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 Cmax (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.
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Table of Contents: ASCO 2019
Featured articles
Endocrine therapy plus ribociclib yields overall survival advantage in HR+/HER2-negative breast cancer
Breast Cancer
Endocrine therapy plus ribociclib yields overall survival advantage in HR+/HER2-negative breast cancer
Biomarker analysis predicts response to adjuvant trastuzumab, pertuzumab in HER2+ breast cancer
Melanoma
Nivolumab-mediated adverse events are independent of efficacy in resected advanced melanoma
Kidney Cancer
Classification of metastatic renal cell carcinoma patients in immunotherapy era and positive responses for sarcomatoid tumours
Sarcoma
Olaratumab trial in soft tissue sarcoma fails to meet overall survival endpoint
Gastrointestinal Cancers
FOLFOXIRI plus bevacizumab an option for patients with mCRC and poor prognosis
KEYNOTE-062: Pembrolizumab combination fails to improve survival in gastric/GEJ cancer
Neoadjuvant chemotherapy as a potential treatment option in colon cancer
Laparascopic surgery; less morbidity, same survival benefits as open surgery in colorectal cancer with liver metastases
Maintenance olaparib improved PFS in patients with BRCA+ pancreatic cancer
Hematologic Malignancies
Daratumumab a promising treatment option for transplant-eligible multiple myeloma
Paediatric Oncology
Entrectinib produces rapid and durable responses in children with refractory CNS and solid tumours
Head and Neck Cancer
Ado-trastuzumab emtansine a potential new treatment option for HER2-amplified advanced salivary gland cancer
Sentinel lymph node biopsy shows promise for early oral cancer
Genitourinary Cancer - Prostate Cancer
Enzalutamide offers survival advantage over other NSAAs in mHSPC
Benefits seen with apalutamide plus ADT in metastatic castration-sensitive prostate cancer
Enfortumab vedotin highly active in previously treated advanced urothelial carcinoma
Multiple Myeloma
Anti-CD38 antibody isatuximab improves treatment response, PFS in R/R multiple myeloma
Lung Cancer
Neoadjuvant nivolumab/ipilimumab shows promise in resectable NSCLC
Overcoming the challenges of immunotherapy in non–small cell lung cancer
Repotrectinib shows encouraging safety, efficacy for patients with ROS1+ NSCLC
Pembrolizumab monotherapy leads to 5-year survival in some patients with NSCLC
Novel RET inhibitor BLU-667 offers promise for RET+ advanced NSCLC
Lurbinectedin shows promise as second-line therapy for SCLC
Early results from TAK-788 in NSCLC with EGFR exon 20 insertions
Developmental Therapeutics - Immunotherapy
IL-6 and C-reactive protein as potential biomarkers for checkpoint inhibition
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