In the phase 2 KEYNOTE-942 trial, the 18-month distant metastasis-free survival rate was 91.8% with mRNA-4157 plus pembrolizumab vs 76.8% with pembrolizumab alone.
In the phase 2 KEYNOTE-942 trial (NCT03897881), mRNA-4157 (V940) in combination with pembrolizumab (Keytruda) led to a reduced risk of developing distant metastasis or death by approximately 65% vs with pembrolizumab alone as adjuvant therapy in patients with resected melanoma at high risk of recurrence, according to findings presented at the 2023 ASCO Annual Meeting.1
The median follow-up was 23 months for mRNA-4157 plus pembrolizumab and 24 months for pembrolizumab monotherapy. The 18-month distant metastasis-free survival (DMFS) rate was 91.8% with the combination vs 76.8% with pembrolizumab alone (HR, 0.347; 95% CI, 0.145-0.828; P = .0063).
“mRNA-4157-P201/KEYNOTE-942 is the first randomized trial to demonstrate improvement in recurrence-free survival [RFS] and distant metastasis-free survival [DMFS] with an individualized neoantigen therapy approach,” lead study author Muhammad Adnan Khattak, PhD, FRACP, MBBS, One Clinical Research and Edith Cowan University in Joondalup, Australia, said in a presentation of the data.
Previously, the phase 3 KEYNOTE-054 trial (NCT02362594) established improved 3.5-year DMFS with pembrolizumab (65.3%) vs placebo (49.4%) in patients with high-risk melanoma (P < 0001).2 Despite effective adjuvant therapy, metastasis rates remain high.
mRNA-4157 is a personalized neoantigen therapy designed to target an individual patient’s tumor mutations and encodes up to 34 neoantigens. Neoantigen-directed therapy can boost endogenous neoantigen T-cell responses, leading to epitope spreading to novel antigens that can drive antitumor activity and maintain memory with cytolytic properties, resulting in durable disease control.
KEYNOTE-942 is a randomized, phase 2, open-label study. To be eligible for enrollment, patients had to have resected stage IIIB, IIIC, IIID, or IV cutaneous melanoma, and have undergone complete surgical resection within 13 weeks before the first dose of pembrolizumab. Additionally, patients had to be free of disease at study entry and have an ECOG performance status of 0 or 1. Tissue also needed to be available for next-generation sequencing.
Patients were randomly assigned 2:1 to the combination arm (n = 107) or the control arm (n = 50). In the combination arm, patients received 1 mg of mRNA-4157 intramuscularly every 3 weeks for up to 9 doses plus 200 mg of pembrolizumab intravenously (IV) every 3 weeks for up to 18 cycles. In the control arm, patients received 200 mg of IV pembrolizumab every 3 weeks for up to 18 cycles. Patients were followed for up to 3 years following the first dose of pembrolizumab.
Patients were stratified by disease stage, and the primary end point was relapse-free survival (RFS). Secondary end points included DMFS, safety, and tolerability.
Regarding baseline demographics, most patients in the investigative and control arms were male (65.4% vs 62.0%), below the age of 65 years (55.1% vs 56.0%), had an ECOG performance status of 0 (84.1% vs 80.0%), and had stage IIIC disease (83.2% vs 84.0%). Median lactate dehydrogenase was 189.5 U/L (range, 118-528) and 185.5 U/L (range, 113-1180) in the combination and single-agent arms, respectively. Additionally, most patients had positive PD-L1 expression (64.5% vs 54.0%), wild-type BRAF (61.7% vs 60.0%), and tumor mutational burden of at least 10 mut/mB (73.8% vs 60.0%).
Prior results presented at the 2023 AACR Annual Meeting demonstrated improved RFS with the combination, with 12- and 18-month RFS rates of 83.4% and 78.6% vs 77.1% and 62.2% with pembrolizumab alone (HR, 0.561; 95% CI, 0.309-1.017; P = .0266).3
In February 2023, the FDA granted breakthrough therapy designation to mRNA-4157 plus pembrolizumab as adjuvant treatment for patients with high-risk melanoma following complete resection. The designation was based on findings from KEYNOTE-942.4
Additional findings presented at the 2023 ASCO Annual Meeting showed that regarding recurrence type, 13.1%, 6.5%, and 2.8% of patients in the combination arm experienced local/regional, distant, or other type of recurrence, respectively. In the pembrolizumab monotherapy arm; these rates were 18%, 20%, and 2%, respectively.
Additionally, more patients in the pembrolizumab-alone arm experienced distant recurrence or death vs those in the combination arm, at 24.0% and 8.4%, respectively. The site of distant recurrence in the combination and monotherapy arms, respectively, was the lymph node (1.9% vs 8.0%), lung (1.9% vs 8.0%), liver (2.8% vs 2.0%), bone (0.9% vs 4.0%), brain (0.9% vs 6.0%), skin (0% vs 8.0%), colon (0.9% vs 2.0%), spleen (0% vs 2.0%), soft tissue (0.9% vs 0%), or other (1.9% vs 2.0%) site. Non–disease-related death occurred in 1 patient in the combination arm.
Investigators also noted improved DMFS with the combination in patients who had negative circulating tumor (ct)DNA at baseline (HR, 0.048; 95% CI, 0.006-0.380). The difference between arms in patients with positive ctDNA at baseline was not evaluable.
Regarding safety, all patients experienced treatment-related adverse effects (AEs) in the combination arm, with 25.0% experiencing grade 3 or higher AEs; these rates were 82.0% and 18.0%, respectively, in the pembrolizumab monotherapy arm. Moreover, serious AEs occurred in 14.4% of patients who received the combination, with 12.5% of these events grade 3 or higher; in the monotherapy arm, these rates were 10.0% and 8.0%, respectively.
Common mRNA-4157 or combination-related AEs reported in more than 10% of patients included fatigue (any grade, 60.6%; grade ≥3, 4.8%), injection site pain (55.8%; 0%), chills (50.0%; 0%), pyrexia (48.1%; 1.0%), headache (31.7%; 0%), injection site erythema (31.7%; 0%), influenza-like illness (30.8%; 0%), nausea (25.0%; 0%), and myalgia (21.2%; 1.0%). Common pembrolizumab or combination-related AEs were elevated in the investigational arm and included fatigue (69.2%), diarrhea (29.8%), pruritus (28.8%), nausea (22.1%), chills (21.2%), and pyrexia (21.2%).
All-cause, immune-mediated AEs in the combination (35.6%) and pembrolizumab-alone (36.0%) arms, respectively, included adrenal insufficiency (4.8% vs 4.0%), colitis (5.8% vs 4.0%), hepatitis (1.0% vs 2.0%), hyperthyroidism (5.8% vs 6.0%), hypophysitis (1.0% vs 0%), hypothyroidism (20.2% vs 16.0%), myositis (0% vs 2.0%), nephritis (2.9% vs 2.0%), pancreatitis (0% vs 2.0%), pneumonitis (3.8% vs 0%), sarcoidosis (0% vs 2.0%), severe skin reaction (2.9% vs 2.0%), thyroiditis (0% vs 4.0%), type 1 diabetes mellitus (0% vs 2.0%), and uveitis (1.0% vs 2.0%).
“mRNA-4157 in combination with pembrolizumab was well tolerated without an increase in immune-mediated AEs compared with pembrolizumab monotherapy,” Khattack concluded.