Nadunolimab is a fully humanized monoclonal IgG1 antibody targeting the IL1 receptor accessory protein (IL1RAP). By binding to IL1RAP, nadunolimab induces antibody-dependent cellular cytotoxicity (ADCC) of IL1RAP-expressing tumor cells and inhibits tumor-promoting signals mediated by IL-1α and IL-1β within the tumor microenvironment. The Phase I/IIa CANFOUR trial evaluated nadunolimab combined with nab-paclitaxel and gemcitabine in previously untreated, unresectable, locally advanced, or metastatic pancreatic ductal adenocarcinoma (PDAC). The trial showed promising efficacy, with a median overall survival of 13.2 months, a median progression-free survival of 7.2 months, a one-year survival rate of 58%, and an objective response rate of 33%, all with a favorable safety profile. Notably, only one of 73 patients experienced Grade 3 or higher peripheral neuropathy, suggesting that targeting IL1RAP may also alleviate the neuroinflammation leading to chemotherapy-induced peripheral neuropathy (CIPN).

Among the 73 PDAC patients in the CANFOUR trial, those receiving nadunolimab at doses of 2.5 mg/kg, 5 mg/kg, and 7.5 mg/kg showed trends towards a lower incidence and longer time to onset of CIPN compared to the 1 mg/kg group. When the higher dose groups (2.5-7.5 mg/kg) were pooled and compared to the 1 mg/kg dose group, there was a lower incidence of any-grade CIPN (36% vs. 60%) and a significantly longer time to onset.

In preclinical studies, mice treated with vincristine and nab-paclitaxel developed long-lasting CIPN. This effect was mitigated by co-administration of an anti-mouse IL1RAP surrogate antibody, without negatively impacting motor performance, blood values, or body weight.

KOL insights

“The new results highlight the potential of nadunolimab as a cancer therapy providing both antitumor effects while, at the same time, reducing neuropathic side effects when combined with chemotherapy. This finding may also be of relevance in other neuroinflammatory conditions.”

–Expert Opinion

“Nadunolimab treatment of cancer patients has generated promising clinical effects. The new results strongly suggest counteraction of neuropathy, a serious side effect of several existing cancer therapies. Neuropathy is common with ADCs and the new data highlight the potential for nadunolimab/ADC combination therapy.” –Expert Opinion

Conclusion

As per Delveinsight’s estimates, there were approximately 60,000 incident cases of Pancreatic Cancer in the United States in 2023, with 90% PDAC contribution. Nadunolimab, when combined with gemcitabine and nab-paclitaxel (GN), demonstrates promising efficacy in first-line PDAC with a median progression-free survival (iPFS) of 7.2 months and median overall survival (OS) of 13.2 months. Peripheral neuropathy, primarily Grade 3, was minimal. Mouse model data using a nadunolimab surrogate indicate protection against chemotherapy-induced neuropathy. In the CANFOUR study, higher nadunolimab doses correlate with reduced neuropathy incidence and delayed onset compared to lower doses, suggesting IL1RAP targeting by nadunolimab may enhance both antitumor efficacy and mitigate chemotherapy-induced neuropathies.