First-in-human study shows IL1RAP-targeting drug safe in solid tumours

Medical writer: Leah Lawrence

The interleukin-1 (IL-1) receptor accessory protein (IL1RAP)-targeting CAN04 (nidanilimab) was well tolerated, with infusion-related reactions as the most common treatment-related adverse events occurring in a first-in-human study (Abstract 2504) presented on June 2.

“IL1RAP is required in order to activate IL-1 receptor signaling,” which is critical in solid tumours, presenter Ahmad Awada, MD, PhD, of Institut Jules Bordet, Belgium, said. Chronic tumour IL-1 signaling is involved in resistance to cancer therapies, immune evasion, and metastases.

CAN04 is a humanized and antibody-dependent cellular cytotoxicity (ADCC)-enhanced IgG1 antibody targeting IL1RAP with two modes of action: blocking IL-1 alpha and beta signaling and triggering ADCC.

This study included 22 patients with non–small cell lung cancer (NSCLC; four patients), pancreatic ductal adenocarcinoma (six patients), or colorectal cancer (12 patients). In a 3+3 design, patients were assigned to CAN04 at doses ranging from 1 to 10 mg/kg. The average age of patients was 62 years, and they had undergone a median of three prior lines of therapy.

No grade 4/5 adverse events occurred, and 55 documented adverse events were potentially related to the study drug. Ten infusion-related reactions occurred in nine patients. Most of the infusion-related reactions occurred after the first drug dose and were resolved within a few hours, Dr. Awada said.

To mitigate these reactions for the first dose, the researchers administered premedication with paracetamol, antihistamines, and corticosteroids, used a priming dose, and prolonged the infusion time from 1 to 2 hours.

Dr. Awada noted that one reversible dose-limiting toxicity occurred. One patient on the 6 mg/kg dose had leukopenia/neutropenia. Three grade 3 events occurred: an infusion-related reaction (3 mg/kg), hypokalemia (6 mg/kg), and leukopenia/neutropenia (6 mg/kg).

Serious adverse events occurred in nine patients; five of the 20 events were considered treatment related. These included one patient with grade 3 leukopenia, three grade 1/2 infusion-related reactions, and one patient with grade 2 embolism.

Dr. Awada said there was a linear increase in area under the curve and C_max (1 to 10 mg/kg). Initial data suggest that the drug half-life is longer than 2 weeks.

All but one patient had pre- and post-treatment imaging used for evaluation of efficacy. The best overall response was stable disease in nine of 21 patients: three of four patients with NSCLC, four of 11 patients with colorectal cancer, and two of six patients with pancreatic cancer. No complete responses or partial responses occurred.

Dr. Awada discussed two patients with durable responses. One patient with NSCLC had 7-month progression-free survival and one patient with pancreatic cancer had a 5-month progression-free survival.

The 10 mg/kg dose was selected as the recommended phase II dose. The phase IIa study will look at CAN04 monotherapy, in combination with cisplatin and gemcitabine for NSCLC, and in combination with gemcitabine/nab-paclitaxel in pancreatic cancer, with expansion of the most promising subgroup.

Discussant Benjamin G. Vincent, MD, of the UNC Lineberger Comprehensive Cancer Centre, said this research is based on compelling preclinical data in multiple murine models showing that knockout or inhibition of IL-1 signaling leads to improved survival and delayed tumour growth, and that this is also additive with anti–PD-1 inhibition.

“However, there are some caveats, in that IL-1 receptor knockout or IL-1 signaling inhibition may differentially affect tumour cells in different subsets of tumour-associated leukocytes or leukocytes residing in lymphatics or circulation,” Dr. Vincent said.

Going forward, studying the IL-1 axis will require very careful and robust studies of different subsets of tumour-associated leukocytes, as well as gut microbiome composition, to parse these differential effects and understand that they can be separated from one another.



Posted on 15 July 201917 May 2024