Promising Early Results
Moderna has released early clinical data that explains why it moved quickly to prioritize a cancer contender in its pipeline. The findings show that many melanoma patients who had stopped responding to checkpoint inhibitors experienced clinical benefit.
The results, set to be presented later this week at the 2025 European Society for Medical Oncology Congress, come from a study of 29 people with relapsed or refractory melanoma. Every participant had previously progressed after receiving at least one PD-1/L1 checkpoint inhibitor. Moderna tested two dose levels of mRNA-4359 – which is designed to trigger immune responses against the PD-L1 and IDO antigens – alongside Merck & Co.’s top-selling cancer therapy Keytruda.
Among patients who could be evaluated, almost a quarter had a confirmed objective response after receiving intramuscular doses of mRNA-4359 every three weeks, for as many as nine administrations. When those with stable disease were counted as well, the disease control rate rose to 60%. The study has not yet generated a median duration of response.
Moderna reported that six of the nine participants whose tumors expressed PD-L1 – and who could be evaluated – responded to treatment. While Keytruda is approved for melanoma regardless of PD-L1 status, certain other cancer indications do require a minimum expression cutoff. Moderna said this subgroup finding points to PD-L1 expression as a possible response predictor in a population with limited treatment options.
A Two-Pronged Mechanism
The new results build on monotherapy findings that were released in 2024. Moderna’s approach aims to use PD-L1 and IDO as vaccine-style antigens to activate the immune system against tumors while also countering the suppressive signals that can blunt those responses. According to Kyle Holen, who oversees development for therapeutics and oncology at the company, this two-pronged mechanism sets mRNA-4359 apart from current treatments.
In a statement, Holen explained that unlike checkpoint inhibitors that generally reactivate T cells without specificity, mRNA-4359 is designed to address two key immune evasion mechanisms, allowing the body to produce fresh T cells directed at specific targets. He added that this approach has the potential to produce wider and longer-lasting immune responses in patients who have not benefited from earlier treatments.
Competitive Landscape
Several drugmakers have explored IDO as a way to boost the effects of PD-1/L1 inhibitors, but enthusiasm faded after Incyte’s epacadostat flopped in clinical testing focused specifically on it. IO Biotech was one of the few that stayed committed to the target, but its cancer vaccine failed to meet the main goal in a phase 3 trial in August. The FDA has since told the company not to move forward with a filing.
At a Bernstein event last month, Rose Loughlin, Moderna’s EVP of research, addressed the competitive landscape. She pointed out that Moderna’s approach and antigen choices differ from IO’s and argued that the rival company’s results actually reduced the perceived risk around mRNA-4359. According to Loughlin, those findings have only strengthened Moderna’s resolve to push forward quickly in this area.
Although it’s still early, Moderna’s data bring hope to a patient population that has limited options after failing checkpoint inhibitors. The 24% objective response rate (ORR) itself is meaningful in this context — especially when compared to historical controls in heavily pre-treated melanoma. The fact that responses were enriched to 67% in the PD-L1 positive subgroup adds practical insight about how Moderna may select patients going forward.
It’s also worth noting that the safety profile thus far appears manageable, with no new immune-related adverse events beyond those expected for checkpoint inhibitor combinations. That gives Moderna room to explore higher doses or expanded indications (e.g., non‐small cell lung cancer) without major red flags.
