CAN-2409/Prodrug Improve OS in ICI-Resistant, Advanced NSCLC

CAN-2409 plus valacyclovir or acyclovir elicited a median OS of 24.5 months in the overall population of patients who progressed after immune checkpoint inhibitor therapy.

CAN-2409, a multimodal biological immunotherapy candidate engineered to deliver the herpes simplex virus thymidine kinase to a patient’s tumor, produced improved overall survival (OS) in patients with advanced non–small cell lung cancer (NSCLC) who had an inadequate response to immune checkpoint inhibitor treatment, according to a press release from the developer, Candel Therapeutics.¹

In the overall population of patients who received 2 doses of CAN-2409 (n = 46), the median OS was 24.5 months; in cohort 2 (n = 41), patients with progressive disease at baseline despite immune checkpoint inhibitor treatment experienced a median OS of 21.5 months. In the press release, the authors noted that prior studies have found median OS data from 9.8 to 11.8 months.^2,3

At the data cutoff of March 3, 2025, with a median follow-up of 32.4 months, trial results demonstrated that a “sizable” number of patients exceeded 24 months of survival with 37% (n = 15/41) of patients with progressive disease despite immune checkpoint inhibitor therapy being alive at 2 years.

Additionally, in patients with non-squamous NSCLC (n = 33), the median OS was 25.4 months in patients with progressive disease despite immune checkpoint inhibitor therapy.

Results come from the phase 2a LuTK02 trial (NCT04495153) that evaluated the efficacy of CAN-2409 plus prodrug in patients with stage III or IV NSCLC who are receiving standard-of-care immune checkpoint inhibitors that elicited non-adequate responses.

“Treatment options are quite limited for patients with unresectable NSCLC who progress on anti-PD-1 therapy,” Charu Aggarwal, MD, MPH, Leslye Heisler professor for Lung Cancer Excellence at the University of Pennsylvania’s Perelman School of Medicine and principal investigator of the study, wrote in the press release.¹ “The survival benefit seen in this study is striking, especially when compared with both the current standard of care treatment of docetaxel chemotherapy and other therapies under investigation for this patient group.”

The trial enrolled patients who presented with several negative prognostic factors, with more than 90% having stage IV disease, most having low or undetectable PD-L1 expression, more than 90% being past or present smokers, and most having failed several lines of chemotherapy.

A total of 46 patients completed the treatment which consisted of 2 courses of CAN-2409 injection into an accessible involved tumor site followed by prodrug—either valacyclovir (Valtrex) or acyclovir (Sitavig).⁴

Eligible patients were 18 years or older with stage III/IV NSCLC who were on first-line treatment with an anti–PD-1/anti–PD-L1 immune checkpoint inhibitor with or without chemotherapy.Evaluable disease per RECIST, not having received focal therapy at more than 3 different sites within 12 months of enrollment, no change of immune checkpoint inhibitor therapy within 6 months of enrollment, an ECOG performance status of 0 or 1, and a willingness to undergo pre-treatment and on-treatment biopsies were among inclusion criteria.

Exclusion criteria include a history of severe immune-related adverse effects due to immune checkpoint inhibitor therapy, a history of autoimmune disease requiring treatment in the past 2 years, uncontrolled intercurrent illness, significant heart disease, hypersensitivity or allergy to valacyclovir or acyclovir, known interstitial lung disease, liver metastases involving more than half the liver, or uncontrolled brain metastases.

The primary trial end points are the response rate at 12 months and safety. Secondary end points include OS, progression-free survival, changes in patient-reported symptoms, and biomarker studies.

Of patients with multiple lesions, 69% (n = 35) of patients experienced a decrease in the size of uninjected tumors; this indicated that the treatment may induce a systemic anti-tumor immune response.

Through the extended follow-up period, the safety and tolerability profile were favorable and consistent with previously known data on CAN-2409.

Paul Peter Tak, MD, PhD, FMedSci, president and chief executive officer of Candel, stated, “CAN-2409 may represent an entirely new approach to solid tumor treatment, with its unique mechanism of action and favorable safety profile to date, enabling potentially meaningful improvements in outcomes beyond the current standard of care. These compelling results mark a potentially transformative advance in our fight against this aggressive disease.”¹

Previously, CAN-2409 in combination with prodrug has been granted fast track designation in stage III/IV NSCLC resistant to first-line PD-L1 inhibitor therapy without activating molecular driver mutations or progression on directed molecular therapy, pancreatic ductal adenocarcinoma, and localized primary prostate cancer.

References

1. Candel Therapeutics reports both prolonged median overall survival and long tail of survival in phase 2a clinical trial of CAN-2409 in advanced non-small cell lung cancer (NSCLC) patients non-responsive to immune checkpoint inhibitor (ICI) treatment. News release. Candel Therapeutics. March 26, 2025. Accessed March 27, 2025. https://tinyurl.com/39h5w3tx
2. Paz-Ares LG, Juan-Vidal O, Mountzios GS, et al. Sacituzumab govitecan versus docetaxel for previously treated advanced or metastatic non-small cell lung cancer: the randomized, open-label phase III EVOKE-01 study. J Clin Oncol. 2024;42(24):2860-2872. doi:10.1200/JCO.24.00733
3. Ahn MJ, Tanaka K, Paz-Ares L, et al. Datopotamab deruxtecan versus docetaxel for previously treated advanced or metastatic non-small cell lung cancer: the randomized, open-label phase III TROPION-Lung01 study. J Clin Oncol. 2025;43(3):260-272. doi:10.1200/JCO-24-01544
4. CAN-2409 plus prodrug with standard of care immune checkpoint inhibitor for stage III/​IV NSCLC. ClinicalTrials.gov. Updated December 7, 2023. Accessed March 27, 2025. https://tinyurl.com/3djbkwkw