Cancer cocktails pairing Moderna’s mRNA-4359 with Merck’s Keytruda and Marengo’s invikafusp alfa with Gilead Sciences’ Trodelvy showed promising results, while a complex combination by Agenus and MiNK Therapeutics failed to elicit an overall response.
Combinations continue to be a primary focus in cancer drug development, as researchers seek out therapeutic cocktails that target tumor cells with optimum efficiency while also mitigating side effects and potential drug resistance.
Indeed, the next wave of combo therapies was on display at the American Association for Cancer Research’s annual meeting in San Diego last week. Companies including Moderna, Marengo Therapeutics and Akeso presented new data at AACR showcasing new uses for existing combinations, as well as blends of experimental therapies with tried-and-true treatments like chemotherapy and more recently approved drugs.
A combination approach is “very, very important,” Zhen Su, a physician-scientist and CEO of Marengo, told BioSpace, pointing as an example to the “transformative care” now available to patients with certain types of lung cancer and multiple myeloma thanks to high-powered drug combos.
“For frontline cancer, the treatment’s oftentimes a combination therapy because tumors are not easy to tackle, and sometimes you need a multi-modality approach to really hit tumors from different angles,” Su said.
Such combos might include a chemotherapy or antibody-drug conjugate (ADC) that can give a tumor “a big hit from the get-go,” he said, alongside an immunotherapy capable of activating cancer-fighting T cells.
When experimental meets approved
At AACR, Marengo shared initial data from a Phase 2 study of invikafusp alfa, an investigational dual T cell agonist, in combination with Gilead Sciences’ ADC Trodelvy, which is FDA-approved for certain forms of heavily pretreated breast cancer. Of 10 patients with heavily pretreated metastatic breast cancer, two had confirmed complete responses to the combo, two had confirmed partial responses and six saw their disease remain stable.
The drug cocktail is one of the first to combine a precision immunotherapy with a precision ADC, Su said, bringing “two of the most potent modalities into a tumor and [lighting] up a fire in their cancer.” The results so far, he continued, are a sign of “the next frontier,” an exciting new phase in the industry after his nearly three decades as a drug developer.
Marengo plans to continue expanding the trial and, “if we continue to see the benefits we’re seeing,” will potentially seek FDA Fast Track designation for the combo in breast cancer before moving into a pivotal trial. Invikafusp alfa already holds the designation as a monotherapy in advanced colorectal cancer.
Also unveiling combo data at AACR last week was Moderna, specifically, early results from a Phase 2 trial of its investigational antigen therapy mRNA-4359 in combination with Merck’s blockbuster immunotherapy Keytruda as a first-line treatment for locally advanced and metastatic melanoma. As of Dec. 1, 2025, two of 12 patients achieved a complete response, while eight had a partial response, for an overall response rate of 83%.
There are several reasons for mRNA-4359’s promise in melanoma, David Berman, Moderna’s recently appointed chief development officer, told BioSpace via email. For one, he said, “this is a novel dual mechanism therapy where we activate T cells to kill cancer cells and recalibrate the tumor microenvironment to a more immune favorable state.”
Berman also pointed to the benefits shown in a study of the combo among patients previously treated with immune checkpoint inhibitors and in late-stage data “from another company using a similar approach.”
Following Monday’s AACR presentation, in a video posted to Moderna’s website, Berman called the early trial results “quite intriguing,” while noting that “it’s hard to tease apart” the contributions of each component of the drug cocktail. Therefore, the next steps will be to determine if, in the larger cohort of patients who have progressed on checkpoint inhibitors, there is sufficient reason to believe that mRNA-4359 is bringing additional activity, he said. Those data should arrive “over the next year.”
In a Monday note to investors, Leerink Partners said that while the patient sample is very small, the 83% ORR “represents a promising signal,” though the analysts cautioned that it is “unlikely to garner meaningful investor enthusiasm.”
Hits and misses
Another promising drug is a combination of Akeso’s PD-1/CTLA-4 bispecific antibody cadonilimab with chemotherapy. The Chinese biotech is evaluating the combo in the Phase 2 Compassion-26 study as a first-line treatment for advanced cases of pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer.
Data presented at AACR showed an objective response rate of just under 34% and disease control rate of 96.4% among 56 patients. The drug combination appeared to be especially effective in patients with locally advanced disease, with a median overall survival rate of more than 23 months and median progression-free survival of 11.1 months, compared to 10.5 months and 7.2 months, respectively, among those with metastatic disease.
“The efficacy of cadonilimab in hard-to-treat tumors is driven by its innovative molecular design and novel mechanism of action,” a company spokesperson told BioSpace via email. “It harnesses the therapeutic benefits of both PD-1 and CTLA-4 pathways while overcoming the traditional efficacy and safety limitations of each target.” This translates into breakthrough clinical value, the spokesperson continued. “For example, it addresses the toxicity challenges that have historically limited the use of CTLA-4 agents and improves response in PD-L1 low/negative populations where PD-1/L1 inhibitors often underperform.”
With these attributes, Akeso’s spokesperson added, “cadonilimab is well-positioned as a backbone agent to combine with novel therapies.”
Less successful, meanwhile, were results from a Phase 2 study of Agenus’ experimental immunotherapies botensilimab and balstilimab plus MiNK Therapeutics’ allogeneic cell therapy agenT-797, alongside the approved VEGFR2 antagonist Cyramza and chemotherapy. The cocktail elicited a 0% response rate among the study’s 15 eligible gastroesophageal adenocarcinoma patients.
Despite missing the study’s primary endpoint, Agenus remained optimistic, suggesting in an April 17 press release that the secondary factors of durability and survival may in fact “be the most clinically relevant endpoints” among the study’s particular population. The combo was tied to a 73% stable disease rate, while three patients experienced overall survival of more than 20 months.
