Overall survival after treatment with CAN-2409 plus valacyclovir in combination with continued ICI in patients with stage III/IV NSCLC with an inadequate response to ICI.

Charu Aggarwal Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA info_outline Charu Aggarwal, Daniel Sterman, Erin R. Alesi, Fabien Maldonado, Ranee Mehra, Christine M. Bestvina, Janani S Reisenauer, Leigh Klaus Swartz, Sonam Puri, Omar Ibrahim, George Eapen, Caroline Duault, Mina Pichavant, Diane Marie Del Valle, Edgar Gonzalez-Kozlova, Sacha Gnjatic, Holden Maecker, William Garrett Nichols, Francesca Barone, Paul Peter Tak

Authors Charu Aggarwal Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA info_outline Charu Aggarwal, Daniel Sterman, Erin R. Alesi, Fabien Maldonado, Ranee Mehra, Christine M. Bestvina, Janani S Reisenauer, Leigh Klaus Swartz, Sonam Puri, Omar Ibrahim, George Eapen, Caroline Duault, Mina Pichavant, Diane Marie Del Valle, Edgar Gonzalez-Kozlova, Sacha Gnjatic, Holden Maecker, William Garrett Nichols, Francesca Barone, Paul Peter Tak Organizations Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, NYU Langone Medical Center, New York, NY, Division of Hematology, Oncology, and Palliative Care, Massey Comprehensive Cancer Center, Virginia Commonwealth University Health System, Richmond, VA, Vanderbilt University Medical Center, Nashville, TN, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, University of Chicago, Chicago, IL, Division of Thoracic Surgery, Division of Pulmonary and Critical Medicine, Mayo Clinic, Rochester, MN, Hunter Holmes McGuire VA Medical Center, Richmond, VA, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, UConn Health, Farmington, CT, The University of Texas MD Anderson Cancer Center, Houston, TX, Stanford Cancer Center GI Surgical Oncology, Stanford, CA, Icahn School of Medicine Mount Sinai, New York, NY, Icahn School of Medicine at Mount Sinai, New York, NY, Stanford University, School of Medicine, Stanford, CA, Candel Therapeutics, Needham, MA, Candel Therapeutics, Inc., Needham, MA Abstract Disclosures Research Funding Candel Therapeutics Inc. Partnership for Accelerating Cancer Therapies (PACT) 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 (5x10 11 vp) 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 (R 2 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.

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