Neoadjuvant treatments in patients with high-risk resectable stage III/IV melanoma

ABSTRACT

Introduction: In recent years, the introduction of targeted therapy and immunotherapy into clinical practice has radically changed the management of advanced melanoma. More recently, these treatments also became the standard of care in the adjuvant setting. However, high-risk resectable stage III melanoma (i.e. with clinically detected regional lymph node involvement and/or satellites/in transit metastases) still has a high risk of relapse, even after adjuvant treatment, suggesting that the activity of immunotherapy and targeted therapy may play a relevant role in a neoadjuvant setting.

Area covered: In this review, we discuss the results of the main clinical trials conducted in the neoadjuvant setting for patients with resectable stage III and stage IV melanoma, with a focus on the hot topics and a look at the future perspectives of the field.

Expert opinion: The long-term effects of immunotherapy and the high response rate of targeted therapy provided the strong rationale to start neoadjuvant clinical trials for patients with resectable stage III and oligometastatic stage IV melanoma. Neoadjuvant therapy may play an important role not only for its possible impact on overall survival, but also as a predictive biological marker to allow for a more accurate personalization of adjuvant treatments.

KEYWORDS:

• Melanoma
• neoadjuvant
• immunotherapy
• targeted therapy
• stage III
• oligometastatic stage IV

Article highlights

• The introduction of MAPK-directed targeted therapy and immune-checkpoint inhibitor immunotherapy into clinical practice for the management of advanced and high-risk resected melanoma led to the investigation of such treatments in a neoadjuvant setting for patients with resectable high-risk melanoma.

• Despite the small sample size of most neoadjuvant trials, the combination of low-dose ipilimumab with nivolumab seems to be the best immunotherapy regimen to pursue in the neoadjuvant setting, thanks to the high clinical activity with a manageable toxicity.

• The combination of BRAF plus MEK inhibitors achieved a high rate of radiological and pathological responses, but longer follow-up is needed to assess their long-term impact on relapse-free survival and overall survival.

• To combine the long-term effects of immunotherapy and the high response rate of targeted therapy, clinical trials are ongoing investigating the combination of BRAF plus MEK inhibitors with an anti-PD-1/PD-L1

Declaration of interest

Francesco Spagnolo has received lecture fees from Bristol-Myers Squibb, MSD, Roche, Pierre Fabre, Sanofi, Merck, Sunpharma, and has served on the advisory board for MSD. Paola Queirolo has received lecture fees from and served on the advisory board for Bristol-Myers Squibb, MSD, Novartis, Roche, Pierre Fabre, Sanofi, Merck and Sunpharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has received honoraria for lectures and for serving on the advisory board of Novartis, MSD, BMS, Pierre Fabre, but have no other relevant financial relationships to disclose.

Additional information

Funding

This paper received no funding.