Canakinumab Reduces Nodule Size in High-Risk Lung Precancers

Treatment with the IL-1β–targeting monoclonal antibody canakinumab (Ilaris) produced reductions in nodule size in a subset of patients with persistent, high-risk indeterminate pulmonary nodules (IPNs) and was well tolerated, according to a planned interim analysis of the phase 2 Can-Prevent-Lung trial (NCT04789681) presented at the 2026 SITC Annual Meeting.¹

Investigators reported that the trial met its revised primary end point and identified baseline markers of myeloid inflammation associated with radiographic response, supporting further study of IL-1 blockade as a lung cancer interception strategy.

In the interim analysis population (n = 15), 10 patients experienced a reduction in nodule size following treatment with canakinumab. Among patients with nodule shrinkage, the largest reductions from baseline were –26.3%, –17.9%, –8.8%, and –6.7%. Plasma IL-1β levels increased in a quantifiable manner during treatment, demonstrating the biological activity of canakinumab.

"This trial suggests that we've got a better handle on the dosing and management of canakinumab, which is, I think, one of the first steps forward in terms of trying to target myeloid-derived inflammation for lung cancer interception," Matthew D. Park, PhD, a postdoctoral fellow in the laboratory of Miriam Merad, MD, PhD, at the Icahn School of Medicine at Mount Sinai in New York, New York, said in an exclusive interview with OncLive^®.

What was the rationale for targeting IL-1 in lung precancers?

Preclinical work from the Merad laboratory showed that aging of the hematopoietic system, rather than aging of the tumor or surrounding tissue, drives age-dependent lung cancer development, and that disrupting IL-1/IL-1 receptor 1 signaling deterred lung adenocarcinoma development and progression in genetically engineered and orthotopic mouse models. Notably, blocking the pathway during tumor initiation was key. Treating established tumors had no meaningful effect.

This stage dependence may help explain prior clinical experience with canakinumab. In retrospective analyses of the phase 3 CANTOS trial (NCT01327846), which evaluated the agent for cardiovascular risk reduction, patients who received canakinumab had a lower incidence of lung cancer.² However, the phase 3 CANOPY-1 (NCT03631199) and CANOPY-A (NCT03447769) trials, which tested canakinumab in patients with established advanced and resected non–small cell lung cancer, respectively, showed no clinical benefit.^3,4 According to Park, these results suggested that the optimal window for IL-1–targeted intervention is early in the disease course.¹

To determine whether this biology holds in humans, the Merad laboratory partnered with Jianjun Zhang, MD, PhD, who directs the lung cancer interception program at MD Anderson Cancer Center and leads a consortium that has collected and profiled more than 500 lung precancer samples. That analysis showed that chromosomal instability generally emerged only after precancers progressed to invasive adenocarcinoma. Instead, the transition from hyperplasia to adenocarcinoma was defined by persistent alveolar macrophages and recruitment of monocyte-derived macrophages, both of which express high levels of IL-1.

For patients with high-risk nodules identified on low-dose CT screening, surveillance and surgery remain the primary options.

"Surgery may address the cancer portion of the disease, but it would severely compromise their overall pulmonary function," Park explained, noting that many of these patients have emphysema or chronic obstructive pulmonary disease and limited lung reserve. "This is where we felt that a pharmacologic method of trying to modulate these nodules, with the potential for them to regress, was what excited us about this particular project."

How was the Can-Prevent-Lung trial designed?

In the single-arm, phase 2 Can-Prevent-Lung trial, which has completed enrollment of 50 patients, canakinumab is given at 200 mg once every 3 weeks for up to 24 weeks, with treatment stopping early if nodules progress.

Eligible patients were at least 18 years of age, had an ECOG performance status of 0 or 1, and had persistent IPNs on at least 2 CT scans spaced 3 months apart without shrinkage.⁵ Patients with no history of lung cancer needed a Brock University–estimated cancer probability of 10% to 30%, and those who had completed curative-intent treatment for stage I to III non–small cell lung cancer needed a probability of greater than 5% to 30%. Nodules with a probability above 30% were eligible if a biopsy showed no clear evidence of malignancy. Patients also needed adequate hematologic, renal, and hepatic function, including an absolute neutrophil count of at least 1500/μL, a platelet count of at least 100,000/μL, and a hemoglobin level of at least 9.0 g/dL.

The primary end point was the proportion of patients whose target IPNs had not progressed at 24 weeks.¹ Patients underwent chest CT at weeks 6, 12, and 24, and blood and plasma were drawn at baseline and at weeks 3, 6, 12, and 24 for spectral flow cytometry, single-cell RNA sequencing, bulk T-cell receptor sequencing, cytokine assays, and proteomics.

"The initial primary end point was defined as regression of nodules. We had not met that primary end point, but given the promising signal [and] the biology that we're seeing on the exploratory side of things, MD Anderson had revised that primary end point to non-progression," Park noted.

Patients in the interim analysis were enrolled between August 6, 2021, and July 1, 2022. Twelve patients completed treatment per protocol; 3 discontinued, including 2 because of neutropenia and 1 because of confirmed malignancy.

What did the safety and biomarker analyses show?

Canakinumab was well tolerated, with all adverse effects (AEs) reported as grade 1 or 2. These included decreased neutrophil count (grade 1, n = 1; grade 2, n = 3), increased creatinine (grade 1, n = 3), fatigue (grade 1, n = 1; grade 2, n = 1), hypercalcemia (grade 1, n = 2), pain (grade 1, n = 2), and grade 2 diarrhea (n = 1). Grade 2 neutropenia led 2 patients to come off study and prompted a switch to a 6-week dosing cycle in another patient; grade 2 diarrhea prompted a switch to a 9-week cycle in 1 patient.

References

1. Park MD, Hu X, Montégut L, et al. Targeting IL-1 to intercept lung precancers: preclinical studies and interim results of Can-Prevent-Lung trial. Paper presented at: 2026 Society for Immunotherapy of Cancer (SITC) Annual Meeting; November 4-8, 2026; Phoenix, AZ. Abstract 541
2. Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ; CANTOS Trial Group. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10105):1833-1842. doi:10.1016/S0140-6736(17)32247-X
3. Tan DSW, Felip E, de Castro G, et al. Canakinumab versus placebo in combination with first-line pembrolizumab plus chemotherapy for advanced non-small-cell lung cancer: results from the CANOPY-1 trial. J Clin Oncol. 2024;42(2):192-204. doi:10.1200/JCO.23.00980
4. Garon EB, Lu S, Goto Y, et al. Canakinumab as adjuvant therapy in patients with completely resected non-small-cell lung cancer: results from the CANOPY-A double-blind, randomized clinical trial. J Clin Oncol. 2024;42(2):180-191. doi:10.1200/JCO.23.00910
5. Canakinumab for the prevention of lung cancer, the Can-Prevent-Lung trial. ClinicalTrials.gov. Updated June 12, 2026. Accessed November 6, 2026. https://clinicaltrials.gov/study/NCT04789681