SUMMARY: The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.
A New Approach to Overcoming Resistance
For patients with advanced Non-Small Cell Lung Cancer (NSCLC), Immune Checkpoint Inhibitors (ICIs) have changed the treatment landscape. Yet, many patients develop resistance or fail to respond altogether, leaving clinicians with limited options. A novel gene therapy, CAN-2409, is offering a different strategy, one that uses the tumor itself as a source of immune activation.
How It Works: An In Situ Vaccination
CAN-2409 is an engineered, replication-defective adenovirus designed to deliver the Herpes Simplex Virus thymidine kinase (HSV-tk) gene directly into tumor cells. Once inside, the cells express HSV-tk. When patients take the oral prodrug Valacyclovir, the enzyme HSV-tk converts it into a toxic metabolite, selectively killing the tumor cells.
But the therapeutic effect goes far beyond cell death.
- Immunogenic cell death releases tumor-specific antigens and creates a pro-inflammatory environment.
- The adenovirus itself adds inflammatory cues.
- Dendritic cells capture and present these antigens, training cytotoxic T cells to recognize the tumor.
The result is a two-step, multimodal effect: localized destruction followed by a systemic immune response. This “in situ vaccination” primes the immune system not just against the injected lesion, but also against distant metastases, creating the potential for durable control.
Clinical Trial in ICI-Refractory NSCLC
A Phase IIa open-label trial evaluated CAN-2409 plus Valacyclovir in patients with unresectable Stage III/IV NSCLC who had failed to respond adequately to anti-PD-(L)1 therapy. Patients continued on their checkpoint inhibitor therapy and received two intratumoral injections of CAN-2409 (5 × 10^11 vp) five to seven weeks apart via bronchoscopic or percutaneous injection into lung tumor, disease-positive lymph node, or peripheral metastasis, followed by oral prodrug Valacyclovir administered for 15 days. The median age was 67 yrs, 44% were female, 68% were on checkpoint inhibitor therapy alone and 32% were on checkpoint inhibitor therapy plus Pemetrexed regimen. Majority of patients (90%) had Stage IV disease, 46% had PD-L1 TPS < 1%, 91% were former or current smokers.
Participants were enrolled into two cohorts:
- Cohort 1: Stable disease while on ICI therapy
- Cohort 2: Progressive disease despite ICI therapy
The goal was to assess Overall Survival (OS), abscopal responses, and immune correlates.
Extended Follow-Up Results
Seventy-six patients were enrolled, of whom 46 patients were considered evaluable
At a median follow-up of 32.4 months, the findings were striking:
- Median OS (all evaluable patients): 24.5 months
- Median OS in Cohort 2 (progressive disease): 21.5 months
- Long-term survival: 37% alive beyond 2 years
- Histology-specific benefit: Patients with nonsquamous disease had longer OS than those with squamous histology (25.4 vs. 13.3 months).
Notably, patients with nonsquamous tumors showed greater expansion of cytotoxic T cells, B cells, and dendritic cells, suggesting that histology-linked biology may shape immune responsiveness to CAN-2409.
Evidence of Systemic Immune Activation
One of the most compelling signals came from the observation of abscopal responses. Among patients with multiple lesions, 69% experienced shrinkage at uninjected sites, confirming that local therapy could indeed drive a systemic anti-tumor effect.
Safety and Tolerability
Throughout extended follow-up, CAN-2409 maintained a favorable safety profile. The most common Treatment Related Adverse Events (TRAEs) were Grade 1/2, with fatigue, fever, and chills in 18-39% of patients. No dose-limiting toxicities or Grade 4 or more treatment-related AEs were noted. No new safety signals emerged, underscoring its feasibility as a repeat intratumoral intervention alongside checkpoint blockade.
Looking Ahead
These results highlight the promise of CAN-2409 as a next-generation immunotherapy platform for patients with advanced NSCLC resistant to ICIs. With durable survival in a subset of patients, particularly those with nonsquamous histology, the findings support the initiation of a larger, randomized trial to validate efficacy and refine patient selection strategies.
Key Takeaway for Oncology Practice
CAN-2409 represents a novel paradigm in NSCLC, transforming tumors into personalized vaccines that harness both direct cytotoxicity and immune training. For patients progressing on ICIs, this dual mechanism could offer a meaningful new avenue of durable disease control.
MA10.02 CAN-2409 With Continued Immune Checkpoint Inhibitor (ICI) in Patients With Stage III/IV NSCLC With Inadequate Response to ICI. Aggarwal C, Sterman D, Nicholas G, et al. Presented at the 2025 World Conference on Lung Cancer. September 6-9, 2025. Barcelona, Spain.
