Neoadjuvant therapy for locally advanced disease or potentially resectable metastatic melanoma is expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment as it is for sarcoma, breast, rectal, esophageal, or gastric cancers. Patients with locoregional recurrence after initial surgery and those with advanced regional lymphatic metastases are at a high risk of relapse and melanoma-related death. There is an unmet clinical need to improve the outcomes for such patients. Patients with resectable bulky stage III or resectable stage IV histologically confirmed melanoma were enrolled and received standard-dose BRAFi/MEKi for at least 12 weeks before feasible resection of the pre-therapy target and then received at least for the next 40 weeks further BRAFi/MEKi. Of these patients, 37 were treated with dabrafenib and trametinib, three were treated with vemurafenib and cobimetinib, five with vemurafenib, and one with dabrafenib alone. All patients underwent surgery with 78% microscopically margin-negative resection (R0) resection. Ten patients achieved a complete pathological response. In patients with a major pathological response with no, or less than 10%, viable cells in the tumor, median disease free survival and progression free survival were significantly longer than in patients with a minor pathological response. No patient discontinued neoadjuvant BRAFi/MEKi due to toxicity. BRAFi/MEKi pre-treatment did not result in any new specific complications of surgery. Fourteen patients experienced disease recurrence or progression during post-operative treatment. We confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of melanoma. Pathological response to neoadjuvant treatment may be considered as a surrogate biomarker of disease recurrence.

Background: Currently, limited data on targeted therapy and immunotherapy sequencing in patients with BRAF-mutant melanoma is available. Targeted therapy and immunotherapy are expected to be comparable in terms of overall survival (OS) when used as second-line therapies; therefore, understanding the characteristics of patients who completed sequential treatment is needed. Methods: The primary objective of this study was to analyze the efficacy of BRAFi/MEKi activity as second-line therapy in patients with advanced melanoma. We also aimed to describe the clinical characteristics of patients with advanced melanoma who were treated sequentially with immunotherapy and targeted therapy. We enrolled 97 patients treated between 1st December 2015 and 31st December 2020 with first-line immunotherapy with programmed cell death 1 (PD-1) checkpoint inhibitors; and for the second-line treatment with at least one cycle of BRAFi/MEKi therapy with follow-up through 31 January 2022. Results: Median OS since first-line treatment initiation was 19.9 months and 12.8 months since initiation of BRAFi/MEKi treatment. All BRAFi/MRKi combinations were similarly effective. Median progression free survival (PFS) was 7.5 months since initiation of any BRAFi/MEKi treatment. Conclusions: BRAFi/MEKi therapy is effective in the second-line in advanced and metastatic melanoma patients. For the first time, the efficacy of all BRAFi/MEKi combinations as second-line therapy is shown.

e21539 Background: The use of targeted therapies (TT) and checkpoint inhibitors (IT) significantly prolonged survival in patients with metastatic melanoma, especially in patients with BRAF mutation-positive melanoma. Optimal sequence of therapies use is still a matter of debate. The aim of this study was to evaluate real-life practice and outcomes in melanoma patients treated sequentially. Methods: Consecutive patients with BRAF mutation-positive unresectable or metastatic melanoma started treatment with TT (BRAF and MEK inhibitors) and/or IT (anti-PD1) between 1/Oct/2016 and 31/Dec/2020. Clinical factors including age, gender, ECOG performance status, baseline LDH level, and location of metastases, response to treatment and irAEs occurrence were analyzed. Survival analyses were performed using the Kaplan-Meier method, Log-rank and chi-square tests were used for comparison between groups. Data cut-off was 31/Dec/2021. Results: In total 585 patients were enrolled. 170 (29%) patients were treated with IT and 415 (71%) with TT in the first line. 331 patients (56%) received only one line of treatment – 247/415 (59%) patients only TT and 84/170 (49%) patients received only IT (anti-PD1). Disease progression was found in 175 (71%) patients in the only TT group and in 43 (51%) in the only IT group. 254 patients qualified for sequential treatment 168 (29%) patients received TT then IT (TT-IT), 64 (11%) IT then TT (IT-TT), and 22 (4%) IT-IT (anti-PD-1 then anti-CTLA-4). Patients with brain metastases and elevated LDH were statistically more often treated with first line TT and more patients with normal LDH level received IT-IT therapy. No other statistically significant differences in baseline characteristics was found for IT-TT, TT-IT and IT-IT groups. The estimated median OS (mOS) was not reached in patients treated with only one line of IT treatment, while for TT only it was only 11.8 months. Estimated mOS for patients treated in the first line with IT or TT was significantly different (p = 0.02; HR = 0.74, Cl 95% 0.6-0.9) and reached 25.6 and 15.3 months, respectively; although no statistically significant mOS differences was found in the subgroups without brain metastases (p = 0.56) and with normal LDH (p = 0.36). For sequential treatment groups mOS for IT-TT, TT-IT, and IT-IT was 19.6, 19.9 and 35.9 months, respectively. There was no statistically significant difference in OS between IT-TT and TT-IT treated groups (p = 0.56), and between IT-TT, TT-IT and IT-IT groups (p = 0.19). Conclusions: Patients who were treated with IT in the 1st line had better OS than patients treated TT in the 1st line in real-world data but this may be related to better prognostic factors in the IT group. Selected patients receiving IT in the first line achieve long OS, which is a result of a long-term response to IT. Novel predictive biomarkers factors of IT response should be incorporated in prospective trials.

Pembrolizumab and nivolumab (anty-PD-1 antibody) are commonly used for the treatment of melanoma patients. However, their efficacy and safety have never been directly compared, leaving little guidance for clinicians to select the best therapy. The study included patients with inoperable or metastatic melanoma treated in first line with anti-PD-1 immunotherapy (nivolumab or pembrolizumab). In total 1037 patients were enrolled in the study, 455 (44%) patients were treated with pembrolizumab and 582 (56%) with nivolumab. The estimated median overall survival (OS) in the pembrolizumab and nivolumab groups was 17.4 and 20.0 months [P = 0.2323; hazard ratio (HR), 1.1; 95% confidence interval (CI), 0.94–1.28], respectively, whereas the median progression-free survival (PFS) was 5.6 and 7.5 months (P = 0.0941; HR, 1.13; 95% CI, 0.98–1.29), respectively. The estimated 2- and 3-year OS in the pembrolizumab and nivolumab groups were 42/34% and 47/37%, respectively, and the PFS was 25/21% and 29/23%, respectively. There were 391 (49%) immune-related adverse events (irAEs) of any grade during treatment, including 133 (42%) related to pembrolizumab treatment and 258 (53%) to nivolumab treatment. A total of 72 (9.6%) irAEs were in G3 or G4, including during pembrolizumab 29 (9%) and nivolumab 48 (11%). There were no differences in OS, PFS and overall response rates between nivolumab and pembrolizumab therapy in previously untreated patients with advanced/metastatic melanoma. There were no differences in the frequency of G1/G2 or G3/G4 irAEs. The choice of treatment should be based on the preferences of the patient and the clinician.

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