Moderna (NASDAQ:MRNA) used an ASCO oncology event to highlight updated clinical and translational data for intismeran, its individualized neoantigen therapy being studied in combination with pembrolizumab in melanoma and other cancers.
David Berman, Moderna’s chief development officer, described intismeran as “the most advanced individualized neoantigen therapy in development” and said he joined the company three months ago because he believes the therapy has the potential to become “the world’s first RNA immunotherapy for cancer.”
Updated Phase 2 Data in Melanoma
Matt Carlino, a medical oncologist at Westmead Private Hospital, reviewed five-year data from the randomized phase 2 KEYNOTE-942 study in high-risk melanoma. Carlino said the study showed intismeran plus pembrolizumab reduced the risk of recurrence by 49% and the risk of distant metastasis by 59% compared with pembrolizumab alone.
According to Carlino, the relapse-free survival hazard ratio was 0.51, while distant metastasis-free survival had a hazard ratio of 0.41. He said those results were notable because the comparator was pembrolizumab, an active therapy, rather than placebo.
“It’s actually harder to get a big benefit when you’re comparing yourself against something that’s effective,” Carlino said.
Carlino also discussed an overall survival hazard ratio of 0.47, while noting that the confidence interval crossed 1 because of a limited number of events. He said the data suggested a possible survival benefit, but the study remains small.
Safety Profile Remains a Focus
Carlino said the combination’s safety profile is an important consideration in the adjuvant setting. He said treatment-related adverse events were somewhat higher with the combination, but described the incremental side effects as predictable and manageable. He cited chills, sore arm, fever-like symptoms and symptoms responsive to nonsteroidal anti-inflammatory drugs, paracetamol and fluids.
He emphasized that immune-related adverse events were similar, or numerically lower, with the combination than with pembrolizumab alone. Carlino said that matters because permanent immune toxicities, such as type 1 diabetes or cortisol deficiency, are among the major concerns when treating patients after surgery.
“I cannot think of a patient that I am willing to give adjuvant pembrolizumab to that I’m not willing to give adjuvant intismeran and pembrolizumab to,” Carlino said.
Translational Data Links T Cells to Neoantigens
Moderna also presented translational findings aimed at explaining how intismeran may be working. Berman said prior personalized cancer vaccines have shown they can generate novel T cell clones in blood, but he said intismeran is the first to demonstrate efficacy in a randomized trial.
Carlino said KEYNOTE-942 data showed increased T cell clonality in patients receiving intismeran plus pembrolizumab. Among patients treated with the combination, those who did not relapse had higher levels of novel T cell clones than those who did relapse, he said.
Ryan Sullivan, associate professor at Harvard Medical School, then described deeper translational work in seven patients from phase 1 and phase 2 studies. Sullivan said researchers were able to map de novo T cell clonotypes to individualized neoantigens encoded by intismeran. Across the seven patients, at least one neoantigen-specific T cell response was identified in each patient, with one patient showing responses to 18 of 34 neoantigens.
Sullivan said the responses included CD4-positive and CD8-positive T cells and appeared durable, persisting after intismeran dosing ended. He also said the T cells showed functional markers, including granzyme B and interferon gamma, consistent with cancer-killing immune activity.
Algorithm and Manufacturing Discussed
Brown said intismeran’s algorithm selects up to 34 neoantigens for each patient based on factors including mutation presence, expression, HLA presentation and predicted immune engagement. In KEYNOTE-942, she said 91% of treated patients had a full 34-neoantigen cassette, and 99.1% of selected neoantigens were unique to individual patients.
Brown said this supports the need for a personalized approach because “no two patients and no two tumors are the same.” She also said Moderna is in discussions with regulators about how the algorithm could be adapted over time as additional clinical and translational data are generated.
During the question-and-answer session, Brown said Moderna has now dosed more than 2,000 intismeran patients, compared with 107 doses manufactured during KEYNOTE-942. She said ongoing global studies with Merck span more than 46 countries, and Moderna has maintained manufacturing and distribution timelines as the program has scaled.
Broader Development Plans
Berman said Moderna is studying intismeran in several settings, including adjuvant melanoma, lung and genitourinary tumors, as well as metastatic disease and tumors that are generally less sensitive to immunotherapy, such as gastric and pancreatic cancer. He also noted a phase 3 study in stage 1 non-small cell lung cancer that includes an intismeran monotherapy arm and a phase 2 study in non-muscle invasive bladder cancer.
Berman closed by pointing to Moderna’s broader oncology pipeline, including off-the-shelf cancer antigen therapies, an in vivo T cell engager program and other emerging research programs expected to be highlighted at the company’s science day later this month.
About Moderna (NASDAQ:MRNA)
Moderna, Inc is a biotechnology company headquartered in Cambridge, Massachusetts, specializing in messenger RNA (mRNA) therapeutics and vaccines. The company’s platform leverages synthetic mRNA to instruct cells to produce proteins that can prevent or treat diseases. Since its founding in 2010, Moderna has advanced from early-stage research into a broad pipeline of vaccine and therapeutic candidates designed to address infectious diseases, rare genetic disorders and chronic illnesses.
Moderna’s flagship product is its mRNA-based COVID-19 vaccine, which was the first of its kind to receive emergency use authorization and later full approval in multiple jurisdictions.
