mRNA Vaccine Slows Melanoma Recurrence

Adding the investigational vaccine mRNA-4157/V940 (Moderna) to adjuvant pembrolizumab (Keytruda; Merck) appears effective for patients with operable high-risk melanoma, according to data from the phase IIb KEYNOTE-942 trial. The combination considerably boosted recurrence-free survival, compared with pembrolizumab alone.

Like Moderna's COVID-19 vaccine, mRNA-4157/V940 consists of a nano­particle-encapsulated mRNA molecule, albeit highly personalized, encoding up to 34 patient-specific tumor neoantigens, explained Jeffrey Weber, MD, PhD, of New York University's Langone Medical Center in New York. Upon intramuscular injection, these neoantigen sequences undergo processing and presentation, ultimately provoking cytotoxic and memory T cells into tumor-targeting action.

During the American Association for Cancer Research (AACR) Annual Meeting 2023 in Orlando, FL, April 14–19, Weber reported results for 157 patients who, following surgery, were randomized 2:1 to receive mRNA-4157/V940—given every 3 weeks for a total of nine shots—with pembrolizumab, or just the PD-1 inhibitor. At 18 months, the vaccine–pembrolizumab combination cut disease recurrence risk by 44%. Most side effects were mild, he said; no severe immune-mediated toxicities were seen.

“This is a great advance for cancer therapeutic vaccines in the adjuvant setting,” said Antoni Ribas, MD, PhD, of the University of California, Los Angeles, who was not involved in the study. “It's thanks to Moderna's efforts with mRNA-based strategies,” prior to the pandemic, “that we got COVID-19 vaccines so quickly—which in turn made it easier to do clinical trials on candidates like mRNA-4157.”

“For the first time with a melanoma vaccine, we have randomized data showing a hint of benefit; past trials with different approaches—peptides, dendritic cells, viral vectors—all failed,” said Ryan Sullivan, MD, of Massachusetts General Hospital Cancer Center in Boston. “The question now is, are we seeing benefit because this vaccine serves as a nice adjunct to pembrolizumab, providing more T-cell populations with antitumor activity? Or is the key the mRNA platform itself, which seems to be a fairly potent delivery system?”

Separately at AACR, Sullivan disclosed findings from a subset analysis of KEYNOTE-942, in which patients’ baseline biopsies were utilized to assess the relevance of tumor mutational burden (TMB) to a neoantigen vaccine. The TMB-high threshold was defined as 10 mutations per megabase. Compared with the control arm, patients given the vaccine plus pembrolizumab “did similarly better, independent of TMB,” he said: Recurrence risk was slashed by 35% and 41%, respectively, in TMB-high and TMB-low cohorts.

That TMB status may not matter “could be due to immunodominance,” Ribas said—the phenomenon whereby out of multiple neoantigens presented, immune responses are skewed toward just a few. “The problem is there's no good way to detect immunodominance,” he noted, “and it's still poorly understood.”

Sullivan's data “confirm what my former boss [Steven Rosenberg, MD, PhD, of the NCI] has said about neoantigens: ‘It only takes one,’” Weber remarked. “Bottom line, the number of neoantigens isn't as important as having the right ones.”

Further studies of mRNA-4157/V940 are in the works, including a larger phase III trial to confirm KEYNOTE-942, which will launch this summer. According to Ribas, “we should start thinking about how to incorporate it in the new era where anti–PD-1 will be given neoadjuvantly,” as well as after surgery, for stage III/IV melanoma, based on a recent SWOG Cancer Research Network report (N Engl J Med 2023;388:813–23).

Looking ahead, this vaccine strategy “should also be applicable to any tumor type that's operable, sensitive to PD-1 blockade, and generates neoantigens,” Weber observed, such as non–small cell lung cancer, hepatocellular carcinoma, and triple-negative breast cancer, among others.

mRNA-4157/V940 has “absolutely breathed new life” into the cancer ­vaccine field, Weber added. “I say that as a bona fide skeptic who's put ­hundreds of patients on prior trials and seen no evidence of benefit until now.” –Alissa Poh

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.