Checkpoint inhibitors are standard after surgery for high-risk melanoma, and many patients recur anyway. An takes the mutations in one person’s resected tumor and builds an mRNA treatment aimed at them. So 157 patients with completely resected stage IIIB to IV melanoma were randomized two to one to that treatment plus , or pembrolizumab alone. Did move?
It moved in the right direction and just missed significance. Recurrence-free survival was longer with the combination, a for recurrence or death of 0.561 with a 95 percent interval from 0.309 to 1.017, and a two-sided P value of 0.053. Recurrence or death occurred in 22 percent of the combination group against 40 percent on monotherapy, and 18-month recurrence-free survival was 79 percent against 62 percent.
Checkpoint inhibitors are standard adjuvant treatment for resected stage IIB to IV melanoma, and a substantial share of patients recur despite them. The idea tested here is to add something aimed at the particular tumor that was removed, rather than at melanoma in general.
mRNA-4157 works as an individualized neoantigen therapy. Each resected tumor is sequenced, targets specific to that patient are chosen, and an mRNA treatment encoding them is manufactured for that person alone. The trial was open-label, randomized and phase 2b, enrolling patients in the USA and Australia with completely resected high-risk cutaneous melanoma at stage IIIB to IV.
One hundred fifty-seven patients were assigned two to one. The 107 patients on the combination received mRNA-4157 intramuscularly, to a maximum of nine doses, plus pembrolizumab. The other 50 received pembrolizumab alone, to a maximum of 18 doses, in three-week cycles. Median follow-up was 23 and 24 months respectively.
Recurrence-free survival was longer with the combination, with a hazard ratio of 0.561, a 95 percent interval from 0.309 to 1.017, and a two-sided P value of 0.053. Recurrence or death occurred in 24 of 107 patients on the combination against 20 of 50 on monotherapy, and 18-month recurrence-free survival was 79 percent against 62 percent. Most treatment-related adverse events were grade 1 or 2, with grade 3 or higher in 25 percent of the combination group and 18 percent on monotherapy. mRNA-4157 was not linked to any grade four or grade five events. The effect size is encouraging and the interval crosses no benefit, which is why this justifies a phase 3 rather than a conclusion.
wat. Adding a tumor-specific mRNA therapy cut recurrences from 40 percent to 22 percent, and the result landed a whisker outside statistical significance.
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An individualized therapy manufactured per patient is a genuinely different model of cancer treatment. A phase 2b signal of this size is what justifies the much larger trial, not what replaces it.
How do we know?
Weber and colleagues ran an open-label, randomized, phase 2b adjuvant study in the USA and Australia, assigning 157 patients two to one to mRNA-4157 plus pembrolizumab or to pembrolizumab alone. Recurrence-free survival was the primary endpoint.
What is still unknown
The primary endpoint missed statistical significance at a P value of 0.053, the trial was open-label with 157 patients, and median follow-up was about two years. This is a promising phase 2b result, not an established benefit.
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