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

• Published in: Cancer Vol. 130; no. 20; pp. 3463 - 3472
• Main Authors: Czarnecka, Anna M., Ostaszewski, Krzysztof, Błoński, Piotr J., Szumera‐Ciećkiewicz, Anna, Świtaj, Tomasz, Kozak, Katarzyna, Koseła‐Patreczyk, Hanna, Rogala, Paweł, Kalinowska, Iwona, Zaborowski, Konrad, Krotewicz, Maria, Borkowska, Aneta, Rutkowski, Piotr
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15-10-2024
• Subjects: adjuvant; Adjuvant therapy; Adult; Aged; Aged, 80 and over; BRAF; Cancer therapies; Chemotherapy, Adjuvant; Effectiveness; Female; Health services; Humans; Inhibitors; Male; MEK; MEK inhibitors; Melanoma; Melanoma - drug therapy; Melanoma - mortality; Melanoma - pathology; Melanoma - therapy; Metastases; Metastasis; Middle Aged; Molecular Targeted Therapy - methods; neoadjuvant; Neoadjuvant Therapy - methods; Neoplasm Staging; Patients; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf - genetics; Skin Neoplasms - drug therapy; Skin Neoplasms - mortality; Skin Neoplasms - pathology; Skin Neoplasms - surgery; Skin Neoplasms - therapy; Surgery; Survival; targeted; Therapy; Treatment Outcome; targeted; melanoma; MEK; neoadjuvant; BRAF; adjuvant
• ISSN: 0008-543X; 1097-0142; 1097-0142
• DOI: 10.1002/cncr.35425

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.