Best Survival With Neoadjuvant Immunotherapy in Melanoma

BARCELONA, SPAIN — Patients with high-risk stage III resectable melanoma treated with neoadjuvant combination immunotherapy achieved higher event- and recurrence-free survival than patients who received monotherapy with immunotherapy or a targeted agent or targeted therapy plus immunotherapy, according to a large-scale pooled analysis from the International Neoadjuvant Melanoma Consortium.

Importantly, the analysis — presented here at the European Society for Medical Oncology (ESMO) Annual Meeting 2024 — showed that achieving a major pathological response to neoadjuvant therapy is a key indicator of survival outcomes.

After 3 years of follow-up, the results showed that neoadjuvant therapy is not delaying melanoma recurrence, “it’s actually preventing it,” co-investigator Hussein A. Tawbi, MD, PhD, Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, told Medscape Medical News. That’s “a big deal.”

Since 2010, the introduction of novel adjuvant and neoadjuvant therapies for high-risk stage III resectable melanoma has led to incremental gains for patients, said Georgina V. Long, MD, PhD, BSc, chair of Melanoma Medical Oncology and Translational Research, The University of Sydney, Sydney, Australia, who presented the results.

The first pooled analysis of neoadjuvant therapy in 189 patients, published in 2021, indicated that those who achieved a major pathological response — defined as either a pathological complete response (with no remaining vital tumor) or a near-complete pathological response (with vital tumor ≤ 10%) — had the best recurrence-free survival rates.

In the current study, the researchers expanded their cohort to include 818 patients from 18 centers. Patients received at least one dose of neoadjuvant therapy — either combination immunotherapy, combination of targeted and immunotherapy agents, or monotherapy with either an immune checkpoint inhibitor or a targeted agent.

The median age was 59 years, and 38% of patients were women. The median follow-up so far is 38.8 months.

Overall, the 3-year event-free survival was 74% in patients who received any immunotherapy, 72% in those who received immunotherapy plus a targeted BRAF/MEK therapy, and just 37% in those who received targeted therapy alone. Similarly, 3-year recurrence-free survival rates were highest in patients who received immunotherapy at 77% vs 73% in those who received immunotherapy plus a targeted BRAF/MEK therapy and just 37% in those who received targeted therapy alone.

Looking specifically at PD-1–based immunotherapy regimens, combination therapy led to a 3-year event-free survival rate between 77% and 95%, depending on the specific combinations, vs 64% with PD-1 monotherapy and 37% with combination targeted therapy.

Overall, patients who had a major pathological response were more likely to be recurrence free at 3 years. The 3-year recurrence-free survival was 88% in patients with a complete response, 68% in those with a partial pathological response, and 40% in those without a response.

Patients who received immunotherapy were more likely to have major pathological response. The 3-year recurrence-free survival was about 94% in patients who received combination or monotherapy with immune checkpoint inhibition, and about 87% in those who received immunotherapy plus targeted therapy. The recurrence-free survival rate was much lower in patients given only BRAF/MEK inhibitors.

The current overall survival data, which are still immature, suggested a few differences when stratifying the patients by treatment. Almost all patients with a major pathological response were alive at 3 years compared with 86% of those with a partial pathological response and 70% of those without a pathological response.

Overall, the results showed that immunotherapy — as either combination or monotherapy — is “quite a bit” better than targeted therapy with BRAF/MEK agents, which offers no substantial benefit, said Twabi.

“When you see the same pattern happening in study after study, in a very clear, robust way, it actually becomes very powerful,” Twabi explained.

Rebecca A. Dent, MD, MSc, chair of the ESMO Scientific Committee who was not involved, told a press conference that the introduction of immunotherapy and combination immunotherapy has dramatically changed outcomes in melanoma.

Commenting on the current study results, Dent said that “combination immunotherapy is clearly showing exceptional stability in terms of long-term benefits.”

The question now is what are the toxicities and costs that come with combination immunotherapy, said Dent, from National Cancer Centre Singapore and Duke-NUS Medical School, Singapore.

No funding declared. Long declared relationships with a variety of companies, including AstraZeneca UK Limited, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis Pharma AG, and Regeneron Pharmaceuticals Inc. Twabi declared relationships with Bristol Myers Squibb, Novartis, Merck, Genentech, GlaxoSmithKline, Eisai, and others. Dent declared relationships with AstraZeneca, Roche, Eisai, Gilead Sciences, Eli Lilly and Company, Merck, and Pfizer.