Aglatimagene Besadenovec Shows Durable Survival in ICI-Refractory NSCLC

Extended follow-up data from a phase 2a clinical trial (NCT04495153) indicate that 50% of patients with advanced non–small cell lung cancer (NSCLC) who had an inadequate response to immune checkpoint inhibitor (ICI) therapy remained alive at 24 months after treatment with aglatimagene besadenovec (CAN-2409), an investigational intratumoral gene therapy.¹

Among the 46 evaluable patients who received 2 administrations of aglatimagene (per-protocol population), 35% survived beyond 30 months, 26% beyond 36 months, 24% beyond 40 months, and 13% beyond 50 months. These figures are notably higher than the prior data cut-off, in which 39% of patients in the per-protocol population were alive at 24 months, with 10 patients surviving beyond 30 months and only 2 surviving beyond 50 months. Median overall survival (mOS) was 25.4 months in the per-protocol population (cohorts 1 and 2 combined), 21.5 months among patients with progressive disease at baseline despite prior ICI therapy (cohort 2; n = 41), and 25.4 months in patients with nonsquamous histology within cohort 2 (n = 33).

Historical reference mOS data for patients with progressive disease following ICI treatment who receive standard-of-care docetaxel have been reported in the range of 9.8 to 11.8 months.The observed mOS with aglatimagene-based therapy represents approximately a 2-fold improvement relative to that benchmark in this difficult-to-treat population, though direct comparisons between single-arm data and historical controls should be interpreted with caution given differences in patient populations and study design.

Mechanism of Action

Aglatimagene besadenovec is an off-the-shelf, replication-defective adenovirus engineered to deliver the herpes simplex virus thymidine kinase (HSV-tk) gene intratumorally. Following administration, HSV-tk converts concomitantly administered valacyclovir (Valtrex) into DNA-incorporating nucleotide analogs that induce immunogenic cell death in proliferating and DNA-damaged cells, liberating tumor neoantigens into the microenvironment. Simultaneously, adenoviral serotype 5 capsid proteins stimulate expression of pro-inflammatory cytokines, chemokines, and adhesion molecules. The combined effect is intended to elicit an individualized, CD8+ T cell–mediated immune response targeting both the injected tumor and uninjected distant metastases, essentially functioning as an in situ tumor vaccine.

In the open-label, multi-arm, phase 2 trial, patients with unresectable stage III/IV NSCLC who had experienced an inadequate response to anti–PD-(L)1 therapy received 2 intratumoral injections of aglatimagene approximately 6 weeks apart, each followed by 14 days of oral valacyclovir, in combination with continued ICI therapy. Key exclusion criteria included prior ICI-related immune-mediated adverse events and known activating alterations in EGFR, ALK, or ROS1. The trial’s primary end points were overall response rate and disease control rate per RECIST 1.1 criteria, along with safety; secondary end points included duration of response, progression-free survival, OS, and biomarker analyses.²

Biomarker and Immunologic Findings

Molecular profiling of paired baseline and posttreatment tumor biopsies revealed upregulation of genes associated with immune activation and antigen presentation among long-term survivors. Statistically significant increases were observed in expression of IFNγ (P =.010), CSF1 (P =.026), CX3CL1 (P =.013), and IL-1β (P =.034), reflecting enhanced interferon signaling and activation of myeloid and antigen-presenting cell programs within the tumor microenvironment.

T-cell receptor (TCR) repertoire sequencing demonstrated expansion of TCR diversity both in tumor tissue and peripheral blood following treatment, consistent with broadening of the adaptive antitumor immune response. The investigators noted a similar TCR expansion pattern was previously reported in patients with glioblastoma treated with aglatimagene,suggesting a reproducible immunologic mechanism across tumor types.³

Histologic analysis of evaluable patients surviving beyond 24 months with available PD-L1 data showed that 85% (n = 17/20) had baseline PD-L1 tumor proportion scores below 50%, a threshold generally associated with reduced responsiveness to ICI monotherapy. This finding supports the hypothesis that aglatimagene may upregulate PD-L1 expression in the tumor microenvironment and convert immunologically “cold” tumors to a more immune-reactive state, potentially rendering previously ICI-resistant patients more susceptible to checkpoint inhibition.

Safety

Aglatimagene maintained its previously reported tolerability profile throughout the extended follow-up period. More than 1000 patients have now been dosed with aglatimagene across clinical trials, and no new safety signals were identified in this updated analysis. Specific adverse event frequencies were not disclosed in the press announcement.

Regulatory Status and Phase 3 Plans

The FDA has previously granted fast track designation to aglatimagene plus valacyclovir in combination with ICI therapy for the treatment of patients with stage III/IV NSCLC who are resistant to first-line PD-(L)1 inhibitor therapy, do not harbor activating molecular driver mutations, or have progressed on directed molecular therapy.⁴

Based on the updated efficacy data and biomarker findings—including the superior outcomes observed in the nonsquamous histology subgroup, Candel Therapeutics has announced plans to initiate a pivotal phase 3 clinical trial in patients with NSCLC with nonsquamous histology in the second quarter of 2026. The company indicated that the nonsquamous subgroup analysis, along with supporting mechanistic data, informed the precision medicine–based design for the planned phase 3 study.

“These updated survival data further strengthen our previously reported findings, demonstrating the potential of aglatimagene to meaningfully extend survival for patients with advanced NSCLC who have limited treatment options after failing to respond to, or progressing despite, ICI therapy,” said Paul Peter Tak, MD, PhD, FMedSci, president and CEO of Candel Therapeutics, in a news release. “With its differentiated mechanism of action and favorable safety profile observed to date, aglatimagene represents a novel therapeutic approach for solid tumors, with the potential to improve outcomes beyond current standards of care. These compelling results reinforce our commitment to advancing this program as we continue to develop new treatment options for patients facing this aggressive disease.”

REFERENCES

1. Candel Therapeutics Reports Extended Survival Tail Observed in Trial of Aglatimagene Besadenovec (CAN-2409) in Advanced Non-Small Cell Lung Cancer Patients with Inadequate Response to Immune Checkpoint Inhibitors. News release. Candel Therapeutics. March 17, 2026. Accessed March 18, 2026. https://tinyurl.com/578n2hd8

2. CAN-2409 Plus Prodrug With Standard of Care Immune Checkpoint Inhibitor for Stage III/​IV NSCLC. ClinicalTrials.gov. Updated August 22, 2025. Accessed March 18, 2026. https://clinicaltrials.gov/study/NCT04495153

3. Wen PY, Manzanera A, Duault C, et al. A multi-institutional phase 1 clinical trial exploring upfront multimodal standard of care and combined immunotherapies for newly diagnosed glioblastoma. Neuro Oncol. 2025 Oct 1;27(10):2617-2631. doi: 10.1093/neuonc/noaf079. PMID: 40120123; PMCID: PMC12833529