A phase 2b trial of pembrolizumab plus a personalized mRNA vaccine resulted in improved recurrence-free survival in patients with resected high-risk melanoma, the first successful randomized trial of its kind.
Patients who received an mRNA vaccine in addition to adjuvant pembrolizumab (Keytruda) had improved recurrence-free survival (RFS) versus the immune checkpoint inhibitor alone following resection of high-risk melanoma, according to an announcement made by Moderna, Inc and Merck.1
Investigators in the phase 2b KEYNOTE-942 trial (NCT03897881) found a 44% reduction in risk recurrence or death (HR, 0.56; 95% CI, 0.31-1.08; one-sided P = .0266) in patients who received both the mRNA vaccine and pembrolizumab versus pembrolizumab alone. This marks the first randomized trial where a personalized mRNA cancer vaccine has been shown to improve clinical outcomes for patients versus an active comparator.
“The results of this randomized phase 2b trial are exciting for the field,” Jeffrey S. Weber, MD, PhD, principal investigator of the study and deputy director of the Perlmutter Cancer Center at NYU Langone Health, said in a statement. “These data provide the first evidence that we can improve on the rates of RFS achieved by PD-1 blockade in resected high-risk melanoma.”
The personalized cancer vaccine (PCV), called mRNA-4157/V940, is designed to promote an immune response to cancer based on an individual patient’s tumor mutational signature. It consists of a single mRNA strand that contains up to 34 neoantigen sequences that are endogenously translated within the body into antigens that promote adaptive immunity to the targeted cancer cells.
The previous phase 1 KEYNOTE-603 trial (NCT03313778) tested the PCV in resected solid tumors with or without pembrolizumab. It showed safety as well as neoantigen-specific T cell–mediated antitumor activity, with evidence suggesting additive benefit from the combination with pembrolizumab.2
The ongoing open-label phase 2b KEYNOTE-942 trial enrolled 157 patients. The participants were patients with stage III or IV resectable cutaneous melanoma, which had metastasized to a lymph node, who were considered to have high risk of recurrence. They were eligible if following complete resection, they had no loco-regional relapse or distant metastasis and no clinical evidence of brain metastases. Patients also had to have ECOG performance status of 0 or 1 and normal organ and bone marrow function.1
Patients were randomly assigned on a 2:1 basis to receive PCV plus pembrolizumab or pembrolizumab alone. In addition to the primary end point of RFS assessed radiographically for up to 3 years, secondary end points included distant metastasis-free survival and safety.
In order to create the PCV, next-generation sequencing was performed on a formalin-fixed, paraffin-embedded tumor sample. Patients’ genomic data, including the patient’s normal DNA and RNA sequencing, tumor DNA sequencing, and HLA typing, were fed into an algorithm to generate the optimal PCV sequence for each patient. During a media roundtable discussion hosted by Moderna, Kyle Holen, MD, head of development for oncology and therapeutics at Moderna, said that the personalized mRNA sequence is generated in only 2 hours based on these data. The entire process from acquiring a tissue sample to manufacturing the vaccine takes approximately 6 weeks, according to Holen.
Patients received 200 mg of pembrolizumab every 3 weeks for up to 18 cycles, and those who received mRNA-4157 were given 9 total doses of the PCV. The duration of treatment was up to approximately 1 year until disease recurrence or unacceptable toxicity.
“Essentially, those patients that had combination with [pembrolizumab] versus [pembrolizumab] alone had a reduced chance of having a recurrence event or death, which we believe demonstrates a statistically significant and clinically meaningful improvement for these patients [who] are at high risk of relapse,” Michelle Brown, MD, PhD, program lead for oncology at Moderna, said during the media roundtable. “Importantly, what this also means is that we believe that we have a differentiated proof of concept for the neoantigen approach.”
Importantly, in terms of safety, mRNA-4157 was well tolerated and its adverse event (AE) profile was consistent with the phase 1 results.1 AEs from pembrolizumab were also consistent with past trials. Serious treatment-related AEs occurred in 14.4% of patients who received mRNA-4157 plus pembrolizumab versus 10% with pembrolizumab alone.
“Patients had the type of AEs that they would expect with [pembrolizumab] alone.” Brown said. “Unlike other combinations that have been tested in this space, we didn't see an increase in these AEs; each one was really its unique profile.”
Moderna and Merck plan to report these results in an upcoming publication and discuss them with regulatory authorities. A phase 3 trial is planned for patients with melanoma in 2023. According to Brown, due to their confidence in these results, they plan to launch a series of trials not only in melanoma but in other tumor types as well.
“We will begin additional studies in melanoma and other forms of cancer with the goal of bringing truly individualized cancer treatments to patients,” Stéphane Bancel, MBA, CEO of Moderna, said in a statement. “We look forward to publishing the full data set and sharing the results at an upcoming oncology medical conference, as well as with health authorities.”
1. Moderna and Merck announce mRNA-4157/V940, an investigational personalized mRNA cancer vaccine, in combination with Keytruda(R) (pembrolizumab), met primary efficacy endpoint in phase 2b KEYNOTE-942 trial. Moderna. December 13, 2022. Accessed December 14, 2022. https://bit.ly/3Pwoake
2. Burris HA, Patel MR, Cho DC, et al. A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. J Clin Oncol. 2019;37(15_suppl):2523. doi:10.1200/JCO.2019.37.15_suppl.2523