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New Approaches to Systemic Therapy for Patients with Stage III Melanoma

ASCO 2021 Highlights
Alexander M. Menzies, MBBS, PhD

Adjuvant therapy (treatment after the primary therapy, such as surgery) is here to stay for patients with stage III (advanced) melanoma, but the current options are not good enough, according to Alexander M. Menzies, MBBS, PhD, a Medical Oncologist at the Melanoma Institute, The University of Sydney in Australia.

At the 2021 ASCO Annual Meeting, Dr. Menzies discussed the evolving role of systemic therapy as a neoadjuvant therapy (before) and adjuvant therapy (after) surgery in patients with stage III melanoma.

“Whether targeted therapy or PD-1-based immunotherapy, the use of adjuvant therapy after surgical resection in stage III melanoma reduces the risk of recurrence by approximately 50%, and is currently standard therapy across the world,” Dr. Menzies said. “That is because PD-1 immunotherapy has a durable benefit, and may even cure patients in the metastatic setting. It’s unclear, however, whether we should treat people now in the adjuvant setting or wait until recurrence.”

The current problem with adjuvant therapy is selecting the right patients, Dr. Menzies explained, because there is a group of patients who will have disease recurrence despite receiving drug treatment, and another group that will never have disease recurrence. Although only 1 in 5 patients truly receive benefit from adjuvant therapy, currently all patients are receiving drug therapy before surgery.

“We need to move forward with adjuvant immunotherapy, but we also need more data,” Dr. Menzies said.

Adjuvant Immunotherapy

Final analysis of the S1404 phase 3 clinical trial compared the current standard of care of immunotherapy with high-dose interferon or Yervoy (ipilimumab) therapy or adjuvant immunotherapy with Keytruda (pembrolizumab) in patients with high-risk melanoma that was resected (removed by surgery).

The analysis confirmed an improvement in relapse-free survival with adjuvant pembrolizumab. There was also a trend toward improved survival with adjuvant immunotherapy with pembrolizumab, said Dr. Menzies, but this was ultimately insignificant, because of the small number of deaths in either study arm.

“As one would expect, recurrence after treatment has the potential to affect overall survival, but there is a large number of patients who don’t have any post-recurrence treatment reported, and I think this affects the results of this study,” said Dr. Menzies.

He added that pembrolizumab was also a better tolerated adjuvant regimen than high-dose interferon or ipilimumab. “Less than 50% of patients had PD-1 therapy after recurrence in the control arm, so this doesn’t completely answer the question,” Dr. Menzies added.

Crossover and Rechallenge Linked to Poor Survival

In the phase 3, double-blind, EORTC 1325/KEYNOTE-054 clinical trial, investigators compared pembrolizumab versus placebo in patients with stage III cutaneous (skin) melanoma and complete surgical removal of lymph nodes. The study also evaluated patients who had disease recurrence and who crossed over to treatment with pembrolizumab or received additional treatment (were rechallenged) with this immunotherapy.

According to Dr. Menzies, this was the first study to test the “now versus later” approach. Only 50% of eligible patients crossed over to immunotherapy during the study.

For those who did cross over to pembrolizumab, progression-free survival was poor, with second melanoma recurrence (coming back) occurring early, often within 12 months. In addition, only about one-third (33%) of patients were still recurrence-free after 3 years.

“These data were similar for resected stage III patients [with melanoma] and unresected disease, and it suggests that further recurrence is inevitable, unless drug therapy works,” said Dr. Menzies.

According to Dr. Menzies, delayed adjuvant PD-1 therapy has limited efficacy, because most patients with resected disease have a second cancer recurrence, regardless of treatment, and most patients whose cancer was not unresected also have disease progression or recurrence.

“Similarly, re-challenging with PD-1 therapy after recurrence of therapy has little efficacy,” Dr. Menzies said. He discussed the option of other immunotherapy combinations that include Opdivo (nivolumab), another PD-1 inhibitor. “Perhaps ipilimumab plus nivolumab or other combinations may be best.”

Neoadjuvant Nivolumab plus Relatlimab Therapy

Given the poor rates of survival outcomes associated with adjuvant therapy, neoadjuvant therapy (before surgery or other primary therapy) may soon be an option for patients with melanoma.

According to Dr. Menzies, the combination of nivolumab plus relatlimab, an investigational LAG-3 inhibitor, could improve response in the neoadjuvant setting, while mitigating the side effects associated with the combination of a PD-1 inhibitor and a CTLA-4 inhibitor.

“This combination looks impressive and should be taken forward,” said Dr. Menzies. “The high efficacy of nivolumab plus relatlimab is similar to PD-1 plus CTLA-4 combination therapy, and the toxicity is most likely less,” he added.

“Neoadjuvant therapy is the future, and we hope it will soon become the standard of care,” Dr. Menzies emphasized. “The phase 3 trials should demonstrate that, but we also believe it’s a robust model for drug development.”

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