Clinical updates in neoadjuvant immunotherapy for melanoma before surgery

ABSTRACT

Introduction

Locoregionally advanced melanoma represents a large group of high-risk melanoma patients at presentation and poses major challenges in relation to management and the risks of relapse and death.

Areas covered

Melanoma systemic therapy has undergone substantial advancements with the advent of immune checkpoint inhibitors and molecularly targeted therapies, which have been translated to the neoadjuvant setting for the management of locoregionally advanced disease. Notably, PD1 blockade as monotherapy, in combination with CTLA4 blockade or LAG3 inhibition, has demonstrated significant progress in reducing the risk of relapse and mortality, attributed to high pathologic response rates. Likewise, BRAF-MEK inhibition for BRAF mutant melanoma has yielded comparable outcomes, albeit with lower response durability than immunotherapy. Localized intralesional therapies such as Talimogene laherparepvec (T-VEC) and Tavokinogene Telseplasmid (TAVO) electro-gene-transfer combined with anti-PD1 have demonstrated favorable pathologic responses and increased immune activation. Most importantly, the S1801 randomized trial has demonstrated for the first time the advantage of the neoadjuvant approach over standard surgery followed by adjuvant therapy.

Expert opinion

Current evidence supports neoadjuvant therapy as a standard of care for locoregionally advanced melanoma. Ongoing research will define the optimal regimens and the biomarkers of therapeutic predictive and prognostic value.

KEYWORDS:

• CTLA-4 blockade
• immunotherapy
• melanoma
• neoadjuvant
• targeted therapy
• pathologic response
• PD-1 blockade

Article highlights

• Pembrolizumab as monotherapy achieve pathologic complete responses (pCR) of about 20%.

• Combination therapies such as nivolumab-ipilimumab and nivolumab-relatlimab significantly improved pathologic response rates but with higher toxicity risks.

• Intralesional approaches have shown promise in terms of improved pathologic response and less systemic toxicities supporting further investigation.

• For the first time in the management of locoregionally advanced melanoma, a randomized trial has demonstrated improved event-free survival (EFS) with neoadjuvant versus adjuvant approaches.

• Neoadjuvant trial designs can be optimized by including EFS, pathologic response, and time to surgery as endpoints among other standard endpoints

• A significant role for the index lymph node (ILN) pathology exists in de-escalating surgical resection

Declaration of interest

A Tarhini declares contracted research grants with institution from Bristol Myers Squib, Genentech-Roche, Regeneron, Sanofi-Genzyme, Nektar, Clinigen, Merck, Acrotech, Pfizer, Checkmate, OncoSec, Scholar Rock, InflaRx GmbH, Agenus; personal consultant/advisory board fees (less than $10k per year) from Bristol Myers Squibb, Merck, Easai, Instil Bio, Clinigin, Regeneron, Sanofi-Genzyme, Novartis, Partner Therapeutics, Genentech/Roche, BioNTech, Concert AI, AstraZeneca outside the submitted work. 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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.