First report of safety/tolerability and preliminary antitumor activity of CAN-2409 in inadequate responders to immune checkpoint inhibitors for stage III/IV NSCLC.
Authors: Aggarwal Charu , Haas Andrew , Gordon Sarah W. , Mehra Ranee , Lee Peter M , Bestvina Christine M. , Maldonado Fabien , Velcheti Vamsidhar , Herbst Roy S. , Bell Susan D. , Gillmor Rachael , Manzanera Andrea , Matheny Christopher Jon , Aguilar-Cordova Estuardo , Aguilar Laura K. , Barone Francesca , Tak Paul Peter , Sterman Daniel 
Published: June 2022

9037 Background: Immune checkpoint inhibitors (ICI) are standard of care for advanced NSCLC. Even among patients with initial response, a majority ultimately progress, and rational combination approaches are needed to improve outcomes. CAN-2409 is a replication-deficient adenoviral gene construct that delivers the thymidine kinase gene, resulting in local conversion of a prodrug (valacyclovir) into a toxic metabolite. This leads to tumor cell lysis and immunization against the injected tumor and uninjected metastases. We have previously shown that monotherapy intra-tumoral (IT) delivery of CAN-2409 followed by oral valacyclovir in NSCLC patients is safe and results in CD8+ T cell infiltration in the injected tumor and activation of this cell population in tissue and peripheral blood. Methods: This open-label Ph2 experimental medicine clinical trial evaluates safety and clinical activity of IT CAN-2409 combined with ICI (± chemo) for stage III/IV NSCLC. Three cohorts are defined based on response to ICI at enrollment: stable disease (SD; Cohort 1; C1), progressive disease (PD) after ≥18 weeks (w) of ICI (Cohort 2; C2), or ICI refractory disease (RD; Cohort 3; C3). Two doses of CAN-2409 (5x1011 vp) are given 5-7w apart via bronchoscopic or percutaneous injection into a lung tumor, disease-positive lymph node or peripheral metastasis, followed by valacyclovir. Patients are assessed for safety, immunologic biomarkers (analysis in progress), and clinical response. Results: As of data cutoff (10Jan22), 28 patients received ≥1 dose of CAN-2409 (safety population). Median age was 70 years; 86% stage IV; 32% squamous; 11% PD-L1 >50%; 82% receiving pembrolizumab and 18% nivolumab. Study treatment and procedures were generally well tolerated. The most common TRAEs were Gr1/2, with fatigue, fever, and chills in 18-39% of patients; 1 patient had Gr3 fever. Twenty-two patients are alive and 6 patients died due to disease. Of the 14 RECIST evaluable patients who received 2 doses of CAN-2409, clinical response was seen in 4 patients (Table 1). Two PRs are ongoing (6w, 24w) and reduction in tumor size was observed in non-injected lesions. In C2, 6 of 7 patients achieving SD are ongoing with median duration of 13w (range 10-40w). Conclusions: The addition of CAN-2409 for patients with advanced NSCLC and inadequate response to front-line ICI (± chemo) appears to be well tolerated. Preliminary clinical data suggest that CAN-2409 induced a clinical response in 4/14 evaluable patients and produced disease stabilization in most patients entering the trial with PD, with evidence of abscopal effect in a subset of patients. Clinical trial information: NCT04495153. [Table: see text]