5-Year Data Support Personalized Vaccine in High-Risk Melanoma

Patients with high-risk melanoma who have undergone surgery remain at risk of their cancer returning, even when treated with modern immunotherapy. New five-year data from the phase 2 KEYNOTE-942 trial suggest that a personalized cancer vaccine combined with Keytruda (pembrolizumab) may help reduce that risk and potentially generate lasting immune memory against the disease.

The findings were highlighted at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting by Dr. Matteo Carlino, a medical oncologist at Westmead Hospital and the Melanoma Institute Australia in Sydney.

"Patients still recur and die of their melanoma despite adjuvant immunotherapy," Carlino explained. "This trial was designed to test whether the addition of a personalized neoantigen-directed therapy could further reduce the risk of recurrence."

Why Was KEYNOTE-942 Conducted?

Patients with resected stage 3 or stage 4 melanoma often receive adjuvant immunotherapy such as Keytruda or Opdivo (nivolumab) after surgery to reduce the risk of their cancer returning.

Although these treatments have improved outcomes, recurrence remains a major challenge.

KEYNOTE-942 was designed to determine whether adding mRNA-4157 (V940), a personalized cancer vaccine created using genetic information from an individual patient's tumor, could improve outcomes beyond those achieved with Keytruda alone.

The vaccine is designed to train the immune system to recognize unique mutations, known as neoantigens, found within a patient's cancer cells.

Five-Year Results Show Sustained Reduction in Recurrence Risk

According to Carlino, the updated analysis continues to support the benefit of the combination approach.

Patients treated with mRNA-4157 (V940) plus Keytruda experienced a 49% reduction in the risk of recurrence compared with those who received Keytruda alone.

The combination also reduced the risk of distant metastasis-free recurrence by 59%.

For patients, preventing distant recurrence is particularly important because melanoma that spreads to other organs can be significantly more difficult to treat.

The updated findings suggest that the benefit observed in earlier analyses has remained durable over time.

Evidence Points to a Lasting Immune Response

In addition to the clinical outcomes, researchers presented new translational data that may help explain why the treatment appears effective.

The personalized vaccine was designed to encode up to 34 neoantigens identified from each patient's tumor. Investigators found that patients receiving the vaccine plus Keytruda developed increased T-cell clonality and generated new T-cell populations not seen before treatment.

Further analyses demonstrated that these newly developed T cells were targeting the specific neoantigens incorporated into the vaccine.

According to Carlino, these findings provide evidence linking the vaccine's mechanism of action with the improved recurrence-free survival observed in the study.

"We found that those T cells were in fact targeting the neoantigens expressed in the vaccine," Carlino said, noting that the findings connect the biological activity of the therapy with the clinical outcomes seen in patients.

Could the Vaccine Create Long-Term Immune Memory?

One of the most intriguing questions raised by the updated data is whether the therapy may generate long-term immune memory capable of protecting patients years after treatment ends.

Carlino said researchers have already observed persistence of vaccine-induced T-cell populations well after therapy was completed.

Investigators detected these novel T-cell clones in patients' blood one year after treatment initiation, approximately six months after the final vaccine dose was administered.

While longer follow-up is needed, the findings raise the possibility that the treatment could provide durable immune surveillance against melanoma recurrence.

"Certainly, that's the hope, that we can get long-term immune memory," Carlino said.

Researchers are now interested in determining whether these vaccine-generated T cells remain detectable many years after treatment and whether their persistence correlates with long-term protection from recurrence.

Phase 3 Trial Results Awaited

Although the results from KEYNOTE-942 are encouraging, the study included just over 150 patients and was designed as a randomized phase 2 trial.

The next major test for the approach will come from the ongoing phase 3 INTerpath-001 trial, which has completed enrollment and is evaluating the personalized vaccine in a broader population of patients with melanoma.

"The definitive randomized phase 3 trial has now completed accrual," Carlino said. "Results are eagerly awaited by investigators, patients and the field more generally."

If the phase 3 study confirms the benefit seen in KEYNOTE-942, the personalized vaccine could become a new adjuvant treatment option for patients with high-risk melanoma following surgery.

What This Means for Patients

The five-year update from KEYNOTE-942 provides some of the longest follow-up data reported to date for a personalized mRNA cancer vaccine.

While additional confirmation from phase 3 testing is still needed, the results suggest that combining mRNA-4157 (V940) with Keytruda may not only reduce the risk of melanoma recurrence but also generate durable immune responses that could help protect some patients for years after treatment.

For patients with high-risk melanoma, the findings represent another step toward more personalized cancer treatments designed around the unique genetic makeup of an individual's tumor.

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