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The addition of the investigational, off-the-shelf, replication-defective adenovirus CAN-2049 and a prodrug (valacyclovir or acyclovir) to a standard-of-care immune checkpoint inhibitor with or without chemotherapy led to a potential overall survival (OS) benefit in patients with stage III/IV non–small cell lung cancer (NSCLC) who had an inadequate response to an immune checkpoint inhibitor, according to data from the final analysis of a phase 2a trial (NCT04495153).1
Findings showed that evaluable patients treated between cohorts 1 and 2 (n = 46) achieved a median OS of 24.5 months. Patients with progressive disease at baseline who were treated in cohort 2 (n = 41) experienced a median OS of 21.5 months. Among patients who survived for at least 24 months, 37% were still alive at the March 3, 2025, data cutoff.
Notably, patients who had nonsquamous histology and experienced disease progression on an immune checkpoint inhibitor (n = 33) had a median OS of 25.4 months. Among the 15 patients to survive more than 24 months, 14 had nonsquamous histology, and all 9 patients alive at 30 months had nonsquamous histology.
“Treatment options are quite limited for patients with unresectable NSCLC who progress on anti–PD-1 therapy,” Charu Aggarwal, MD, MPH, the Leslye Heisler Professor for Lung Cancer Excellence at the University of Pennsylvania’s Perelman School of Medicine and Principal Investigator of the phase 2 study, stated in a news release. “The survival benefit seen in this study is striking, especially when compared to both the current standard of care treatment of docetaxel chemotherapy and other therapies under investigation for this patient group.”
Candel Therapeutics, the developer of CAN-2049, announced that these data would support the advancement of the development of CAN-2049 in NSCLC, potentially via a registration-enabling trial further investigating the agent in patients with nonsquamous NSCLC.
CAN-2049 is designed to deliver the herpes simplex virus thymidine kinase (HSV-tk) gene with the goal of inducing an individualized, systemic immune response against the tumor. HSV-tk converts valacyclovir to a toxic nucleotide analogue that kills nearby cancer cells.
The single-arm phase 2 trial enrolled patients at least 18 years of age with stage III/IV NSCLC receiving first-line treatment with an immune checkpoint inhibitor with or withou chemotherapy.2 Patients in cohort 1 needed to have persistent but stable disease at least 18 weeks after starting treatment with an immune checkpoint inhibitor, and those in cohort 2 were required to have radiographic progressive disease at least 18 weeks after starting treatment.
Other key inclusion criteria consisted of evaluable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate hematologic and organ function. Patients needed to be able to continue treatment with an immune checkpoint inhibitor for the 12-week treatment period. No changes to the immune checkpoint inhibitor used were allowed within 6 months of enrollment, and patients could not have experienced dose interruptions of more than 4 weeks.
In cohorts 1A and 2A, patients received 2 doses of CAN-2049 followed by 14 days of prodrug as they continued standard-of-care treatment with an immune checkpoint inhibitor with or without chemotherapy. Those in cohorts 1B and 2B received 3 doses of CAN-2049, although the third dose was optional in cohort 1B.
Overall response rate and safety served as the trial’s primary end points. Secondary end points included OS, progression-free survival, and ORR per iRECIST criteria.
Additional data showed that among evaluable patients with multiple lesions (n = 35), a decrease in the size of uninjected tumors occurred in 69% of patients.
Regarding safety, the profile of CAN-2409 was favorable and tolerable profile throughout the extended follow-up period.
“These updated survival data confirm and strengthen our previously reported findings, demonstrating that CAN-2409 has the potential to extend survival for patients with advanced NSCLC, who have limited treatment options after failing to respond to, or progressing, despite immune checkpoint inhibitor therapy,” Paul Peter Tak, MD, PhD, FMedSci, president and chief executive officer of Candel Therapeutics, stated in a news release.1 “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 current standard of care. These compelling results mark a potentially transformative advance in our fight against this aggressive disease.”
### **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 31, 2025. https://ir.candeltx.com/news-releases/news-release-details/candel-therapeutics-reports-both-prolonged-median-overall
2. CAN-2409 plus prodrug with standard of care immune checkpoint inhibitor for stage III/IV NSCLC. ClinicalTrials.gov. Updated December 7, 2023. Accessed March 31, 2025. https://clinicaltrials.gov/study/NCT04495153