U.S. pharmaceutical firm Merck and biotech company Moderna announced on Aug. 19 the successful Phase 3 trial of their new intismeran treatment in combination with Keytruda (pembrolizumab). The treatment met its endpoints for recurrence-free and distant-metastasis-free survival in patients with completely resected stage IIB-IV melanoma. It is the first positive Phase 3 result ever obtained for an individualized neoantigen therapy, and the first for any mRNA-based cancer therapy.
Melanoma is one of the deadliest skin cancers; more than 330,000 people were diagnosed worldwide in 2022, and some 112,000 new U.S. cases and over 8,500 U.S. deaths are expected this year. Surgery does not cure it. Recurrence, usually metastatic, most often arrives within two years. Treatment after surgery is the attempt to prevent it.
Intismeran works from the specifics of each tumor. A sample of the patient’s own removed tumor is sequenced to identify the mutations that distinguish those cells from every other cell in that person’s body, providing the tumor’s fingerprint. Up to 34 of the resulting neoantigens, proteins that exist nowhere else in the patient, are encoded into messenger RNA. When administered, the mRNA produces the neoantigens and trains the immune system to recognize and fight them. The T-cells trained by this process circulate in the body and kill any residual tumor cells carrying the same markers. Keytruda does the complementary work of preventing tumors from switching off the T-cells that find them.
The trial enrolled 1,137 patients, randomized 2:1 to intismeran plus Keytruda versus Keytruda alone. (Since Keytruda is already known to improve outcomes, it was used instead of a placebo.) Every patient in the treatment arm received a different medicine: each designed from a different tumor and manufactured separately.
This means that what was tested was not a specific treatment, but a procedure for producing a different treatment for each patient.
The companies report the interim analysis shows statistically significant improvements in outcomes and no new safety signals. Principal investigator Prof. Georgina Long of the Melanoma Institute Australia called it a landmark moment.
The full data have not been presented or published, and the trial has not yet been completed. The preceding Phase 2b trial showed a 49% reduction in the risk of recurrence or death and a 59% reduction in the risk of distant metastasis or death.
Eight other trials in the Merck-Moderna INTerpath program extend the same method to lung, bladder and kidney cancer, with Phase 1 work in pancreatic and gastric disease. Each requires a factory capable of making individualized products. Moderna built one in Marlborough, Massachusetts, designed around robotics and automation to shorten the interval from biopsy to injection to a matter of weeks. Mass production organized to yield a unique product per patient is a new kind of manufacturing. Industrial capacity is a bigger bottleneck than biology.
About a year ago, HHS Secretary RFK, Jr.’s department announced the cancellation of 22 BARDA mRNA projects worth nearly $500 million. Those were for treatments for respiratory viruses, not cancer, but the science is all related.
