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Background: Neoadjuvant–adjuvant therapy for locally advanced or potentially resectable metastatic melanoma was expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment only. Methods: Forty‐seven consecutive patients were treated with neoadjuvant–adjuvant BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) and surgery. Results: Twelve (26%) patients achieved a pathological complete response and 10 (21%) patients achieved a near‐complete response. In the whole group, median recurrence‐free survival was 19.4 months and median distant metastasis‐free survival (mDMFS) was 21.9 months. In patients with a pathological complete response (pCR)/near‐pCR median recurrence‐free survival (RFS) and distant metastasis‐free survival (DMFS) were significantly longer than in patients with minor pathological response with hazard ratio (HR) = 0.37 (p =.005) for RFS and HR = 0.33 (p =.002) for DMFS. After median follow‐up of 52.5 months, median progression‐free survival since BRAFi/MEKi therapy initiation was 25.1 months. The median time‐to‐treatment‐failure since initiation of neoadjuvant therapy was 22.2 months and was significantly longer in patients with pCR/near‐pCR (HR = 0.45; p =.022). Neoadjuvant therapy did not result in any new specific complications of surgery. After 48 months, RFS and overall survival were 36.3% and 64.8% or 20% and 37.4% in patients with pCR/near‐pCR and pathological partial response/pathological nonresponse, respectively. Conclusions: The authors confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of stage III/IV melanoma. Major pathological response to neoadjuvant treatment is a surrogate marker of recurrence including DMFS in these patients. Plain Language Summary: Our study presents a large comprehensive analysis of neoadjuvant‐adjuvant systemic therapy in patients diagnosed with marginally resectable stage III or IV melanoma.Neoadjuvant therapy effectively reduced the volume of the disease, which facilitated subsequent surgical resection.After median follow‐up of 52.5 months, median progression‐free survival since therapy initiation was 25.1 months. Twelve patients had complete pathological response and 10 patients had a near‐complete pathological response—and together they had median recurrence‐free survival and distant metastasis‐free survival significantly longer than in patients with pathological partial response or nonresponse.Complete/near‐complete pathological response to neoadjuvant treatment is a surrogate marker of recurrence‐free, including distant metastasis‐free, survival in these patients. The results of this real‐world study indicated that BRAF/MEK‐targeted therapy is effective in neoadjuvant treatment of patients with marginally resectable stage III or IV melanoma, facilitating surgical resection. The level of pathological response to the neoadjuvant treatment is a prognostic factor for disease recurrence (as well for overall survival), and relapses were most often seen in the central nervous system. [ABSTRACT FROM AUTHOR]

Simple Summary: Second line anti-PD1 immunotherapy is effective in selected BRAF-mutated melanoma patients after BRAFi/MEKi immunotherapy failure. Nivolumab and pembrolizumab are of similar efficacy as a second line therapy. Worse performance status as well as high LDH levels are negative clinical biomarkers that correlated with shorter OS. The presence of brain and liver metastases correlates with shorter PFS and OS of these patients. (1) Background: BRAFi/MEKi are usually offered as a first line treatment for patients requiring rapid response; with elevated lactate dehydrogenase (LDH) activity, large tumor burden, and with brain metastases. The efficacy of second line therapies after BRAFi/MEKI failure is now well defined. (2) Methods: Patients treated with first line target BRAFi/MEKi therapy (vemurafenib plus cobimetinib, dabrafenib plus trametinib or encorafenib plus binimetinib); and for the second line treatment immunotherapy with programmed cell death 1 (PD-1) checkpoint inhibitors (nivolumab or pembrolizumab) with at least one cycle of second line were analyzed for survival and prognostic biomarkers. (3) Results: There were no statistically significant differences in ORR between the treatment groups with nivolumab and pembrolizumab, as well as median progression free-survival (PSF) and overall survival (OS) since the initiation of second line therapy; on nivolumab OS was 6.6 months, and on pembrolizumab 5.0 months. The greatest clinical benefit with second line immunotherapy was observed in patients with LDH ≤ ULN and <3 organ sites with metastasis at baseline. Longer OS was also noted in patients with time to PD  >6 months in first line (slow progression). (4) Conclusions: Second line anti-PD1 immunotherapy is effective in BRAF-mutated melanoma patients after BRAFi/MEKi therapy failure. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant therapy for locally advanced disease or potentially resectable metastatic melanoma is expected to improve operability and clinical outcomes over upfront surgery. 46 patients were treated with BRAFi/MEKi or BRAFi before surgery with 78% R0 resection. In patients with a major pathological response with no, or less than 10%, viable cells in the tumor, median DFS and PFS were significantly longer than in patients with a minor pathological response. 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. [ABSTRACT FROM AUTHOR]