Nadunolimab Shows Promise in Phase 2 TRIFOUR Trial for Advanced TNBC

On July 17, 2025, preliminary results from the Phase 2 TRIFOUR trial revealed that nadunolimab, an investigational monoclonal antibody, demonstrates significant potential in treating advanced triple-negative breast cancer (TNBC). Conducted by the Spanish Breast Cancer Group (GEICAM), this trial is pivotal as it explores the efficacy and safety of nadunolimab in combination with the chemotherapy agents carboplatin and gemcitabine for patients facing this aggressive malignancy.

The TRIFOUR trial, designated as NCT05181462, commenced with a goal to assess early efficacy signals for nadunolimab among TNBC patients, a group that historically has faced limited treatment options. The Phase 2 component of the trial reported an overall response rate (ORR) of 40% for the nadunolimab combination regimen, closely aligning with the 43% ORR noted for the reference arm receiving carboplatin and gemcitabine alone. These findings, while not replicating the higher ORR of 73% observed in the earlier Phase 1b segment, indicate a clinically relevant outcome when compared to the historically documented ORR of approximately 30% for carboplatin-gemcitabine in first-line and second-line TNBC settings.

Dr. Eva Carrasco, CEO of GEICAM, emphasized the significance of these findings, stating, “TNBC is a heterogeneous and difficult-to-treat disease, with a high unmet medical need. We welcome the efforts to explore new treatments and appreciate the learnings we are making from the TRIFOUR study.”

The safety profile of nadunolimab appears consistent with that of chemotherapy alone. The most frequently reported adverse effects included neutropenia and asthenia, both common with gemcitabine and carboplatin treatments. This tolerability is crucial for patients with advanced TNBC, who often endure a high burden of disease coupled with limited therapeutic avenues.

Nadunolimab functions by targeting IL1RAP, which is integral to IL-1α and IL-1β signaling pathways—key contributors to inflammation and immune suppression within the tumor microenvironment. By inhibiting IL1RAP, nadunolimab may enhance chemotherapy efficacy and counteract resistance mechanisms. This dual action mechanism positions it as a promising immunotherapeutic agent.

Cantargia, the sponsor of the trial, has investigated nadunolimab across various malignancies, with over 300 patients involved in clinical studies. Beyond TNBC, nadunolimab has exhibited encouraging results in other aggressive cancers, including pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). The FDA has granted fast track designation for nadunolimab in PDAC patients with high IL1RAP expression, illustrating its potential in unmet medical needs.

Moving forward, Cantargia plans to conduct comprehensive discussions to define the future development pathway for nadunolimab based on the TRIFOUR trial findings. Further detailed analyses, including overall survival data and subgroup assessments, are anticipated to be presented at upcoming scientific conferences. As researchers continue to refine treatment protocols for advanced TNBC, the implications of these findings could significantly reshape therapeutic strategies for this challenging patient population.

In conclusion, the preliminary topline results from the TRIFOUR trial signify a crucial advancement in the fight against advanced TNBC. While further analyses are required, nadunolimab's potential to improve patient outcomes in a disease characterized by high unmet medical needs offers hope to many stakeholders within the oncology community.