
• Grade ≥3 Treatment-Related Adverse Events (TRAEs): Ipilimumab/Nivolumab has the highest risk of ≥G3 TRAEs, while Relatlimab/Nivolumab shows a trend towards a lower risk (RR = 0.71, 95% CI 0.30-1.67).
• Serious Adverse Events (SAEs): Encorafenib + Binimetinib has fewer SAEs compared to Vemurafenib + Cobimetinib (OR = 0.51, 95% CrI 0.29-0.91) and Atezolizumab + Vemurafenib + Cobimetinib (OR = 0.41, 95% CrI 0.21-0.82).
• Specific Adverse Events: Vemurafenib is associated with the highest incidence of cutaneous SCC, rash, photosensitivity, and KA; combined BRAF and MEK inhibitors increase the risk of pulmonary embolism, decreased LVEF, and arterial hypertension compared to BRAF inhibitor monotherapy (RR: 4.36, 3.72, 1.49 respectively).
• Population Types and Subgroup Considerations: Nivolumab/Ipilimumab shows the highest RFS benefit in Stage IV Malignant Melanoma, Dabrafenib/Trametinib shows significant RFS benefit in Stage III BRAF-Mutant Melanoma, BRAF mutation presence is associated with higher RFS rates, adjuvant therapy effectiveness is not influenced by patient age, and non-ulcerated melanoma cases have lower RFS with immune checkpoint inhibitor monotherapy. Additionally, in terms of safety, patients under 55 years of age have a higher risk of decreased LVEF with combined BRAF and MEK inhibitors, and those with follow-up time over 15 months have a higher risk of pulmonary embolism with the same combination.