Merck and Moderna's Individualized Neoantigen Therapy met Phase 3 endpoints in melanoma
Merck and Moderna announced success with their jointly developed intismeran autogene (intismeran), a personalized mRNA-based cancer vaccine, in combination with KEYTRUDA (pembrolizumab), an anti-PD-1 immunotherapy, in preventing the remission and spread of melanoma based on positive top-line results from the Phase 3 INTerpath-001 trial. The trial result marks a groundbreaking moment in validating individualized neoantigen therapy (INT) as adjuvant therapy in providing clinically meaningful improvement over the standard-of-care therapy by KEYTRUDA alone in cancer treatment. Intismeran works by sequencing the patient’s tumor and healthy cells to identify the unique genetic mutations that cause the formation of neoantigens in their tumor cells. Neoantigens are mutated proteins exclusively present on the tumor cell surface that are foreign to the immune system and trigger an anti-tumor immune response. Up to 34 neoantigens unique to the patient’s tumor are selected to induce the optimal immune response. A synthetic mRNA encoding for the selected neoantigens is encapsulated in lipid nanoparticles and administered to patients like a standard vaccine. Translation of the mRNA-encoded sequences into neoantigens activates specific T-cell responses and train the patient’s immune system to recognize and target the cancer cells.
The success in personalized immunotherapy potentially brings a paradigm shift in oncology treatment. Established immunotherapies like KEYTRUDA are patient-agnostic by leveraging the PD-1 pathway conserved across all patients to unmask the cancer cells and activate T-cells to trigger an anti-tumor immune response with the downside of indiscriminating immune attack on normal healthy cells, too. Because the same immunotherapy is given irrespective of patient’s unique genetic mutation profile, its efficacy varies with the extent of T-cell activity restoration brought by PD-1 inhibitor. Patients with mutations that impede the immune system’s ability to prime the T-cells with tumor antigens are left with too few cancer-reactive T-cells to be reactivated and respond poorly to the same treatment. Individualized neoantigen therapy adopts a patient-specific approach, where a therapeutic treatment is constructed from patient’s unique genetic mutation de novo and imparts cancer-specific T-cell affinity. When the two approaches work in complements, a synergistic effect is created from expanded high-affinity tumor-targeting T-cell workforce due to intismeran and immune booster for T-cell reactivation due to KEYTRUDA to actively attack cancer cells and warrant no cancer resurrection and metastasis long past removal of localized tumor.
The announcement marks another milestone for Moderna following its success in mRNA-based COVID-19 vaccines in November 2020, sending its stock soaring over 170%. The pivotal result also boosts confidence in Merck as it faces the imminent 2028 patent cliff from the loss of KEYTRUDA exclusivity. The two partners continue to work together to test the safety and efficacy of personalized cancer vaccine as adjuvant therapy and monotherapy in nine other trials in treating more advanced melanoma and other tumor types like non-small cell lung cancer, a major driver of KEYTRUDA’s sales, bladder cancer, and renal cell carcinoma.
