Phase I trial of talimogene laherparepvec for the treatment of peritoneal surface malignancies (TEMPO).

Abstract

2668 Background: Peritoneal surface malignancies (PSM) constitute a group of difficult-to-treat metastatic diseases that respond poorly to standard chemotherapy. Talimogene Laherparepvec (T-VEC), the first FDA-approved oncolytic virus (OV), demonstrates potential in treating various malignancies by effectively initiating crucial immune responses. Yet, the utility of intraperitoneal (ip) T-VEC for unresectable PSM is still unexplored. Methods: TEMPO (NCT03663712) was a nonrandomized, open-label, multicenter phase I trial involving 18 patients with unresectable PSM originating from the appendix (n=14), ovary (n=3), or small bowel (n=1). The trial aimed to determine the recommended Phase 2 dose (RP2D) and maximum tolerated dose (MTD) of ip T-VEC, as well as to evaluate its safety and tolerability. An exploratory endpoint was the Restricted Mean Survival Time (RMST), the estimated non-parametric mean survival time up until the longest patient follow-up time (i.e. maximum of the longest follow-up, and generally an underestimate of the actual mean survival time especially in small samples). Patients received an initial dose of 4x106 plaque-forming units (pfu) of ip T-VEC, followed by their assigned dose every two weeks for up to four additional doses, using a standard ‘3+3’ dose escalation scheme. The doses tested were 4x106, 4x107, and 4x108 pfu of ip T-VEC. Safety assessments were conducted regularly. Results: The RP2D is 4x108 pfu of T-VEC. The trial reported no dose-limiting toxicities, thus the MTD was not reached. Treatment-Related Adverse Events (TRAEs) were recorded and categorized by the maximum dose received (Table).One patient treated with 4x106 pfu had grade 3 abdominal pain and another grade 3 fatigue. No severe TRAEs occurred with 4x107pfu. One patient showed a grade 3 neutrophil count decrease at 4x108 pfu. The RMST, calculated with a truncation time of 5.5 months, varied across the doses. Patients receiving 4x106 pfu had an RMST of 3.1 (95% CI= 1.550-4.733) months, while those treated with 4x107 and 4x108 pfu had RMSTs of 4.2 (95% CI= 2.492-5.884) and 4.6 (95% CI= 3.551-5.722) months, respectively. Conclusions: We conclude that ip T-VEC is safe in patients with unresectable PSM. TEMPO successfully identified 4x108 pfu as the RP2D for TVEC. Notably, the RMST increased with increasing doses of TL. These results are promising, considering the limited benefit of conventional chemotherapy in treating PSM. This study positions T-VEC as a promising candidate for combination immunotherapies for PSM that amplifies the bystander immune response induced by OVs. Clinical trial information: NCT03663712 . [Table: see text]