Anti-PD-(L)1 plus BRAF/MEK inhibitors (triplet therapy) after failure of immune checkpoint inhibition and targeted therapy in patients with advanced melanoma

• Published in: European journal of cancer (1990) 2024-05, Vol.202, p.113976-113976, Article 113976
• Main Authors: Albrecht, Lea Jessica, Dimitriou, Florentia, Grover, Piyush, Hassel, Jessica C., Erdmann, Michael, Forschner, Andrea, Johnson, Douglas B., Váraljai, Renáta, Lodde, Georg, Placke, Jan Malte, Krefting, Frederik, Zaremba, Anne, Ugurel, Selma, Roesch, Alexander, Schulz, Carsten, Berking, Carola, Pöttgen, Christoph, Menzies, Alexander M., Long, Georgina V., Dummer, Reinhard, Livingstone, Elisabeth, Schadendorf, Dirk, Zimmer, Lisa
• Format: Article
• Language: English
• Subjects: Advanced melanoma; Anti-PD-(L)1 plus BRAF/MEK inhibitors; Anti-PD-1 resistance; BRAF V600 mutation; Triplet combination; Triplet therapy
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2024.113976

Effective treatment options are limited for patients with advanced melanoma who have progressed on immune checkpoint inhibitors (ICI) and targeted therapies (TT). Preclinical models support the combination of ICI with TT; however, clinical trials evaluating the efficacy of triplet combinations in first-line setting showed limited advantage compared to TT only. We conducted a retrospective, multicenter study, that included patients with advanced melanoma who were treated with BRAF/MEK inhibitors in combination with an anti-PD-(L)1 antibody (triplet therapy) after failure of at least one anti-PD-(L)1-based therapy and one TT in seven major melanoma centers between February 2016 and July 2022. A total of 48 patients were included, of which 32 patients, 66.7% had brain metastases, 37 patients (77.1%) had three or more metastatic organs and 21 patients (43.8%) had three or more treatment lines. The median follow-up time was 31.4 months (IQR, 22.27–40.45 months). The treatment with triplet therapy resulted in an ORR of 35.4% (n = 17) and a DCR of 47.9% (n = 23). The median DOR was 5.9 months (range, 3.39–14.27 months). Patients treated with BRAF/MEK inhibitors as the last treatment line showed a slightly lower ORR (29.6%) compared to patients who received ICI or chemotherapy last (ORR: 42.9%). Grade 3–4 treatment-related adverse events occurred in 25% of patients (n = 12), with seven patients (14.6%) requiring discontinuation of treatment with both or either drug. Triplet therapy has shown activity in heavily pretreated patients with advanced melanoma and may represent a potential treatment regimen after failure of ICI and TT. •Unmet need for advanced melanoma after failure of immune- and targeted therapy (TT)•Combination of BRAF/MEK inhibitors plus anti-PD-(L)1 as so-called triplet therapy•Triplet therapy showed efficacy after failure of anti-PD-1-based therapy and TT•Triplet therapy as a viable regimen after failure of immune- and targeted therapy