CHICAGO – Three years into the KEYNOTE-942 clinical trial, patients with high-risk melanoma are still seeing a significant benefit from the addition of Merck and Moderna's personalized neoantigen vaccine, mRNA-4157, to Merck's checkpoint inhibitor Keytruda (pembrolizumab).
Jeffrey Weber, the deputy director of the Perlmutter Cancer Center at NYU Langone Health, presented the latest results from the Phase II trial during the American Society of Clinical Oncology's annual meeting on Monday.
In the ongoing Phase II trial, 157 patients are randomized to receive either up to one year of Keytruda or up to a year of Keytruda plus up to nine doses of the personalized messenger RNA neoantigen vaccine.
The therapies are administered to patients in the adjuvant setting after they undergo surgical resection. Researchers analyze patients' tumor and normal tissue samples using tumor-normal sequencing to identify up to 34 patient-specific neoantigens, which Merck and Moderna then encode into an mRNA strand. They pack these strands into injectable lipid nanoparticles to create a bespoke vaccine for each patient that can be injected intramuscularly.
As of the data cutoff last November, patients with stage III and IV melanoma who received the personalized vaccine plus the immune checkpoint inhibitor saw a 49 percent reduction in the risk of disease recurrence or death compared to patients who received just Keytruda. The median relapse-free survival was not reached for those who got the vaccine plus Keytruda versus 42.5 months for patients on Keytruda alone, and the 2.5-year relapse-free survival rate was 74.8 percent versus 55.6 percent, respectively.
The personalized vaccine also reduced patients' likelihood of developing distant metastases. After 30 months, 89.3 percent of patients receiving the combination were alive without distant metastases, while the same was true for 68.7 percent of patients on Keytruda alone. This translated to a 62 percent reduction in the risk of distant recurrence or death, Weber noted.
Although overall survival data aren't yet mature, Weber noted an encouraging trend favoring the mRNA-4157 plus Keytruda arm. "The numbers are small … and obviously we need to follow these out over time to at least five years," he said. "But there are clearly more survivors in the combination arm."
At the meeting, Weber also presented updated biomarker analyses from KEYNOTE-942, which showed that "whatever your biomarker was, you benefited from the combination versus pembrolizumab." Previously, Merck and Moderna had presented data showing that patients benefited from the addition of the personalized vaccine regardless of their PD-L1 status or tumor mutational burden.
Now, Weber said, the data also show that the benefit was consistent across circulating tumor DNA analyses and regardless of HLA class I allele heterozygosity or homozygosity. "In melanoma, it's not uncommon to see an allele loss," he said. "Beta II microglobulin loss is pretty rare, but individual allele loss can happen, and obviously, that could compromise your ability to mount a T-cell response."
But whether patients had homozygous or heterozygous HLA class I alleles, he said, the combination therapy still improved outcomes. When asked during a panel discussion what the mechanism is for why the HLA heterozygous patient population would benefit from the personalized neoantigen vaccine, Weber explained that people have six HLA class I alleles and at least six class II alleles. "You could have class II responses, which could overcome the loss of class I alleles," Weber said. "That's the beauty of having a wide spread of neoantigens that are restricted to two different alleles."
In terms of the safety of the neoantigen vaccine-checkpoint inhibitor combo, researchers didn't observe any changes since the trial's previous data cutoff. "The big issue for the FDA and for all of us was, would you see more immune-related adverse events at grade 3 or more, and the answer is, you don't," he said. Weber added that the toxicities were very similar between the two treatment arms and that the vaccine-related side effects were expected given what was known already about COVID-19 mRNA vaccines.
Merck and Moderna have already begun evaluating the combination in a Phase III trial dubbed INTerpath-001 in high-risk melanoma. "It's recruiting like crazy," Weber said. "It'll end before the end of 2024 and provide the definitive evidence for whether there's benefit."
And if that trial is positive, Weber said that he believes the Keytruda-vaccine combination will become a new standard of care for that patient population.
Additionally, Merck and Moderna said in December 2023 that they were also evaluating the Keytruda-vaccine combination in a Phase III trial dubbed INTerpath-002, which is enrolling patients with stage II, IIIA, or IIIB resected non-small cell lung cancer.
The partnered firms believe this combination could have activity in other treatment settings. Earlier this year, they announced a Phase II/III randomized trial, evaluating mRNA-4157 plus Keytruda as neoadjuvant treatment in patients with resectable, locally advanced, cutaneous squamous cell carcinoma. They are also studying the combo in a Phase II trial as adjuvant treatment in certain renal cell carcinoma patients and in a Phase II trial as adjuvant treatment in certain urothelial carcinoma patients.
During the panel discussion on Monday, Weber also said he would like to see a clinical trial where all patients first receive dual checkpoint inhibitors in the neoadjuvant setting — Bristol Myers Squibb's Opdivo (nivolumab) plus Yervoy (ipilimumab) — and then are randomized to receive either Keytruda or Keytruda with the personalized vaccine.