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By Mandi Murph

Treatment may be changing for patients with Stage III melanoma. Recent clinical trial results show improved outcomes when ipilimumab plus nivolumab is given to Stage III patients with melanoma before the melanoma is removed by surgery. Giving drugs before surgery would be a major change to the order of treatment for this patient population.

Usually, patients with resectable (meaning it can be removed with surgery) Stage III melanoma begin treatment by receiving surgery to remove lymph nodes that contain melanoma. Following their surgery, many are treated with immunotherapy that is given every three, four, or six weeks for up to a year. Much of cancer is treated in this way – surgery before drug therapy. This is referred to as “adjuvant therapy.”

However, a Phase 3 clinical trial (NADINA) published in The New England Journal of Medicine and detailed in the plenary session at the 2024 ASCO meeting showed that patients with Stage III melanoma who received two rounds of ipilimumab plus nivolumab before surgery did better than those who first underwent surgery and then received 12 cycles of nivolumab. These results have the potential to reverse the order of melanoma treatment for Stage III patients.

Receiving the combination immunotherapy treatment before surgery led to an event-free survival of 83.7%. The group receiving 12 cycles of nivolumab after surgery had an event-free survival of 57.2%. Event-free survival was defined as the time of randomization to the occurrence of progression to unresectable (meaning it cannot be removed by surgery) melanoma before surgery, disease recurrence (meaning the return of the melanoma), or death due to melanoma or due to treatment.

Changing the regimen to two cycles of the combination immunotherapy first, followed by surgery, increased event-free survival and reduced the risk of melanoma recurrence by 27% within the first 12 months. Also, 47.2% of the patients had a pathological complete response, meaning no tumor was detected by the pathologist when the remaining mass was surgically removed and examined under the microscope. These results confirm earlier Phase 1 and 2 studies, which showed similar outcomes.

Clinicians think combination immunotherapy before surgery works better because it generates a stronger immune response. They believe that the presence of the melanoma tumor is involved in inducing a more diverse and powerful response among immune cells than can be obtained with only microscopic circulating tumor cells, such as in the setting of postoperative treatment with immunotherapy. Additionally, ipilimumab may broaden the immune response (make it recognize and kill a wider variety of melanoma cells) and is known to improve the effectiveness of nivolumab.

Patients in the study had resectable, macroscopic (can be felt or can be seen without a microscope) lymph nodes, arising from Stage III cutaneous or acral melanoma or melanoma of an unknown origin. The patients also had at least one lymph node with melanoma and a maximum of three other sites of metastases.

The study had limitations. Patients receiving ipilimumab plus nivolumab before surgery experienced higher rates of serious complications (36.3%) compared to other patients (23.6%). Clinicians say this emphasized the need to identify which patients will do better on one of these sequences rather than the other. Much of today’s cancer immunotherapy research is directed toward ways to identify the best match between patients and treatment so that the balance of benefit and risk may be optimized when choosing the best therapy.