A novel viral immunotherapy has demonstrated encouraging long-term survival outcomes in patients with advanced non-small cell lung cancer (NSCLC) who previously failed to respond to immune checkpoint inhibitors, according to results from a phase 2a clinical trial presented at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer in Barcelona.
The study investigated CAN-2409, an experimental viral immunotherapy that combines intratumoral injections with an oral prodrug, in patients with unresectable stage III/IV NSCLC. Among 76 patients enrolled, 46 were considered eligible for analysis in the per protocol population. At a median follow-up of 32.4 months, median overall survival for the eligible population reached 24.5 months, with 37% of patients still alive more than two years post-treatment.
Mechanism and Treatment Approach
CAN-2409 utilizes a non-replicating adenoviral vector to deliver herpes simplex virus thymidine kinase (HSV-tk) directly into tumor cells via intratumoral injections. The treatment is combined with valacyclovir, an oral prodrug that is activated by HSV-tk and converted into toxic metabolites that induce immunogenic cell death. This process not only eliminates tumor cells locally but also primes the patient's immune system to recognize and fight cancer systemically.
The trial, sponsored by Candel Therapeutics, enrolled patients separated into two cohorts based on their disease status at enrollment: those with stable disease despite immune checkpoint inhibitor therapy and those with progressive disease despite such treatment.
Histology-Specific Outcomes
A notable finding emerged regarding differential outcomes based on tumor histology. Patients with non-squamous histology demonstrated significantly longer overall survival compared to those with squamous histology (25.4 vs. 13.3 months). This survival advantage was linked to a significant increase in cytotoxic effector T cells and other favorable immunological changes following treatment.
"Notably, patients with non-squamous histology demonstrated longer OS than those with squamous histology (25.4 vs. 13.3 months), linked to a significant increase in cytotoxic effector T cells and other favorable immunological changes following treatment," said Dr. Charu Aggarwal of the Abramson Cancer Center at the University of Pennsylvania.
Even among patients with progressive disease at baseline, the treatment showed meaningful benefit, with median overall survival reaching 21.5 months.
Systemic Immune Activation
The study documented robust systemic immune activation beyond the local injection site. Abscopal responses were observed in 69% of patients with multiple lesions, indicating that the intratumoral administration of CAN-2409 triggered a profound systemic anti-tumor effect. The abscopal effect refers to the regression of untreated metastatic lesions distant from the site of local therapy, suggesting the treatment converts the tumor into an in situ cancer vaccine.
Safety Profile and Future Directions
Throughout the extended follow-up period, CAN-2409 continued to demonstrate a favorable safety and tolerability profile with manageable adverse events. Dr. Aggarwal noted that the treatment maintained its safety profile throughout the extended follow-up period.
"This extended follow-up confirms the durable survival benefit of CAN-2409 for patients who otherwise have limited treatment options after failing ICI therapy," said Dr. Aggarwal. "These results strongly support advancing CAN-2409 into a larger, randomized controlled trial, particularly in patients with non-squamous histology."
The sustained clinical benefit and immunomodulatory capacity of CAN-2409 support its advancement to larger, randomized controlled trials, with particular focus on patients with non-squamous histology given their pronounced survival advantage and immunologic responsiveness.
