In Stage III Melanoma, Immunotherapy Combo Before Surgery Leads to Improved Survival, Less Therapy

Giving patients with resectable stage III melanoma a combination of ipilimumab (Yervoy) and nivolumab (Opdivo) followed by surgery—and tailoring treatment after surgery to each patient’s response—led to dramatic improvements in event-free survival (EFS), according to results presented today at the annual meeting of the American Society of Clinical Oncology (ASCO).¹

The phase 3 NADINA trial (NCT04949113) represents the fruits of a decade-old idea and follow-up on results seen in smaller studies. Of note, a phase 2 study of pembrolizumab showed patients who had 3 neoadjuvant cycles before 15 adjuvant cycles had better EFS than those who received 18 adjuvant cycles. Ipilimumab and nivolumab are both made by Bristol Myers Squibb, which was among the study's sponsors.

NADINA not only confirms that immunotherapy before surgery improves survival in these patients; it also suggests that for some, it may be possible to eliminate therapy after surgery altogether—a result with huge implications for both patients and the health system. In the study, investigators reported that about 3 of every 5 patients who received neoadjuvant therapy did not need additional adjuvant therapy. Because they had a major pathological response, these patients only needed 6 weeks of treatment.

Christian U. Blank, MD, PhD | Image credit: ESMO

As explained during the plenary session by lead study author Christian U. Blank, MD PhD, medical oncologist at the Netherlands Cancer Institute, Amsterdam, the existing standard of care for stage III melanoma calls for removing the tumor and affected lymph nodes via surgery, then treating the patient with immunotherapy or targeted therapy to keep the cancer from coming back.

However, as Blank and coauthors wrote in the New England Journal of Medicine, which simultaneously published results, “Despite adjuvant systemic treatment, a substantial proportion of patients have disease recurrence within the first few years after surgery.”² This is true whether patients receive immune checkpoint inhibitors nivolumab or pembrolizumab—or, for patients with a BRAF mutation, dafrabenib plus trametinib.

During the plenary session, Blank said exactly 10 years ago, he and collaborator Ton Schumacher developed the idea that checkpoint inhibition “shouldn’t be most effective when given at a lower tumor burden,” and moving therapy ahead of surgery in the treatment queue produced stronger responses. Following the recent studies, the phase 3 NADINA study was designed to test outcomes after administering ipilimumab and nivolumab before lymph nodes were removed.

According to the study protocol, if this neoadjuvant treatment did not destroy at least 90% of the cancer cells—called a major pathological response—patients would receive 1 of the following: adjuvant treatment with nivolumab, or dabrafenib plus trametinib if a BRAF mutation was present.

Between August 2021 and December 2023, NADINA enrolled 423 patients, with 212 receiving neoadjuvant therapy and 211 participants receiving adjuvant therapy. Data cutoff was January 12, 2024, with a median follow-up of 9.9 months. Detailed results show¹:

• Significantly fewer events occurred in the neoadjuvant arm vs the adjuvant arm (28 events vs 72 events), for an HR of 0.32 (99% CI, 0.15-0.66; P < .0001).
• Estimated 12-month EFS rates are 83% (99.9% CI, 73.8-94.8) vs 57.2% (99.9 CI, 45.1-72.6), favoring the neoadjuvant arm.
• Among patients with BRAF-mutated melanoma, estimated EFS rates were 83.5% and 52.1%, and in BRAF-mutated wild type, 83.9% and 62.4%, favoring the neoadjuvant arm.
• 58.0% of patients in the neoadjuvant arm had a major pathological response, 8.0% had a partial pathological response, and 26.4% had a pathological nonresponse, whereas 2.4% had progression before surgery.
• Adverse events related to treatment of grade 3 or higher were seen in 29.7% in the neoadjuvant arm vs 14.7% in the adjuvant arm; 1 patient died due to pneumonitis.
• Surgery-related grade 3 or higher AEs were similar: 14.6% in the neoadjuvant arm and 14.4% in the adjuvant arm.

Lynn Schuchter, MD, FASCO | Image credit: Penn Medicine

ASCO President Lynn M. Schuchter, MD, FASCO, a melanoma specialist at the University of Pennsylvania, remarked how the idea of using less therapy would run counter to what so many physicians have done for years.

“I have a clinic on Thursday when I get back to Philadelphia, and I'm sure the clinic has scheduled many new patients,” she said. “So, really for the first time, I am going to consider [ipilimumab and nivolumab]… I will say based upon these data and this dosing I am feeling more comfortable. But I am also used to giving a year of therapy.”

Schuchter asked for more discussion on the idea of stopping therapy after only 6 weeks. And commentator Harriet M. Kluger, MD, of Yale Cancer Center, reminded Schuchter and the audience that back when immunotherapy was first approved, some patients had to stop treatment due to toxicity, but their responses continued. Per the study protocol, patients’ pathological responses will drive decisions on adjuvant therapy.

She’s seen the data, and the idea of giving patients less toxic therapy certainly has appeal. But Schuchter said, “It’s just very different from how we've been doing things.”

References

1. Blank CU, Lucas MW, Scolyer RA, et al. Neoadjuvant nivolumab plus ipilimumab versus adjuvant nivolumab in macroscopic, resectable stage III melanoma: the phase 3 NADINA trial. J Clin Oncol. Abstract LBA2. Published June 2, 2024. doi:10.1200/JCO.2024.42.17_suppl.LBA2

2. Blank CU, Lucas MW, Scolyer RA, et al. Neoadjuvant nivolumab and ipilimumab in resectable stage III melanoma. N Engl J Med. Published June 2, 2024. doi:10.1056/NEJMoa2402604

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