Results of the phase III NADINA trial support a new standard of care for the treatment of resectable macroscopic stage III melanoma. Treatment with preoperative ipilimumab plus nivolumab followed by total lymph node dissection, with adjuvant therapy guided by depth of response, led to a highly significant 68% relative reduction in the risk of disease recurrence or death as compared to standard-of-care dissection and adjuvant nivolumab. Of the 59% of patients achieving a major pathologic response, some were able to avoid adjuvant therapy altogether, limiting their total treatment time to 6 weeks.

“We showed that we can treat patients with pure immunotherapy alone…, and if they achieve a very deep response, they don’t need adjuvant treatment at all,” said Christian U. Blank, MD, PhD, Group Leader in the Division of Molecular Oncology and Immunology at the Netherlands Cancer Institute, Amsterdam. He presented the findings at the 2024 ASCO Annual Meeting Plenary Session.¹ The study was simultaneously published in the The New England Journal of Medicine.²

Christian U. Blank, MD, PhD

Lynn Schuchter, MD, FASCO

Upon hearing the results, Plenary Session co-moderator, outgoing ASCO President, and melanoma expert Lynn Schuchter, MD, FASCO, Director of the Tara Miller Melanoma Center and the Madlyn and Leonard Abramson Professor of Clinical Oncology at Penn Medicine, Philadelphia, commented, “I’ll be back in the clinic Thursday, and for the first time I am going to consider [ipilimumab/nivolumab]. I have not been using combination therapy for stage III disease, only for stage IV melanoma, but based on these data and the dosing, I’m feeling more comfortable.” She added that she remains more hesitant to forgo 1 year of adjuvant PD-1 blockade. “I’ll say that as oncologists, it takes us a lot longer to adapt to giving a lot less, but this is the direction we should be going.”

Study Background and Rationale

NADINA is the first phase III trial to test a neoadjuvant checkpoint inhibitor without chemotherapy. The phase II SWOG S1801 study evaluated three courses of pembrolizumab, followed by surgery and 1 year of adjuvant pembrolizumab, showing a 72% event-free survival rate at 2 years as compared to 49% for adjuvant pembrolizumab alone (P = .004).³

“Together with SWOG 1801, NADINA defines neoadjuvant immunotherapy as the new standard of care for macroscopic stage III melanoma. NADINA is the new template for other malignancies implementing a neoadjuvant immunotherapy regimen followed by response-driven adjuvant therapy,” Dr. Blank said, suggesting that all trials still using adjuvant therapy “need to be amended.”

NADINA’s study design has a strong biological basis: the observation that in the setting of intact tumors, immune response to a checkpoint inhibitor is stronger. In addition, in previous studies, the doublet of ipilimumab and nivolumab has produced higher pathologic responses and longer event-free survival than single-agent PD-1 blockade. Reduced dosing of the doublet has increased safety while preserving efficacy. In addition, patients achieving major pathologic responses have been shown to have excellent long-term outcomes without further treatment, and the addition of adjuvant therapy can boost outcomes in poor responders, he explained.

NADINA Details

The international phase III trial randomly assigned 423 previously untreated patients with stage III resectable melanoma and at least one positive lymph node to one of two arms. The experimental arm received two courses of ipilimumab at 80 mg plus nivolumab at 240 mg every 3 weeks, followed by total lymph node dissection. The comparator arm underwent total lymph node dissection and then received 12 courses of adjuvant nivolumab. In the experimental arm, patients who achieved a major pathologic response (≤ 10% viable tumor cells) received no additional treatment. The others received 11 cycles of adjuvant nivolumab or, if they had BRAF-mutated disease, adjuvant dabrafenib plus trametinib for 46 weeks. The primary endpoint was event-free survival.

After almost 10 months’ follow-up, the 12-month event-free survival rate was 83.7% in the neoadjuvant arm and 57.2% in the adjuvant arm (hazard ratio [HR] = 0.32; P < .001), based on the occurrence of 28 and 72 events, respectively. By BRAF status, for the neoadjuvant and adjuvant arms, respectively, event-free survival rates were 83.5% and 52.1% (HR = 0.29; P < .0001) in patients with BRAF-mutant disease and 83.9% and 62.4% (HR = 0.35; P = .0014), respectively, in those with BRAF wild-type disease. “You see for both groups a highly statistically significant outcome favoring neoadjuvant therapy. For all other subgroups, neoadjuvant therapy was also favored,” Dr. Blank reported.

“In line with previous trials, [ipilimumab/nivolumab] induced nearly 60% major pathologic responses. Major pathologic response is important because it’s an excellent surrogate for event-free survival,” he said. Patients with complete and near complete responses had equally good outcomes, with 12-month event-free survival rates of 95.4% and 94.1%, respectively. For partial responders this rate was 76.1%, and for nonresponders, only 57.0%.

“Of note, quality of life was equal between the arms, despite the fact that we saw a 29.7% rate of [nonsurgical related] grade ≥ 3 toxicities in the neoadjuvant arm and 14.7% in the control arm,” he added. “The major quality of life impairment came from the surgery.” Surgery-related adverse events were reported in approximately 14% of each arm. One death occurred from pneumonitis in the adjuvant arm. 

DISCLOSURE: The study was funded by Bristol Myers Squibb and the Australian government. Dr. Blank has stock or other ownership interests in Flinds Therapeutics and Signature Oncology; has had a consulting or advisory role for AstraZeneca, Bristol Myers Squibb, Genmab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Third Rock Ventures; has received research funding from 4SC, Bristol Myers Squibb, NanoString Technologies, and Novartis; holds patents, royalties, or other intellectual property (WO 2021/177822 A1); has provided expert testimony for Freshfields Bruckhaus Deringer; and has been paid for travel, accommodations, or other expenses by Bristol Myers Squibb. Dr. Schuchter reported no conflicts of interest.

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. 2024 ASCO Annual Meeting. Abstract LBA2. Presented June 2, 2024.

2. Blank CU, Lucas MW, Scolyer RA, et al: Neoadjuvant nivolumab and ipilimumab in resectable stage III melanoma. N Engl J Med. June 2, 2024 (early release online).

3. Patel SP, Othus M, Chen Y, et al: Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N Engl J Med 388:813-823, 2023.

EXPERT POINT OF VIEW

Michael Lowe, MD, Associate Professor, Division of Surgical Oncology, and Disease Team Leader and Co-Chair of the Melanoma Working Group at Emory University School of Medicine, Atlanta, commented at an ASCO press briefing that NADINA “pushed the boundaries on the use of systemic therapies in patients with melanoma who are able to undergo curative-intent surgery.”

Michael Lowe, MD

He continued: “NADINA confirms and shows for the first time in a phase III study, that giving immunotherapy before surgery results in superior outcomes to giving immunotherapy only after surgery … and that giving two immunotherapy drugs before surgery results in excellent responses. NADINA confirms that immunotherapy should be given to all patients with advanced melanoma before surgery when possible, and establishes dual treatment with nivolumab and ipilimumab as the standard of care in the appropriate patient.”

He cautioned, however, that the outcomes of neoadjuvant dual checkpoint blockade have not been compared with single-agent blockade and probably never will be. “The question of the best regimen is a difficult decision that medical oncologists will have to make individually with their patients.”

Additional Comments

The study’s invited discussant at the Plenary Session was Harriet M. Kluger, MD, the Harvey and Kate Cushing Professor of Medicine (Oncology) and Dermatology at Yale School of Medicine, New Haven, Connecticut. While noting NADINA’s “staggering hazard ratio” and “many amazing attributes,” she cautioned that the study was not designed to compare the neoadjuvant approach to salvage at the time of recurrence, in terms of long-term survival, and similarly not designed to determine the added benefit of ipilimumab compared to anti–PD-1 alone.

Harriet M. Kluger, MD

“What we do know is that early initiation of systemic immunotherapy in the neoadjuvant setting is superior to later initiation after surgery for recurrence-free survival, based on NADINA and SWOG S1801,¹ but the overall survival benefit is still unknown. And although [immunotherapy was] well tolerated overall, the rate of immune-related adverse events was higher, likely due to ipilimumab,” she said.

Dr. Kluger’s key takeaways included the following observations:

• The NADINA approach is clearly a new standard of care, but longer follow-up and overall survival data are needed to determine if it is the new standard.
• If the intention is to give standard-of-care postoperative anti–PD-1 therapy, giving two to three cycles before surgery, when possible, is highly beneficial.
• The greater the risk of recurrence, the greater the benefit: the NADINA regimen is an outstanding choice for very high-risk patients.
• When the risk of death is low, consider no immunotherapy, due to the risk of irreversible immune-related toxicity and the known potential for “salvage” if needed. 

DISCLOSURE: Dr. Lowe has consulted for BMS/Pfizer and Merck. Dr. Kluger has consulted for Bristol Myers Squibb, ChemoCentryx, Clinigen Group. Eisai, GI Reviewers, GigaGen, Invox Pharma, Iovance, Merck, Pliant, Seranova Bio, Signatera, Werewolf Pharma, and Apexigen.

REFERENCE

1. Patel SP, Othus M, Chen Y, et al: Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N Engl J Med 388:813-823, 2023.