Abstract LB-A32: A clinical insight into therapeutic sequence in advanced melanoma

Background The treatment of metastatic melanoma has been revolutionized by developments in targeted therapy and immunotherapy. BRAF/MEK inhibitors, blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death (PD-1/L1) receptor have shown durable anti-melanoma effects. The optimal sequence strategy of targeted therapy and immunotherapy in metastatic BRAF-mutated melanoma patients (pts) is unknown and no treatment guidelines exist. Therefore, we report a single-institution experience of different treatment approaches using targeted therapy and immunotherapy and its impact on outcomes. Methods Pts with BRAF-mutated metastatic melanoma treated with targeted therapy and immunotherapy from 2012 to2017 were analyzed. Six groups were identified based on treatment strategy: (1) 1 st line BRAF/MEK inhibitors followed by 2 nd line immunotherapy; (1.1) 1 st line BRAF/MEK inhibitors followed by 2 nd line immunotherapy in combination with BRAF/MEK inhibitors (triple therapy);(1.2) same as group 1 followed by triple therapy as 3 rd line; (2) 1 st line immunotherapy followed by 2 nd line BRAF/MEK inhibitors; (2.1) 1 st line immunotherapy followed by 2 nd line triple therapy; (2.2) same as group2 followed by triple therapy as 3 rd line. All time-to-event analysis was calculated using the Kaplan-Meier method and Wilcoxon test. Results Forty four pts were included. The median age at diagnosis was 49 years (range 21-73), 24 (54%) pts were females and 19 (43%) developed brain metastases during their disease course. BRAF V600 mutation was seen in all pts except in 1 pt with p.N581S mutation. The preferred 1 st line targeted therapy was dabrafenib/trametinib used in 17 (94%) out of 18 pts, while ipilimumab was the preferred 1 st immunotherapy used in 11 (42%) out of 26 pts. For 2 nd line therapy, DT was used in 19 (90%) out of 21 pts, while pembrolizumab was used in 16 (69%) out of 23 pts. For 3 rd line, DT was used in 5 (83%) out of 6 pts, while pembrolizumab was used in 6 (100%) out of 6 pts. DT was usually the first choice for patients with high burden disease or brain metastases. The most common approach strategy was immunotherapy followed by targeted therapy (group 2), the median duration of treatment was 11 and 19 weeks respectively; for pts started on targeted therapy followed by immunotherapy (group 1), the median duration of treatment was 17 and 14 weeks respectively. (Table 1) Time-to-next therapy (TTNT) following 1 st line treatment was similar in pts treated with targeted therapy (median 23 weeks [95% CI: 15-31]) or immunotherapy (median 26 weeks [95% CI: 10-33], p=0.94). Following 2 nd line treatment, the TTNT for pts treated with targeted therapy was 18 weeks (95% CI: 4-38), immunotherapy 18 weeks (95% CI: 13-19) and triple therapy 22 weeks (95% CI: 13-41), p=0.48. A trend towards better overall survival (OS) from frontline therapy was seen in pts who received immunotherapy (1 st line) followed by targeted therapy (2 nd line) (median 7 years [95% CI: 2.7-7.08]) compared to those who received targeted therapy (1 st line) followed by immunotherapy (2 nd line) (median 2.3 years [95% CI: 1.3-NR], p=0.09. Interestingly, patients who received salvage chemotherapy had significant longer OS in those treated initially with immunotherapy (median 7 years [95% CI: 3.2-7.08]) (n=6) compared to patients started on targeted therapy (median 2 years [95% CI: 0.6-2.4], p=0.03) (n=5). Conclusion A trend towards longer OS was seen in pts treated with 1 st line immunotherapy followed by 2 nd line targeted therapy with a median therapy time of 11 and 19 weeks respectively. No difference in TTNT was seen with the use immunotherapy, targeted therapy or triple therapy when used as 1 st or 2 nd line. The significant longer OS benefit with f 1 st line immunotherapy was only seen in patients who received chemotherapy later in their treatment course. Citation Format: Jesus Vera-Aguilera, Jonas Paludo, Narjust Duma, Marcella Tschautscher, Cecilia Yu, Svetomir Markovic. A clinical insight into therapeutic sequence in advanced melanoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A32.