Newly reported data from a Phase III trial led by researchers at the Netherlands Cancer Institute demonstrated the success of immunotherapy before surgery (neoadjuvant therapy) for patients with metastatic melanoma, supporting data from previous Phase II studies. Results from the Phase III NADINA study showed that 59% of percent of patients with resectable stage III melanoma responded so well to neoadjuvant therapy using the PD-1 inhibitors ipilimumab plus nivolumab that adjuvant immunotherapy—treatment given after surgery—was no longer needed.

Headed by Christian Blank, PhD, the team reported on the NADINA trial findings at ASCO 2024, the international congress of the American Society of Clinical Oncology in Chicago, and in a published paper in NEJM, titled “Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma.” In their paper the team concluded, “Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab.”

Standard treatment for patients with metastatic skin cancer (melanoma, stage III) consists of local lymph node removal followed by a year of adjuvant treatment with immunotherapy or targeted therapy. However, the authors wrote, “despite adjuvant systemic treatment, a substantial portion of patients have disease recurrence within the first few years of surgery.” Blank added, “… we still see disease recurrence within three to five years in nearly half of these patients.”

Ten years ago Blank set up the Phase II OpACIN study, in which immunotherapy before surgery was compared to immunotherapy after surgery. The results indicated that neoadjuvant immunotherapy could induce a stronger and broader immune response against the tumor, at the cost of more side effects. “That’s why we initiated the OpACIN-neo trial, comparing three schedules with varying doses and eventually finding a safe and effective schedule,” Blank noted. In the subsequent PRADO trial, we applied this optimal dose to 99 patients. The patients who responded well to the treatment were able to forgo surgery and adjuvant treatment.”

In 2022, Blank and his research group published the PRADO study results, which found that 60 out of 99 patients with metastatic melanoma responded well to immunotherapy before surgery. “Conducting these studies eventually led to the design of the NADINA trial, the first Phase III trial investigating neoadjuvant checkpoint inhibition for early stage melanoma,” Blank stated.

The international investigator-initiated NADINA trial is “… distinctive in that it is evaluating a neoadjuvant regimen of immunotherapy alone” the team pointed out. For the study 423 patients were randomized to two groups. One group received two immunotherapy treatments with ipilimumab and nivolumab, followed by surgery. The second group received standard treatment involving surgery followed by 12 rounds of immunotherapy with nivolumab.

Fotografie voor NKI - AvL (Nederlands Kanker Instituut - Antoni van Leeuwenhoek Ziekenhuis) © Fotografie: Martin Hogeboom
Professor Christian Blank [Netherlands Cancer Institute]
The results showed that “In 59% of patients who had received immunotherapy before surgery, the tumor was nearly entirely or completely gone, which meant that they did not require additional treatment,” Blank said. The authors further noted, “As determined by central review, 47.2% of the patients had a pathological complete response (0% residual viable tumor) and 11.8% had a pathological near-complete response (1–10% residual viable tumor), which  yielded a major pathological response of 59.0%.”

Even people who did not respond well to the therapy and had an unfavorable prognosis benefited from the therapy: they were able to start adjuvant treatment with immunotherapy or targeted therapy after surgery.

The effects of the treatment become apparent quickly. After one year, almost 84% of patients who had received neoadjuvant treatment were still tumor-free, compared to 57% of the group receiving standard treatment. Blank further commented “Patients whose tumors were nearly entirely or completely gone, saw even better results; 95% remained tumor-free, after only six months of treatment.”

The authors further commented. “The results in the neoadjuvant group (an estimated event-free survival at 12 months of 83.7% and a major pathological response in 59.0% of the patients) are in line with the efficacy found in the preceding phase II trials that evaluated neoadjuvant ipilimumab plus nivolumab.”

The data further showed that 76% of patients whose tumors were only partially gone were still tumor-free one year after the start of their treatment, compared to 57% of patients who did not respond well to neoadjuvant therapy. These two patient groups received additional adjuvant treatment after their neoadjuvant treatment and surgery. In three years, the researchers expect to know whether this positive trend continues and could improve survivorship.

Besides a greater chance of tumor-free survival, most patients were able to cut down their treatment time to only six weeks. Blank said, “Treatment is a lot cheaper—€16,000 instead of €68,000, which would free up about 30–40 million euros in the Netherlands, and could reach a billion euros worldwide.”

The treatment still needs to be registered and approved in the Netherlands to qualify for health care insurance coverage. Blank noted “We are talking with various public authorities to ensure that the treatment can eventually receive coverage.”

The next challenges in this field will be to improve treatment outcomes of patients who responded less favorably. “… the estimated one-year recurrence-free survival of 57.0% among the patients who had a pathological nonresponse indicates that new adjuvant therapies need to be explored in this subgroup,” the investigators further stated.

In summary, they noted, “Here, we show that two cycles of ipilimumab plus nivolumab followed by a therapeutic lymph node dissection and response-driven adjuvant treatment resulted in longer event-free survival than adjuvant treatment, with an absolute reduction of 27 percentage points in the risk of an event in the first 12 months as compared with the current standard care of up-front therapeutic lymph-node dissection followed by 12 cycles of adjuvant nivolumab … Despite the evident superiority of neoadjuvant treatment over adjuvant treatment, this first, preplanned interim analysis reflects a relatively short follow-up. Follow-up is ongoing for the assessment of long-term event-free and distant metastasis–free survival, health-related quality of life, and ultimately overall survival.”

There are many studies looking into neoadjuvant treatments for various cancer types, including lung cancer, bladder cancer, and breast cancer. “These trials often combine a neoadjuvant approach with standard adjuvant treatment after surgery, instead of adapting treatment to the response to the neoadjuvant part,” Blank explained. “The NADINA trial is the very first trial within the oncological field that researched a purely immune-therapeutic and personalized treatment. Eventually we aspire to be able to provide personalized immunotherapy by reading out the tumor RNA in every individual patient, and providing a treatment that we know works best based on the results.”

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