Single-agent LV305 to induce anti-tumor immune and clinical responses in patients with advanced or metastatic sarcoma and other cancers expressing NY-ESO-1.

3093 Background: Immune approaches that stimulate specific anti-tumor cytotoxic T cells (CTLs) can have single agent activity, be synergistic with check point inhibitors (CPIs) and enhance adoptively transferred T cells. LV305 is a replication-incompetent, integration-deficient, hybrid viral vector based on the ZVex platform. It is designed to target dendritic cells in vivo and induce the expression of NY-ESO-1 in order to potently generate and expand anti-cancer CTLs. In this first-in-human study, the safety, immunogenicity and efficacy of LV305 were examined in patients (pts) with sarcoma or carcinoma. Methods: Pts with previously treated, advanced or metastatic malignancies expressing NY-ESO-1 (IHC) were eligible. In Part 1, Dose Escalation, 3 pts enrolled into each of 4 cohorts to receive 3 or 4 intradermal injections every 3 weeks of 108, 109 or 1010 vector genomes (vg) per dose. Cohort advancement followed a 3+3 design and safety was reviewed with a DSMB. In Part 2, additional pts were treated at the max dose/MTD. Results: In Part 1, no DLT or SAEs were observed in the 12 sarcoma patients; all related AEs were grade 1/2. In Part 2 (1010 vg dose), only 1 grade 3 AE was reported in 27 pts (12 sarcoma, 5 melanoma, 9 ovarian and 1 NSCLC). Of evaluable sarcoma pts, NY-ESO-1 specific CD4 12/23 (52%), CD8 12/23 (52%) and CD4 and/or CD8 16/23 (70%) were induced by LV305. Clinical responses included: sarcoma, 1 PR (recent SD to PR change {Study Day 579}, 606+ days), 13 SD (defined as > 84 days, range 136 – 585+ days); melanoma 4 SD; ovarian, 2 SD; and NSCLC 1 SD. In sarcoma pts, median PFS was 140 days and 7/10 pts with pretreatment PD had SD or PR following LV305. Conclusions: LV305 demonstrated acceptable safety up to 1010 vg and induced significant anti-NY-ESO-1 T cell responses in advanced malignancies. Clinical benefit (PR/SD) was seen in 14/24 pts with sarcoma, have been durable > 1 year in 5 pts and includes a late conversion of SD to PR. The median PFS for sarcomas was similar to that of trabectedin as reported in a recent US Ph3 study. The induction of immune responses, favorable safety profile and clinical activity indicate LV305 is an active agent that warrants further investigation. Clinical trial information: NCT02122861.