Nadunolimab Misses Efficacy Mark in TNBC, Despite Strong OS

In the phase 1b/2 TRIFOUR trial (NCT05181462), adding the anti-IL1RAP monoclonal antibody nadunolimab (CAN04) to gemcitabine/carboplatin chemotherapy (GC) demonstrated comparable overall survival (OS) with GC alone in metastatic triple-negative breast cancer (TNBC), surpassing historical references but ultimately confirming no clinically meaningful efficacy benefit with nadunolimab.¹

The newly reported data on OS, TRIFOUR’s secondary end point, demonstrated no difference in median OS between patients receiving nadunolimab plus GC and GC alone. However, both groups attained a survival duration of 26 months, nonetheless surpassing the historical expectations in this particularly aggressive breast cancer subtype, where the median OS typically hovers around 11 to 13 months.²

Preliminary data toplined earlier this year also reported no clinically meaningful difference in the study’s primary end point of overall response rate (ORR) between the investigational and comparator groups (40% vs 43%).³ Even so, both ORRs still exceeded the historically reported figure (approximately 30%) with GC alone in first-line and second-line TNBC settings, as was achieved with OS.

The safety profile of the therapy remained consistent with previous data of nadunolimab, with neutropenia and asthenia continuing to be the most common adverse events. Of note, there were no significant differences in safety observed between the 2 treatment groups, indicating that the addition of nadunolimab does not adversely impact the treatment’s overall safety profile.

Based on the lack of meaningful efficacy signals, Cantargia, developer of nadunolimab, has decided to cease development in TNBC. Treatment in TRIFOUR will continue, however, on the basis that some patients continue to benefit from the study treatment. Final data from the TRIFOUR trial will be presented at a forthcoming medical conference, according to Cantargia.

“We view this outcome in TNBC as indication specific, not predictive and not translating to pancreatic or lung cancer, where the biology, standard of care, and heterogeneity of the TRIFOUR patient population differ significantly,” said Wolfram Dempke, MD, PhD, MBA, chief medical officer at Cantargia, in a news release.¹

TRIFOUR Study Design

The phase 1b/2 TRIFOUR trial is an open-label study in Spain conducted by the Spanish Breast Cancer Group.⁴ Its objective was to assess the safety and preliminary efficacy of nadunolimab in combination with GC in patients with advanced TNBC.

In the randomized phase 2 portion of the trial, 99 patients with metastatic TNBC eligible for first- or second-line GC treatment were randomized to receive either nadunolimab plus GC (n = 51) or GC alone (n = 48). Those assigned to receive the investigational treatment received 2.5 mg/kg of nadunolimab twice per every 3- to 4-week cycle following initial step-up dosing, along with intravenously administered GC.

Alternative Paths for Nadunolimab

Although the TRIFOUR data were not sufficiently compelling for further development in TNBC, nadunolimab has shown promise in other indications, as evidenced by its FDA fast track designation in metastatic pancreatic ductal adenocarcinoma (PDAC) with high IL1RAP expression.⁵

In the first-in-human phase 2 CANFOUR trial (NCT03267316), completed in 2024, nadunolimab combined with gemcitabine/nab-paclitaxel demonstrated promising efficacy and manageable safety in patients with locally advanced or metastatic PDAC.⁶ Here, a median OS of 13.2 months and a 1-year survival rate of 58% were achieved.

The CANFOUR trial also included 40 patients with advanced or metastatic non–small cell lung cancer (NSCLC).⁷ Data published in Lung Cancer this year likewise revealed promising efficacy with nadunolimab and chemotherapy followed by nadunolimab monotherapy, reporting a median OS of 13.7 months, 54% 1-year survival, and pronounced benefit among those previously treated with pembrolizumab (Keytruda).

“While the combined results, including the primary end point and subgroup analyses, indicate that the TRIFOUR study did not meet its objectives, we recognize the valuable insights gained from this trial,” said Hilde Steineger, CEO of Cantargia, in the news release.¹ “Although this is not the outcome we had hoped for, we remain confident in the strong potential of nadunolimab, particularly in PDAC, where we see strong scientific rationale, robust data and significant opportunities for impact.”

REFERENCES

1. Cantargia provides update on overall survival data from TRIFOUR. News release. Cantargia. December 5, 2025. Accessed December 9, 2025. https://tinyurl.com/5ax6uz79

2. Kesireddy M, Elsayed L, Shostrom VK, et al. Overall survival and prognostic factors in metastatic triple-negative breast cancer: A National Cancer Database analysis. Cancers (Basel). 2024;16(10):1791. Published 2024 May 8. doi:10.3390/cancers16101791

3. 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 December 9, 2025. https://tinyurl.com/mshaffzf

4. Nadunolimab in combination with gemcitabine plus carboplatin in patients with advanced triple negative breast cancer (TRIFOUR). ClinicalTrials.gov. Updated March 14, 2024. Accessed December 9, 2025. https://clinicaltrials.gov/study/NCT05181462

5. Cantargia’s nadunolimab antibody awarded US FDA Fast Track Designation. News release. Cantargia. June 11, 2025. Accessed December 9, 2025. https://tinyurl.com/4vbuy6hn

6. Van Cutsem E, Collignon J, Eefsen RL, et al. Efficacy and safety of the anti-IL1RAP antibody nadunolimab (CAN04) in combination with gemcitabine and nab-paclitaxel in patients with advanced/metastatic pancreatic cancer. Clin Cancer Res. 2024;30(23):5293-5303. doi:10.1158/1078-0432.CCR-24-0645

7. Cantargia announces publication of clinical data showing benefit of nadunolimab combination therapy in advanced lung cancer. News release. Cantargia. July 16, 2025. Accessed December 10, 2025. https://tinyurl.com/2cr57pax