Abstract LB-A32: A clinical insight into therapeutic sequence in advanced melanoma
Authors: Vera-Aguilera Jesus , Paludo Jonas , Duma Narjust , Tschautscher Marcella , Yu Cecilia , Markovic Svetomir 
Published: August 2018

Abstract
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) 1st line BRAF/MEK inhibitors followed by 2nd line immunotherapy; (1.1) 1st line BRAF/MEK inhibitors followed by 2nd line immunotherapy in combination with BRAF/MEK inhibitors (triple therapy);(1.2) same as group 1 followed by triple therapy as 3rd line; (2) 1st line immunotherapy followed by 2nd line BRAF/MEK inhibitors; (2.1) 1st line immunotherapy followed by 2nd line triple therapy; (2.2) same as group2 followed by triple therapy as 3rd 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 1st line targeted therapy was dabrafenib/trametinib used in 17 (94%) out of 18 pts, while ipilimumab was the preferred 1st immunotherapy used in 11 (42%) out of 26 pts. For 2nd line therapy, DT was used in 19 (90%) out of 21 pts, while pembrolizumab was used in 16 (69%) out of 23 pts. For 3rd 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 1st 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 2nd 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 (1st line) followed by targeted therapy (2nd line) (median 7 years [95% CI: 2.7-7.08]) compared to those who received targeted therapy (1st line) followed by immunotherapy (2nd 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 1st line immunotherapy followed by 2nd 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 1st or 2nd line. The significant longer OS benefit with f 1st line immunotherapy was only seen in patients who received chemotherapy later in their treatment course. Table 1.Treatment Characteristics by GroupMedian duration of therapy in weeksGroup(n)1st line therapy(median)2nd line therapy(median)3rd line therapy(median)Totalmedian (range)Chemotherapy (n)1(n=9)Targeted therapy(17)Immunotherapy (14)N/A52 (13-134)51.1(n=7)Targeted therapy(25)Triple therapy (19)Any*(43)69 (22-118)11.2(n=2)Targeted therapy(60)Immunotherapy (16)Triple therapy (21)96 (81-111)12(n=18)Immunotherapy(11)Targeted therapy(19)Any*(24)48 (16-120)52.1(n=4)Immunotherapy(17)Triple therapy (16)Any*(9)41 (25-69)02.2(n=4)Immunotherapy(19)Targeted therapy(16)Triple therapy (19)61 (54-73)1* include any treatment regimen such as immunotherapy, targeted therapy or chemotherapy
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.