Loading ...

Five years after treatment, patients with resected high-risk melanoma who received the personalized messenger RNA (mRNA) vaccine intismeran plus pembrolizumab continued to experience clinically meaningful improvements in recurrence-free and distant metastasis-free survival, according to updated results from the KEYNOTE-942 trial.

Compared with patients who received pembrolizumab alone, those given the combination therapy had a 49% lower risk for recurrence or death and a 59% lower risk for distant metastasis or death. There was also a trend toward improved overall survival.

The 5-year results — which align with earlier data from the trial — were presented at the American Society of Clinical Oncology (ASCO) 2026 in Chicago and published simultaneously in the Journal of Clinical Oncology.

“This study confirms that intismeran plus pembrolizumab demonstrates a durable benefit over pembrolizumab alone in resected high-risk melanoma,” said study presenter Matteo S. Carlino, MD, PhD, a medical oncologist at The University of Sydney in Sydney, Australia.

However, findings from a larger ongoing trial are still needed. And broader questions remain about how a vaccine would fit into current real-world melanoma treatment.

An Antitumor Boost

Even with the use of adjuvant PD-1 inhibitors, about 40%-50% of patients with high-risk melanoma experience recurrence, including distant metastatic disease. And in phase 3 trials, combination PD-1 regimens have failed to improve those outcomes.

Intismeran is an mRNA vaccine that’s personalized based on the patient’s tumor sequencing data. The vaccine encodes up to 34 patient-specific neoantigens designed to strengthen and expand T-cell responses to the cancer.

Combining the vaccine with an immune checkpoint inhibitor, Carlino said, may enhance overall antitumor activity.

To test that idea, the phase 2 KEYNOTE-942 trial enrolled 157 patients with completely resected, high-risk stage IIIB-IV cutaneous melanoma. They were randomly assigned 2:1 to receive up to nine doses of intismeran (1-mg intramuscularly every 3 weeks) plus 18 doses of pembrolizumab (200 mg intravenously every 3 weeks), or 18 doses of pembrolizumab 200 mg alone.

The 5-year analysis — conducted after the last enrolled patient had 4 or more years of planned follow-up — showed that intismeran plus pembrolizumab led to durable improvement in recurrence-free survival, the primary endpoint.

At 4 years, recurrence-free survival rates were 72% with intismeran plus pembrolizumab vs 49% with pembrolizumab alone. That benefit was maintained across the primary analysis (hazard ratio [HR], 0.56), 3-year update (HR, 0.51), and 5-year update (HR, 0.51).

The recurrence-free survival benefit was seen across all key patient subgroups, including disease stage, PD-L1 status, BRAF mutation status, and tumor mutation burden. Notably, Carlino said, the two patients who were circulating tumor DNA-positive and treated with pembrolizumab alone had recurrences.

For the secondary endpoint of distant metastasis-free survival, rates at 4 years were 84% with the combination vs 65% with pembrolizumab alone (HR, 0.41) — in line with the primary and 3-year results.

Overall Survival Benefit?

Data on overall survival remain immature with relatively few events but show an encouraging trend, Carlino reported.

Seven of 107 patients (6.5%) in the combination group had died at the time of analysis compared with 7 of 50 patients (14%) in the pembrolizumab-alone group. Overall survival rates were just over 92% in the combination group and 85.6% in the pembrolizumab-only group (HR, 0.47). But, Carlino said, the CI crossed 1 because of the limited number of events.

No new safety signals emerged with longer-term follow-up. Most vaccine-related adverse events were grade 1 or 2 and predictable, Carlino said — including fatigue, injection site pain, fever, and chills. Overall, 11 patients (10.6%) had a grade 3 intismeran-related adverse event; no grade 4 or 5 events were attributable to the vaccine.

Importantly, Carlino reported, rates of immune-related adverse events were similar between groups, and grade 3 immune-related events were numerically lower with the combination than with pembrolizumab alone (10.6% vs 12%).

The updated analysis also provided mechanistic evidence supporting the vaccine’s proposed mode of action. Intismeran plus pembrolizumab generated sustained expansion of novel T-cell clones, and that expansion was associated with a lower risk for recurrence.

That’s suggestive of “durable immune surveillance,” Carlino said.

Real-World Use

Study discussant Rodrigo Ramella Munhoz, MD, PhD, a clinical oncologist specializing in melanoma, said the translational findings suggest that the platform works. But he stressed that confirmation in the ongoing phase 3 INTerpath-001 trial will be “critical,” particularly given the complexity and cost associated with producing personalized vaccines — issues that could limit widespread use.

Munhoz, of Sírio-Libanês Hospital in São Paulo, Brazil, also pointed to the key bigger-picture question: In an evolving melanoma treatment landscape increasingly dominated by neoadjuvant strategies, where might personalized vaccines fit in? 

Carlino and his colleagues acknowledge that a limitation of this trial was its exclusion of patients who’d received prior neoadjuvant or perioperative systemic therapy.

“Melanoma is moving from a one-size-fits-all perioperative approach toward biologically adaptive, personalized, and intensified strategies,” Munhoz said. “As we expand neoadjuvant treatments for melanoma, the optimal regimen remains unclear, and biomarkers to guide intensification are an unmet need.”

The study was sponsored by Moderna in collaboration with Merck Sharp & Dohme (MSD). Disclosure information for the study authors is available in the JCO publication. Munhoz has disclosed relationships with various pharmaceutical companies including MSD, Novartis, Pfizer, and Bristol Myers Squibb.