Melanoma relapse rates squashed by vaccine and treatment timing

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Combining mRNA vax with standard treatment could stop skin cancer recurrence, and switching to neoadjuvant treatment starts now.

A cancer vaccine combination can substantially improve recurrence-free survival for melanoma patients, according to the three-year findings presented at the American Society of Oncology (ASCO) meeting in Chicago last week.

The joint US-Australian randomised Phase 2 study, which included Australian of the Year Professor Georgina Long AO among its authors, found the combination of mRNA-4157 (V940) and pembrolizumab reduced the risk of recurrence or death by 49% in patients with resected high-risk melanoma (stage IIIB-IV), and risk of distant metastasis by 62% compared with the standard treatment – pembrolizumab alone – at nearly three years after treatment. At 2.5 years, the vaccination combination recurrence-free survival was 75% compared to 56% for pembrolizumab alone.

The mRNA-4157 (V940) vaccine is a new individualised neoantigen therapy (INT); a personalised cancer vaccine. It primes a person’s own immune system to create antibodies that target their specific tumour.

The standard treatment for resected stage IIIB-IV melanoma is currently pembrolizumab, an anti-PD-1 immune checkpoint inhibitor therapy.

The 157 patients were treated for around a year, randomised 2:1 to receive the combination treatment of 1mg of the vaccine every three weeks for up to nine doses and 200 mg of pembrolizumab every three weeks for up to 18 cycles; or just pembrolizumab.

The first differentiation in results between the arms was seen at around eight months. At 18 months there was a 17 percentage point difference in disease free survival, maintained at three years. Distant metastasis free survival also diverged late at over a year from commencement and there’s now a 20 percentage point difference between those who had the combination treatment and those who had pembrolizumab alone.

The overall survival available to date is 96% for the combination compared with 90% for pembrolizumab alone at 2.5 years.

“We now have some survival data with a very late break, we’re talking way out, a couple of years out,” said presenter and first author, Dr Jeffrey Weber from the Perlmutter Cancer Center in New York.

“The numbers are small. Patients, whether on the pembro arm or the combo arm, obviously did well. But these are encouraging data that merit follow up. And obviously we need to follow these out over time to at least five years.”

The advantage for those given the vaccine combination was seen regardless of tumour mutational burden or PD-L1 status, cTDNA or HLA heterozygosity.

The most common adverse events for the combination arm of the trial were fatigue (60%), injection site pain (57%) and chills (49%) and the majority were Grade 1-2. Fatigue was the most common Grade 3 event. The rates of immune-related adverse events were similar in both arms – 38% for the combination group and 36% in those receiving just pembrolizumab.

The update of the Phase 2b KEYNOTE-942/mRNA-4157-P201 study is the second analysis, with five years of follow-up planned from the first dose of treatment.

“This is now in a large randomised phase three study that’s recruiting like crazy, it’ll end before the end of 2024 and provide the definitive evidence for whether there’s benefit,” said Dr Weber.

Stage III melanoma – neoadjuvant now standard of care

The vaccine findings were presented at the same meeting as the NADINA trial Phase 3 results, which showed a 68% decreased risk of progression or recurrence and death when using neoadjuvant nivolumab and ipilimumab in resectable stage III melanoma.

“NADINA defines neoadjuvant immunotherapy as the new standard of care for macroscopic stage III melanoma,” presenter and first author, Dr Christian Blank from the Netherlands Cancer Institute told conference attendees.

Professor Long was a lead investigator of the international research, published in the New England Journal of Medicine this week. The trial found that at a median follow-up of nearly 10 months, the estimated 12-month event-free survival was 84% in the group that received the drugs prior to surgery, compared with 57% in those who were treated after surgery.

“Adjuvant therapy improves relapse-free survival, but none of these trials, either PD1-blockade or targeted therapy, have shown significant overall survival benefit,” said Dr Blank.

“NADINA is the first neoadjuvant checkpoint inhibitor phase 3 trial in melanoma. It is also the first phase 3 trial in oncology testing a neoadjuvant checkpoint only combination [no chemotherapy].

“We hope that all stakeholders will sit together to make neoadjuvant ipi nivo available to all patients everywhere. It is in the patients’ interests.”

Choosing a treatment

Neoadjuvant treatment was appropriate for anyone with a palpable, clinically detectable stage III melanoma, said Dr Weber.

“At my institution we’ve done that for years,” he said, noting that it was approved in the US but it was more problematic elsewhere.

However, “only about 15-20% of patients … have clinically detectable disease, so that leaves 80+% who wouldn’t necessarily be eligible for neoadjuvant therapy,” he pointed out.

“And if the V940 trial is positive, that’ll be a new standard of care for them to get the pembro vaccine.”

In addition, the NADINA trial, “a very well done, very well-presented study”, so far only had 9.9 months of follow-up and the recurrence rate could go up in the second or third year, “so I’d be a little cautious,” said Dr Weber.

Panel member Professor Paolo Ascierto from the Istituto Nazionale Tumori Fondazione in Naples, who was involved in NADINA, said the “real innovation” of the trial was that there was now marker to suggest if a patient required adjuvant treatment.

“The pathological complete response should be evaluated as a possible marker to decide if to go ahead or not,” said Professor Ascierto.

“About 60% of patients get a pathological complete response and the benefit to these patients was high at 95%. Of course, we have 40% of patients that still need adjuvant [treatment] and for these patients, we need a combination with vaccine.”

ASCO annual meeting 2024, 3 June

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