Tak, Paul P.

8634 Background: Patients with unresectable non-small cell lung cancer (NSCLC) with an inadequate response to immune checkpoint inhibitors (ICI) have limited therapeutic options and expected median overall survival (mOS) of 11.6 to 14.5m (PMID: 35658002 ). The immunosuppressive tumor microenvironment and the lack of a specific T cell response underpin inadequate clinical response. CAN-2409 is a replication-defective adenovirus encoding the HSV-tk gene. Transduced cells activate orally delivered valacyclovir, resulting in immunogenic cell death, and in situ immunization against the patient’s tumor antigens, eliciting a specific immune response against the injected tumor and uninjected metastases. Methods: NCT04495153 is an open-label, phase 2 clinical trial of CAN-2409 + valacyclovir in combination with continued ICI in patients with non-resectable, stage III/IV NSCLC, refractory or resistant to anti-PD-(L)1. Patients were enrolled in 2 cohorts (C) depending on disease status at enrolment: C1, stable disease or C2, progressive disease. Two doses of CAN-2409 (5x1011vp) were given 5-7w apart via bronchoscopic or percutaneous injection into lung tumor, disease-positive lymph node, or peripheral metastasis, each followed by oral prodrug. Patients were assessed for safety, immunologic biomarkers, and OS. Results: As of 16Jan2024, 73 patients were treated (safety population: ≥1 dose of CAN-2409) and 44 were evaluable per protocol (received 2 doses of CAN-2409+ valacyclovir and 12-week CT scan). Baseline treated pt median age was 67 [43-88] yrs, 44% female, 68% on aPD(L)1 alone and 32% aPD(L)1 + pemetrexed regimen. We observed no dose-limiting toxicities or ≥grade 4 treatment-related AEs. mOS of the evaluable population was estimated as 22.0m (95% CI: 14.3m, NA; median follow up (mFU) time of 18.2m). In C2 (n = 38) mOS was 20.6 (mFU 19.2.m) and in C1 (n = 6) was N.A. (mFU 15.2m). mOS in the safety population (n = 73) was 14.3.m (mFU16.8m). 64% of evaluable patients had systemic clinical response with shrinkage of both injected and uninjected lesions. We found a significant correlation between increases in T cell populations after the second injection of CAN-2409 (circulating memory and effector memory CD4+ and CD8+T cells, CD4+ Ki67+IFNg+ and CD4+granzymeB+ T cells, CD8+granzymeB+Ki67+ T cells, T regulatory cells) and subsequent OS (R2 between 0.181 and 0.354 and p = 0.043 and 0.004). Conclusions: Experimental treatment with CAN-2409+valacyclovir in NSCLC pts following an inadequate response to ICI is well tolerated and results in the induction of a cytotoxic and memory circulating T cell response associated with shrinkage of injected and uninjected lesions and a raised tail of the survival curve. mOS of the evaluable population was estimated as 22.0m, markedly longer than the expected mOS of 11.6-14.5m. Clinical trial information: NCT04495153 .

TPS9162 Background: Immune checkpoint inhibitors (ICI) are a standard of care (SOC) treatment that have improved outcomes for patients (pts) with non-small cell lung cancer (NSCLC). However, most pts progress, signaling a need for combination approaches to further improve outcomes. CAN-2409 is a replication-defective adenoviral construct encoding the herpes simplex virus thymidine kinase (HSV-tk) gene that is injected intratumorally followed by 2 weeks of prodrug (valacyclovir or acyclovir). HSV-tk converts the prodrug in the tumor microenvironment into a toxic metabolite, resulting in immunogenic cell death, while the adenoviral proteins provide a strong pro-inflammatory signal. Together, this leads to in situ vaccination against the patient’s own tumor. As a result, CD8+ cytotoxic T cells are educated on how to recognize and kill tumor cells in both the injected tumor and the uninjected metastases. A completed neoadjuvant phase I trial in resectable NSCLC demonstrated safety and immune stimulation (Predina et al 2021), warranting further investigation of CAN-2409 + prodrug as a therapy that can lead to improved long-term outcomes for pts with NSCLC who have a suboptimal response to ICI. Methods: LuTK02 (NCT04495153) is an open-label, multi-arm, phase II clinical trial to evaluate CAN-2409 + prodrug added to SOC ICI (anti-PD-(L)1) therapy in pts with stage III/IV NSCLC presenting with inadequate response (as defined below) to ICI. Cohort 1 includes pts with nonresponding but stable disease ≥18 weeks after starting ICI; cohort 2 includes pts with progressive disease ≥18 weeks after starting ICI. Key eligibility criteria include RECIST-evaluable disease; an injectable lesion (via bronchoscopy or US/IR guidance); ability to continue ICI for the treatment period; no change of ICI or prior interruptions of > 4 weeks within 6 months of enrollment; and no focal therapy at > 3 sites of disease within 12 months prior to enrollment. Key exclusion criteria include a history of ICI immune-related adverse events and known alterations in EGFR, ALK, or ROS1. Eligible patients receive 2 injections of CAN-2409 approximately 6 weeks apart followed by prodrug for 14 days. After treatment of ~40 evaluable pts in cohort 2 with two injections of CAN-2409, the protocol has been amended to include a new cohort (n~20) of pts treated with three injections of CAN-2409 approximately 4 weeks apart, each followed by prodrug for 14 days, to further define the optimal therapeutic regimen. Primary endpoints are overall response and/or disease control rate per RECIST 1.1 criteria and safety of CAN-2409 + prodrug. Secondary endpoints include duration of response, PFS, OS, and biomarker studies. Exploratory endpoints include evaluation of effects in non-injected lesions, changes in non-target (per RECIST) lesions, tumor growth trajectory, and viral shedding. Clinical trial information: NCT04495153 .