Long-term efficacy of neoadjuvant-adjuvant targeted therapy in borderline resectable stage IIIB-D and IV melanoma.

Abstract

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. Forty-seven consecutive patients were treated with neoadjuvant-adjuvant BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) and surgery. 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. 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. 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.