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The addition of a personalized cancer vaccine to Keytruda led to a 44% reduction in the risk of death or recurrence in certain patients with melanoma.
Adding a personalized mRNA-based cancer vaccine to the immunotherapy drug Keytruda (pembrolizumab) tended to improve the time patients with resected high-risk melanoma lived without signs of their disease coming back (recurrence-free survival), according to findings from the phase 2b mRNA-4157-P201/KEYNOTE-942 trial.
The findings, which were presented during the 2023 AACR Annual Meeting in Orlando, Florida, showed that the 18-month recurrence-free survival rate overall was 78.6% with the combination, compared to 62.2% with Keytruda alone, leading to a 44% reduction in the risk of disease recurrence or death by adding the vaccine.
These data, which were presented in a press briefing by senior author Dr. Jeffrey S. Weber, were found to be statistically significant and clinically meaningful.
“For the first time in a randomized study with a control arm, the addition of an mRNA neoantigen vaccine appeared to augment the benefit of PD-1 blockade, without adding significant high-grade toxicity,” Weber, who is deputy director of the NYU Langone Perlmutter Cancer Center and Laura and Isaac Perlmutter Professor of Oncology at NYU Grossman School of Medicine, stated in an April 16 press release. “This study is extraordinarily important, because it gives hope that this novel strategy will provide clinical benefit.”
Of note, Keytruda works by blocking PD-1, a protein found on cancer cell surfaces that helps them hide from the immune system. In doing so, it helps the immune system find and kill tumors.
In patients with multiple DNA mutations in cancer cells — a status known as a high tumor mutational burden — there was a 35% reduction in the risk of recurrence or death; this was 41% in those with low tumor mutational burden, suggesting that the vaccine can lead to promising responses regardless of tumor mutational burden, said Dr. Ryan Sullivan, who presented the data alongside Weber in the press briefing.
“The relevance of this study is the impact it could have not just for melanoma patients but for other cancers as well,” Sullivan, associate director of the melanoma program at Massachusetts General Cancer Center and associate professor at Harvard Medical School, stated in the press release. “From a general cancer therapeutic standpoint, this is a potential major breakthrough.”
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As part of the trial, patients’ normal and tumor tissue samples were extracted and analyzed, followed by sequencing to identify new proteins (neoantigens) that were made because of DNA mutations. mRNA-4157 is designed to target an individual patient’s unique tumor mutations, with individualized mRNA encoding for up to 34 neoantigens.
In the mRNA-4157-P201/KEYNOTE-942 study, patients were randomly assigned to receive mRNA-4157 at 1 mg intramuscularly every three weeks for up to nine doses plus Keytruda at 200 mg intravenously every three weeks for up to 18 cycles (107 patients) or Keytruda alone (50 patients). Patients were also stratified by disease stage.
The main goal of the study was relapse-free survival and secondary end points were safety, tolerability and how long patients lived before cancer was found in another body part (distant metastasis–free survival). Follow-up for relapse-free survival was up to three years following the first Keytruda dose.
To be eligible for enrollment, patients had to have stage 3B, 3C, 3D or 4 cutaneous melanoma and have undergone complete surgical removal within 13 weeks prior to the first Keytruda dose. Patients must have been disease-free at study entry, be able to independently perform their daily tasks and had tissue available for next-generation sequencing.
Additional findings showed that the 12-month relapse-free survival rate was 83.4% with the combination and 77.1% with single-agent Keytruda. Disease recurrence or death occurred in 22.4% of patients on the combination regimen and 40% of those on the Keytruda-only group at a median follow-up of 101 and 105 weeks, respectively.
Regarding safety, the combination was found to be well-tolerated and consistent with the safety profiles of each agent alone. Treatment-related side effects were moderate or severe in 25% of patients on mRNA-4157/Keytruda, compared to 18.0% with Keytruda; serious adverse side effects occurred in 14.4% and 10.0% of patients, respectively. Grade 3 or higher immune-mediated side effects were reported in 10.6% and 14.0% of patients on the combination and Keytruda alone groups, respectively.
Grade 3 or higher mRNA-4157–related side effects included fatigue (4.8%), fever (1.0%), and muscle pain (1.0%); grade 3 or higher Keytruda-related side effects in more than 20% of patients were fatigue (5.8%) and diarrhea (1.9%).
Weber and Sullivan noted that the link between the vaccine/PD-1 inhibitor combination and tumor mutational burden will continue to be explored in future studies, and additional analyses will aim to identify predictive biomarkers of response.
It was noted that patients randomized to the combination at the start of the study were more likely to have higher tumor mutational burden compared with those who were on Keytruda inhibitor alone. No difference in PD-L1 expression or tumor inflammation score (TIS), which measures tumors’ immune response, was observed in the two groups.
The relapse-free survival benefit was observed in TIS-high tumors and TIS–non-high tumors.
Limitations of the study were that KEYNOTE-942 was a phase 2b trial with “modest statistical power,” and that the neoantigen vaccine is based on DNA and RNA sequencing of tissue. Because of this, it may not be an optimal therapy for those with earlier-stage disease since there may be a lack of tissue available for patients with tumors smaller in size.
A phase 3 trial of the combination in this patient population is planned.
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