Recent Advances in the Use of Neoadjuvant Immunotherapy in Melanoma

It is well-established that adjuvant immunotherapy enhances outcomes in patients with high-risk, resectable melanoma. Now growing evidence suggests that neoadjuvant immunotherapy is associated with even better outcomes in this patient population.

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Sonia Cohen, MD, PhD, a surgical oncologist at the Mass General Brigham Cancer Institute who primarily cares for patients with cutaneous malignancies, has studied this issue in depth. She says the use of neoadjuvant immunotherapy has become the standard of care for managing her patients.

"We're seeing significant improvements in event-free survival (EFS) and recurrence-free survival (RFS) when giving immunotherapy before rather than after surgery," she says. "That will probably be reflected in overall survival as well, though we don't necessarily have that data yet."

Dr. Cohen adds that these findings are likely relevant to the management of squamous cell carcinoma and other cutaneous diseases.

Making the Case for Neoadjuvant Immunotherapy

In 2018 the American Joint Committee on Cancer reported that patients with high-risk stage 2 or stage 3 melanoma responded poorly when treated with surgery alone. That same year, Eggermont et al. demonstrated that the addition of adjuvant anti-PD-1 therapy for one year following resection in those high-risk, stage 3 patients substantially improved RFS. Multiple additional trials showed similar effects with alternate adjuvant regimens and in high-risk stage 2 melanoma.

Meanwhile, a series of other studies produced early data highlighting the advantages of neoadjuvant immunotherapy in mouse models and in humans. These findings inspired recent pivotal studies of neoadjuvant immunotherapy in melanoma, such as:

• The phase 2 S1801 trial, which showed longer EFS with single-agent pembrolizumab in clinically detectable, measurable stage 3B to 4C melanoma
• The phase 3 NADINA trial, which showed longer EFS with combination nivolumab + ipilimumab in resectable stage 3 melanoma
• The phase 2 PRADO trial, which showed a safe and effective pathway for avoiding extensive lymph node surgery in patients with pathologic response to combination nivolumab + ipilimumab in stage 3 macroscopic melanoma

Collectively, these trials established a foundation for the use of neoadjuvant immunotherapy in patients with high-risk, resectable melanoma. Dr. Cohen highlighted a crucial benefit to this treatment approach: After immunotherapy is administered and the tumor is removed, a pathologist can examine the tumor to determine whether it survived or the immune system killed it.

"Patients who have a major pathologic response might be all set because their immune system has been trained to recognize that tumor going forward—in which case, you might be able to de-escalate systemic treatment and/or surgery," she says. "As for poor responders, you can quickly switch to alternate therapies in the adjuvant setting. Overall, it's a much nicer way to limit toxicity, morbidity, and length of treatment for patients.

"These improved outcomes in responders are hypothesized to be due to exposure of the immune system to a wider diversity of tumor antigens, allowing an improved immune response."

Ongoing trials aim to provide further clarification on this subject. Dr. Cohen, for example, helped lead a study at Massachusetts General Hospital that found response-directed de-escalation of surgical and medical treatments was both safe and did not compromise survival outcomes. The paper was published in Annals of Surgical Oncology. (The authors noted that the data were exploratory and require validation in prospective studies with larger cohorts.)

A Call for Education and Greater Awareness

Many academic medical centers have already embraced neoadjuvant immunotherapy for the treatment of high-risk, resectable melanoma. Adoption is less common among community hospitals.

"This is partly because many pathologists in the community don't have the expertise to review the specimens and offer recommendations based on their evaluation," Dr. Cohen says. "We need to come up with guidelines for community pathologists so that they can help their clinical teams make those downstream treatment decisions."

Dr. Cohen wants to ensure all clinicians caring for this patient population know that starting treatment with immunotherapy might be the best way to optimize a given patient's outcome. She adds that the data around neoadjuvant immunotherapy are equally compelling for patients with advanced, resectable squamous cell carcinoma and Merkel cell carcinoma.

"There hasn't been enough education about this," she says. "It's just as important with squamous cell to identify these patients early so they can get referred to multidisciplinary clinics, where the adoption of neoadjuvant strategies could have a comparable impact on patient outcomes."

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