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Oncologists should consider neoadjuvant immunotherapy for patients with clinical stage III melanoma, which is a paradigm shift away from upfront surgery and adjuvant systemic therapy, according to a review in the .

The standard of care for patients with resectable clinical stage III melanoma has been surgical resection, consisting of therapeutic lymph node dissection and/or resection of in-transit disease and consideration of adjuvant systemic therapy and occasionally adjuvant radiation. But patients tend to have high rates of regional recurrence and progression to metastatic disease post-surgery, highlighting the need for better treatment options, explained Rodabe N. Amaria, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues.

In the following interview, Amaria discussed the rationale for neoadjuvant immunotherapy, the impact of clinical trials, and unanswered questions about neoadjuvant therapy in melanoma.

What is the rationale for using neoadjuvant immunotherapy in melanoma?

Amaria: Neoadjuvant immunotherapy studies focus on patients with clinical stage III melanoma, a high-risk population with a high recurrence rate after surgery. The use of neoadjuvant immunotherapy can lead to pathological complete response (pCR). It also has several benefits, including that clinical trials that lead to pCR with excellent prognosis may not require anything after surgery. We are truly able to interrogate how the patient responds -- if the patient responds poorly, this affects how we treat the patient in the postoperative setting; and early administration of systemic therapy can be beneficial, since we can initiate therapy early without waiting for surgery and can destroy micro-metastases.

What led to the paradigm shift?

Amaria: Many patients with stage III melanoma do poorly because of recurrence after surgery, so we asked what can we do better, and came up with neoadjuvant clinical trials. Neoadjuvant therapy has been used in breast cancer and rectal cancer, but never had it worked in melanoma before. It was natural to use it in patients with earlier stage melanoma.

Clinical trials have demonstrated improved event-free survival and risk-free survival (RFS) for patients treated in the neoadjuvant setting versus the adjuvant setting. Additionally, patients with any pathologic response to neoadjuvant immunotherapy have durable responses, including improved RFS.

What are the advantages of neoadjuvant therapy in this setting?

Amaria: Neoadjuvant therapy is a way to explore drug development. We can get a lot of data in a short time. It makes sense to try new drugs alone and in combination to better understand the pathologic response and assess biomarkers. We can find out if a drug is hitting the intended target and how it is working.

What are the surgical considerations in caring for patients with high-risk stage III melanoma?

Amaria: With favorable data for neoadjuvant immunotherapy, the question is: Does everyone need complete lymph node dissection? This is an area of debate with no clear answer. Sometimes when we give immunotherapy it induces a vigorous immune response and can lead to more challenging surgery. The disease may shrink down, but it is not always an easier surgical procedure, particularly if inflammation is present.

What about newer adjuvant therapies?

Amaria: Despite the excellent efficacy of single-agent anti-PD-1 therapy and anti–PD-1 therapy in combination with either anti–cytotoxic T-cell lymphocyte-4 or anti–LAG-3, a significant number of patients do not respond. New treatment options, including oncolytic viruses, BRAF-targeted therapy, and BRAF therapy and immunotherapy are being investigated in the neoadjuvant setting.

Immunotherapy can be applied in many ways. Traditionally, we have used checkpoint inhibitors, but there is an emerging interest in intra-tumoral therapy, and a drive to use this in earlier stage disease. When we inject directly into a tumor, the injection itself induces immune activation. There's a question whether pCR is the same with intra-tumoral therapy due to the induction of inflammation. Intra-tumoral therapy produces biologically distinct results.

There are a number of ongoing and planned trials to explore the efficacy of novel agents or combinations with the goals of improving clinical outcomes, lowering toxicity, and evaluating new drugs.

What are the unanswered questions regarding neoadjuvant therapy for clinical stage III melanoma?

Amaria: We don't know whether surgery can be tailored down, or what is the right choice of agents to use. Different trials are using different agents, and no one optimal regimen has emerged. Is adjuvant therapy required after neoadjuvant treatment? And another question is: Can we use neoadjuvant therapy in earlier stage disease with thick, primary tumors or for those with high-risk stage II melanoma?

What is your main message for practicing oncologists?

Amaria: Neoadjuvant immunotherapy has emerged as a paradigm shift, with the caveat that there are still some questions to be answered. The success of neoadjuvant therapy in clinical trials has led to interest and excitement. We continue to encourage community oncologists to refer patients for clinical trials.

This is still experimental, and we do recommend referral to a high-volume treatment center for a more definitive understanding of neoadjuvant therapy. If they plan to use neoadjuvant therapy, they should follow the tenants of the clinical trials.

Read the review here and expert commentary about it here.