Moderna Melanoma Therapy Cuts Recurrence Risk 42% in Phase 3 Trial

Key Points

• Moderna’s Phase 3 INTerpath-001 trial met its primary and key secondary endpoints in high-risk resected melanoma. Intismeran plus pembrolizumab reduced the risk of recurrence or death by 42% and the risk of distant metastasis or death by 38% versus pembrolizumab alone.
• Two-year relapse-free survival was 82.2% with the combination, compared with 70% for pembrolizumab alone. The treatment benefit emerged after six months, consistent with the time required to manufacture the personalized therapy and generate an immune response.
• Safety was broadly comparable between groups, although the combination caused more mostly mild, temporary injection-site reactions, chills and fever. Overall-survival data remain immature, while Moderna continues testing the individualized mRNA therapy in additional cancer types.

Moderna NASDAQ: MRNA presented Phase 3 results for intismeran, its individualized neoantigen therapy, in combination with Merck’s pembrolizumab for patients with resected high-risk melanoma. The INTerpath-001 trial met its primary endpoint of relapse-free survival and a key secondary endpoint of distant metastasis-free survival, according to lead investigator Georgina Long of Melanoma Institute Australia.

INTerpath-001 enrolled patients with resected cutaneous melanoma ranging from stage IIB through stage IV. Patients were randomized two-to-one to receive intismeran plus pembrolizumab or placebo plus pembrolizumab. Intismeran was administered intramuscularly at 1 mg every three weeks for nine doses, while pembrolizumab was given every six weeks.

Relapse-Free Survival Results

Among 1,137 randomized patients, 757 were assigned to the intismeran-pembrolizumab combination and 380 received pembrolizumab alone. At a median follow-up of 24.6 months, the combination reduced the risk of recurrence or death by 42% versus pembrolizumab alone, producing a hazard ratio of 0.58 and a P value of less than 0.001.

Two-year relapse-free survival was 82.2% for the combination arm and 70% for pembrolizumab alone. Long said the study’s preplanned piecewise analysis showed that the hazard ratio was 0.99 during the first six months, then improved to 0.42 after six months.

She attributed the delayed separation of the Kaplan-Meier curves to the time needed both to manufacture the personalized therapy and activate an immune response. The median time to a first intismeran dose was 64 days.

In a modified intent-to-treat analysis including patients who received either intismeran or placebo injections, the hazard ratio for recurrence or death was 0.51, representing a 49% reduction in risk, Long said.

Distant Metastasis Endpoint Also Met

The combination also significantly improved distant metastasis-free survival, a key secondary endpoint in the trial’s hierarchical testing plan. The hazard ratio was 0.62, with a P value of 0.002, corresponding to a 38% reduction in the risk of distant metastasis or death compared with pembrolizumab alone.

In the piecewise analysis, the hazard ratio for distant metastasis or death was 1.01 during the first six months and 0.50 thereafter. The modified intent-to-treat analysis produced a hazard ratio of 0.55 for that endpoint.

Long said benefit favored the combination in nearly all prespecified subgroups, while cautioning that some small subgroups had wide confidence intervals. Overall-survival data remain immature, and the study remains ongoing with investigators and patients still blinded, she said.

Safety and Manufacturing

Long said serious and grade 3 to 5 treatment-related adverse events were broadly similar between the treatment arms. Treatment discontinuations due to adverse events were higher in the combination arm, while discontinuations in the pembrolizumab-alone arm were more often due to recurrence.

The combination was associated with higher rates of mostly low-grade, transient events including injection-site pain, injection-site reactions, chills and fever. Pembrolizumab-related or checkpoint inhibitor-related adverse events appeared broadly similar across groups, and Long said intismeran did not appear to potentiate pembrolizumab toxicities.

Of the patients whose treatments were designed, 91% had the maximum 34 neoantigens identified for their intismeran product. Moderna successfully manufactured intismeran for more than 99% of randomized combination-arm patients, Long said. The most common reason patients failed screening was inadequate tumor tissue.

Mechanism and Broader Development

Moderna described intismeran as an mRNA-based therapy designed from each patient’s tumor mutations and HLA type, encoding up to 34 neoantigens. The company said the therapy is intended to improve neoantigen presentation and stimulate both CD4 and CD8 T-cell responses.

Company presenters also reviewed earlier Phase 2 translational findings showing an increase in novel T-cell clones after intismeran administration. In seven evaluated patients, Moderna said it matched T-cell responses to the neoantigens in the individualized treatment cassette and found, on average, that roughly one in three selected neoantigens was immunogenic.

Paolo Ascierto, a full professor of oncology at the University of Naples Federico II and a senior author of INTerpath-001, said the consistency between the Phase 2 and Phase 3 findings was important. He said the results could support a new standard of care in high-risk resected melanoma if the regimen proves superior to existing anti-PD-1-based approaches.

Toni Ribas, a professor at the University of California Los Angeles, called the findings a “landmark in cancer drug development,” saying the individualized approach is designed to expand T-cell responses against tumor-specific mutations.

Moderna said intismeran is also being studied across other tumor types and treatment settings, including lung, renal cell, bladder and pancreatic cancers. The company said a Phase 1 pancreatic cancer study in 20 resected patients found neoantigen-specific T-cell responses in all 19 immunogenicity-evaluable patients, with fuller results scheduled for presentation the following day.

About Moderna (NASDAQ:MRNA)

Moderna, Inc is a biotechnology company that develops medicines and vaccines using messenger RNA (mRNA) technology. Its platform is designed to instruct cells to produce proteins that can stimulate immune responses or support the treatment of disease. The company's research programs span infectious diseases, immuno-oncology, rare diseases, autoimmune conditions and other therapeutic areas.

Moderna's commercial products include Spikevax, an mRNA vaccine for COVID-19, and mRESVIA, an mRNA vaccine for respiratory syncytial virus (RSV) in older adults.

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