Preliminary Phase 2 TRIFOUR Trial Data on Nadunolimab in Advanced TNBC: Clinical Implications

Preliminary topline efficacy data from the phase 2 TRIFOUR trial (NCT05181462) evaluating nadunolimab, an investigational antibody targeting IL1RAP in combination with carboplatin and gemcitabine in patients with advanced triple-negative breast cancer (TNBC), indicate a safety profile consistent with chemotherapy alone and an overall response rate (ORR) that aligns with the established efficacy of the chemotherapy backbone.¹

The findings provide important early insights into the therapeutic potential of nadunolimab in this aggressive malignancy, though further detailed analysis and future development plans are pending.

Trial Design and Key Findings

The TRIFOUR study, an exploratory open-label randomized phase 1b/2 clinical trial conducted by the Spanish Breast Cancer Group (GEICAM), was designed to assess early signals of efficacy for nadunolimab in the TNBC patient population.^1,2 In the phase 2 component of the trial, the combination regimen of nadunolimab plus carboplatin-gemcitabine demonstrated an ORR of 40%. This rate was observed to be similar to the carboplatin-gemcitabine reference arm, which reported an ORR of 43%.¹

While these preliminary phase 2 results did not replicate the higher unconfirmed ORR of 73% (60% confirmed) seen in the earlier phase 1b part of the trial, both response rates in the phase 2 portion surpass the historically reported ORR of approximately 30% for carboplatin-gemcitabine alone in first-line (1L) and second-line (2L) TNBC settings. This historical context suggests that the observed response rates in the TRIFOUR trial, even without a significant difference between the nadunolimab and control arms in phase 2, remain clinically relevant.

"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. We now await the outcome of further analyses from the study, including overall survival," said Eva Carrasco, MD, CEO of GEICAM, in a press release.

Regarding safety, the addition of nadunolimab to the carboplatin and gemcitabine regimen did not appear to adversely affect the overall safety profile of the chemotherapy. The most frequently reported adverse effects (AEs) were neutropenia and asthenia, which are common and anticipated AEs associated with gemcitabine and carboplatin chemotherapy. This tolerability profile is critical for potential integration into existing treatment paradigms, particularly for patients with advanced TNBC who often contend with a high burden of disease and limited therapeutic options.

The Role of Nadunolimab in Oncology

Nadunolimab is a monoclonal antibody that targets IL1RAP, a key component in the signaling pathways of IL-1α and IL-1β. IL1RAP is involved in various cellular processes, including inflammation and immune suppression within the tumor microenvironment, as well as promoting cancer cell survival and proliferation. By binding to IL1RAP, nadunolimab is hypothesized to counteract these protumorigenic effects, potentially enhancing the efficacy of chemotherapy and overcoming resistance mechanisms. Its dual mechanism of action, involving both the induction of antibody-dependent cell-mediated cytotoxicity and the blockade of IL-1 signaling, positions it as a promising immunotherapeutic agent.

Cantargia, the sponsor, has investigated nadunolimab across a broad spectrum of metastatic cancers, with over 300 patients having received the treatment in various clinical studies. Beyond TNBC, nadunolimab has shown promising results in other challenging indications, including pancreatic ductal adenocarcinoma (PDAC) and non–small cell lung cancer (NSCLC).

In PDAC, nadunolimab has received fast track designation from the FDA for patients exhibiting high IL1RAP expression, underscoring its recognized potential in areas of significant unmet medical need. These broader efficacy signals provide a context for the ongoing development of nadunolimab, including its role in TNBC.

Future Directions and Clinical Implications

The preliminary topline results from the phase 2 TRIFOUR trial are an important step in understanding the utility of nadunolimab in advanced TNBC. Cantargia has indicated that a detailed portfolio discussion will be conducted to define the subsequent development plans for nadunolimab based on these and other emerging data. Further comprehensive details of the TRIFOUR study, including additional secondary end points and subgroup analyses, are expected to be presented at a forthcoming scientific conference.

REFERENCES:

1. Cantargia announces preliminary topline efficacy results from the phase 2 TRIFOUR trial of nadunolimab in advanced triple-negative breast cancer (TNBC). News release. Cantargia. July 17, 2025. Accessed July 18, 2025. https://tinyurl.com/mr3enhhb

2. Nadunolimab in combination with gemcitabine plus carboplatin in patients with advanced triple negative breast cancer (TRIFOUR). ClinicalTrials.gov. Updated March 14, 2025. Accessed July 18, 2025. https://clinicaltrials.gov/study/NCT05181462