Add-on mRNA cancer vaccine delivers promise for melanoma

Adding mRNA-4157, an investigational personalized neoantigen cancer vaccine, to the immune checkpoint inhibitor (ICI) pembrolizumab significantly improved recurrence-free survival (RFS) in individuals with resected high-risk melanoma, findings from the phase IIb KEYNOTE 942 study suggest.

“This is the first randomized study to demonstrate improvement in RFS in melanoma with a novel individualized neoantigen vaccine approach,” said study investigator Dr Jeffrey Weber from the New York University Langone Perlmutter Cancer Center, New York City, New York, US, at AACR 2023. “The study arms split apart at 9 months, staying apart through 2 years of follow-up.”

At 18 months, RFS with higher with the combination regimen vs pembrolizumab alone (78.6 percent vs 62.2 percent), yielding an absolute difference of 16 percentage points. The hazard ratio for the difference in RFS was 0.56 (p_one-sided=0.026), corresponding to a 44-percent reduction in the risk of recurrence or death over time. The effect was consistent irrespective of PD-L1 status. [AACR 2023, abstract CT001]

The incidences of grade ≥3 treatment-related adverse events (AEs) between the combination vs pembrolizumab arms were well-balanced (25 percent vs 18 percent), as were the rates of any-grade serious AEs (14 percent vs 10 percent) and immune-mediated AEs (36 percent for both).

Individualized neoantigen therapy

ICIs are FDA-approved standard of care treatment for high-risk resected melanoma. “These are effective therapies. The problem is, if half the patients are going to relapse at 5 years, there is a major unmet clinical need due to high relapse rates even with effective therapies,” said Weber.

The mRNA-4157 vaccine is an individualized neoantigen therapy designed to target an individual’s unique tumour mutations through integrated manufacturing. “Neoantigen-based strategies may overcome the limitations of previous failed cancer vaccine approaches,” Weber noted. “Individualized neoantigen approaches can increase endogenous neoantigen specific key cell responses and induce epitope spreading.”

Weber and colleagues sought to evaluate the effect of combining mRNA-4157 with pembrolizumab in individuals with resected stage III/IV cutaneous melanoma. Resection should have been performed 13 weeks prior to the first pembrolizumab dose, and participants must be disease-free at study entry. A total of 157 patients (mean age 60 years, 63 percent male) were randomized to receive IV pembrolizumab 200 mg Q3W for up to 18 cycles alone (n=50) or in combination with IM mRNA-4157 1 mg Q3W for up to nine doses (n=107).

Next steps

“For the first time in a randomized study with a control arm, the addition of an mRNA neoantigen vaccine appeared to augment the benefit of PD-1 blockade, without adding significant high-grade toxicity,” said Weber in a press release. “This study is extraordinarily important, because it gives hope that this novel strategy will provide clinical benefit.”

Additional analyses are being planned, which shall include distant metastasis-free survival, treatment outcomes by BRAF status, and other translational analyses and RFS with ≥51 events. “We would need longer follow-up to have more RFS events. We will also initiate a phase III study to validate these very interesting and impressive data,” said Weber.

This strategy shall also be expanded to other histologies that are PD1-sensitive, such as non-small-cell lung cancer, renal cell cancer, and gastroesophageal cancer, he added.

However, as this was a phase IIb study, the data should be interpreted with caution, noted Weber. “Also, follow-up is 2 years, which is modest. Nonetheless, I do not think these caveats detract from the significance of the data.”

The mRNA-4157-pembrolizumab combination has been given the Breakthrough Therapy Designation by the FDA in February 2023 and the PRIME Designation by the EMA in April 2023.