Neoadjuvant immunotherapy ‘the new standard’ for resectable stage III melanoma
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Key takeaways:
- Neoadjuvant nivolumab plus ipilimumab extended EFS for individuals with resectable stage III melanoma.
- EFS benefits seen in patients with BRAF mutations.
CHICAGO — Individuals with resectable stage III melanoma derived significant EFS benefits with neoadjuvant immunotherapy compared with standard treatment, results from a randomized phase 3 trial presented at ASCO Annual Meeting showed.
Study participants who received neoadjuvant nivolumab (Opdivo, Bristol Myers Squibb) plus ipilimumab (Yervoy, Bristol Myers Squibb) prior to therapeutic lymph node dissection experienced 68% fewer events —defined as progression to nonresectability or treatment- or melanoma-related death — compared with those who received adjuvant therapy following dissection.
“Together with SWOG S1801, NADINA defines neoadjuvant immunotherapy as the new standard of care for macroscopic stage III melanoma, which means that all trials currently ongoing need to be amended for an adjuvant comparator to neoadjuvant comparator,” Christian U. Blank, MD, PhD, professor of internal medicine at Netherlands Cancer Institute and founding and faculty member of the International Neoadjuvant Melanoma Consortium, said during his presentation.
Background and methodology
Standard care for individuals with resectable, macroscopic stage III melanoma includes therapeutic lymph node dissection followed by adjuvant therapy consisting of either nivolumab or pembrolizumab (Keytruda, Merck), or for patients with a BRAF mutation, dabrafenib (Tafinlar, Novartis) plus trametinib (Mekinist, Novartis), according to background information provided by researchers.
Patients treated with surgery only have a 5-year RFS of 30% and OS of 50%, and adjuvant therapy has shown to improve RFS but not OS.
“Thus, there is an urgent need for novel therapy approaches,” Blank said.
Other trials, including SWOG S1801, which Healio previously reported on, have produced data indicating neoadjuvant therapy improved EFS in the patient population.
The international NADINA trial evaluated a combination of neoadjuvant nivolumab plus ipilimumab before dissection vs. the current standard of care.
“NADINA is the first neoadjuvant checkpoint inhibitor phase 3 trial in melanoma,” Blank said. “It is also the first phase 3 trial in oncology testing a neoadjuvant checkpoint inhibitor without chemotherapy.”
Researchers included individuals with resectable, macroscopic, nodal stage III melanoma who had not received immune checkpoint inhibitors or BRAF or MEK inhibitors. They randomly assigned 423 patients in a 1:1 ratio to the study’s experimental arm of neoadjuvant nivolumab plus ipilimumab followed by therapeutic lymph node dissection, or the study’s control arm, which received standard therapeutic lymph node dissection followed by adjuvant nivolumab.
EFS from study randomization until disease progression, recurrence or death served as the trial’s primary endpoint.
Results and next steps
At a median follow-up of 9.9 months, study participants in the neoadjuvant arm had significantly fewer events (28 vs. 72) compared with the control cohort (HR = 0.32; 99.9% CI, 0.15-0.66).
The neoadjuvant group also had superior estimated 1-year EFS rates (83.7% vs. 57.2%).
All subgroups had superior EFS rates in the neoadjuvant arm, including patients with BRAF-mutant melanoma (83.5% vs. 52.1%) and BRAF-wild type (83.9% vs. 62.4%).
Neoadjuvant therapy produced major pathologic response in 59% of patients.
“This is important because the patients [who] achieve a major pathological response have an excellent outcome, with an EFS of 95%, and this is whether you achieve a complete response or whether if you have still 10% of tumor in your specimen,” Blank said. “If you have only a partial response, then you have an EFS of 76%. If you have a non-response, you have an EFS of 57%.”
Grade 3 or worse adverse events occurred more frequently in the neoadjuvant arm (47% vs. 30%), as well as those caused by systemic treatment (30% vs. 15%), but surgery caused 15% in both, Blank said when taking questions after his presentation. He described most of the adverse events as “transient.”
“NADINA is the new template for other malignancies implementing a neoadjuvant immunotherapy regimen followed by response-driven adjuvant therapy,” Blank said.
Michael C. Lowe, MD, MA, associate professor in the division of surgical oncology at Emory University School of Medicine, praised the results but cautioned that participants received two immunotherapies, so comparisons could not be made with other trials where patients received just one immunotherapy.
“But this study confirms with consistency that patients [who] receive ipilimumab and nivolumab have superior responses compared to single-agent immunotherapy,” he said. “Also, all patients had all of their lymph nodes removed, so this should remain standard of care in terms of surgical approach,” he added. “NADINA confirms that immunotherapy should be given to all patients with advanced melanoma, removed before surgery when possible, and establishes dual therapy with nivolumab and ipilimumab as the standard of care in the appropriate patient.”
Julie R. Gralow, MD, FACP, FASCO, ASCO chief medical officer and executive vice president and press conference moderator, wondered if surgery should be delayed in the future for the patient population.
“Should we keep the tumor intact if we’re giving immunotherapy in the early-stage setting to get more immune response, and not do surgery first, and then try to stimulate the immune system when you’ve taken out all the tumor antigens,” she asked.
Gralow added, “Really tremendous results. I think we’ve got a new standard of care here.”
Perspective
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Sarah Weiss, MD
The results of the NADINA trial confidently confirm our intuition, based on prior smaller clinical and preclinical studies, that neoadjuvant immunotherapy is the new standard of care for resectable, macroscopic stage III melanoma. The primary endpoint of event-free survival heavily favored the neoadjuvant arm.
For the 58% of patients who received only two doses of neoadjuvant ipilimumab plus nivolumab and achieved a major pathologic response, further adjuvant systemic therapy was avoided.
At 1 year, 95% of patients who achieved a major pathologic response remain free of disease relapse. This is a staggering result. Longer follow-up will confirm this finding; however, remaining recurrence-free 1 year after having received only two doses (6 weeks) of ipilimumab plus nivolumab for high-risk melanoma is true progress.
Additionally, only 2.4% of patients had disease progression prior to surgery, further confirming that a short delay to administer immunotherapy does not result in a missed opportunity to undergo surgery for most patients. Further research should define whether all patients who undergo neoadjuvant immunotherapy benefit from surgery, and how to identify those patients who may potentially forgo surgery. More objective data than just imaging alone will be needed because radiographic responses can underestimate the pathologic response.
Treatment-related adverse events from immunotherapy remain a major clinical problem, decrease quality of life, can delay systemic therapy, often require immunosuppression that has its own toxicity, and additionally create financial and psychosocial toxicity. Avoiding unnecessary systemic therapy is a major goal, particularly in the curative setting. The rate of grade 3 or higher treatment-related adverse events in the neoadjuvant arm was not insignificant at 29.7% vs. 14.7% in the adjuvant arm, which also included one death. The less exposure to unnecessary treatment and strategies to lower treatment-related adverse events — including identification of predictive biomarkers — should be a major research focus. The NADINA trial has thus far demonstrated that less immunotherapy is possible in responders.
With additional follow-up, it will be very interesting to see the OS data. Additionally, further research is needed to determine the optimal neoadjuvant immunotherapy regimen because multiple agents — including anti-PD-1 monotherapy, nivolumab plus relatlimab, and ipilimumab plus nivolumab — have all been studied. Certain subgroups of patients such as those with autoimmune disease or poor performance status may need alternative strategies. Overall, the NADINA study represents an important move forward in the melanoma field with an immediate impact on clinical care.
RWJBarnabas Health
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Blank CU, et al. Abstract LBA2. Presented at: ASCO Annual Meeting; May 31-June 4, 2024: Chicago.
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