Individualized neoantigen therapy could be ‘huge leap’ toward personalized medicine
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Key takeaways:
- Treatment induced sustained T-cell responses among patients with melanoma and non-small cell lung cancer.
- Phase 3 trials in both cancer types are open.
A novel therapeutic approach stimulated new and existing T-cell responses among patients with melanoma or non-small cell lung cancer, according to results of a phase 1 trial.
Researchers reported no dose-limiting toxicities and no grade 4 or worse adverse events among participants who received the individualized neoantigen therapy mRNA-4157 (V940) [Moderna/Merck] alone or with pembrolizumab (Keytruda, Merck).
“It’s incredibly exciting. It’s a huge leap in the direction of precision medicine,” investigator Justin F. Gainor, MD, program director for the center for thoracic cancers and director of targeted immunotherapy at Massachusetts General Hospital, told Healio.
Background
Several immune checkpoint inhibitors are approved for treatment of solid tumors.
The agents have improved outcomes for some patients, but not everyone benefits. For example, fewer than half of patients with melanoma respond, according to study background.
“Immune checkpoint Inhibitors are not very personalized,” Gainor told Healio. “We very much have taken a one-size-fits-all approach.”
Chimeric antigen receptor T-cell therapy and tumor-infiltrating lymphocytes have taken personalized medicine further, using a patient’s autologous T cells to treat disease.
Individualized neoantigen therapy attempts to go beyond that.
Phase 1 trial
The investigational agent mRNA-4157 (V940) encodes up to 34 patient-specific tumor neoantigens.
Gainor and colleagues evaluated the safety and clinical activity of the therapy for 16 patients (median age, 67 years). Four had resected NSCLC and 12 had resected melanoma.
Patients with NSCLC received mRNA-4157 (V940) alone. Those with melanoma received the mRNA vaccine plus pembrolizumab.
Twelve participants —nine with melanoma and three with lung cancer — completed the study. One patient died of an unspecified cause more than a year after treatment, one had increased liver enzymes and two were lost to follow-up.
All 15 patients who received at least one dose of mRNA-4157 (V940) developed a treatment-related adverse event. The most common included fatigue (66.7%), pyrexia (60%) and injection site pain (40%).
Researchers reported no mRNA-related adverse events above grade 2. One patient developed grade 3 fatigue attributed to both mRNA-4157 (V940) and pembrolizumab.
One patient in each cohort developed mRNA-related adverse events that required hospitalization.
“This is a very well-tolerated therapy, and I think that it is critically important when you think about earlier stages of disease,” Gainor said. “CAR T-cell therapy and TIL therapy typically have more toxicities, which the risk-benefit profile supports in the advanced-stage setting. But [for] someone who has an earlier-stage tumor, you want a therapy that has a better safety profile. This is a safety profile that certainly supports being explored in early-stage disease.”
Both therapies produced de novo CD4 and CD8 T-cell responses and strengthened existing ones with some sustaining for 30 weeks after treatment.
“It’s meaningful that we’re actually stimulating different components of the immune system,” Gainor said. “The median number of neoantigens recognized was four. When it comes to neoantigen therapy, we’ve learned that even one good neoantigen immune response can be sufficient to produce long-lasting anti-tumor immunity.”
Phase 2 study
The randomized phase 2 KEYNOTE-942 trial evaluated mRNA-4157 (V940) plus pembrolizumab vs. pembrolizumab alone for patients with completely resected, high-risk cutaneous stage IIIB, IIIC, IIID or IV melanoma.
As Healio previously reported, the combination significantly improved PFS (HR = 0.51; 95% CI, 0.28-0.9). A higher percentage of patients assigned the combination remained relapse free for 2.5 years (74.8% vs. 55.6%).
The mRNA-4157 (V940) cohort also achieved sustained improvement in distant metastasis-free survival (HR = 0.384; 95% CI, 0.172-0.858).
OS — which had been similar between treatment groups for the first 2 years of the study — began to favor the combination around month 30 (96% vs. 90.2%; HR = 0.42; 95% CI, 0.11-1.58).
“That’s the most robust efficacy data we have with mRNA-4157,” Gainor said.
Next steps
Phase 3 studies have been launched to investigate mRNA-4157 (V940) plus pembrolizumab in both melanoma and lung cancer.
Gainor said he hopes the approach could be viable for other cancer types.
“The reason to focus on melanoma and lung cancer has been that those have been the paradigms for developing immunotherapies in solid tumors,” he said. “If an immunotherapy is successful in [those malignancies], and you’re producing immunogenicity, then that opens us up to exploring other solid tumors like kidney cancer, head and neck cancer, and esophageal cancer.”
More research is also needed to improve predictions for which neoantigen targets would be most effective, Gainor said.
The FDA granted breakthrough status to mRNA-4157 plus pembrolizumab for treatment of melanoma.
“[In 5 years], my hope is that we’ll see our first regulatory approvals of this agent as adjuvant therapy,” Gainor said. “My hope is we’ll have the phase 3 data and have a registrational approval and start to see data in these other tumor types.”
For more information:
Justin F. Gainor, MD, can be reached at jgainor@mgh.harvard.edu.
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