Phase II study of telomelysin (OBP-301) in combination with pembrolizumab in gastroesophageal (GEA) adenocarcinoma.
Authors: Shah Manish A. , Eads Jennifer Rachel , Sarkar Sandipto , Khan Sahrish , Sharaiha Reem , Carr-Locke David , Chang Lillian , Ginsberg Gregory , DiCicco Lisa , Garcia-Marcano Luis , Hissong Erika , Betel Doron 
Published: June 2023

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Background: OBP-301 is a novel, replication-selective adenoviral construct that incorporates the human telomerase reverse transcriptase gene (hTERT) promoter, which is highly expressed in tumors but not in normal, differentiated adult cells, to regulate expression of the early adenoviral genes, E1A and E1B. OBP-301 has been evaluated as a single agent, and demonstrated immune responses and clinical activity in phase I studies. We examined OBP-301 in combination with pembrolizumab in a multicenter phase II study as a novel mechanism to improve immunotherapy in advanced gastric cancer. Methods: Eligible patients had advanced GEA that had progressed on at least 2 lines of prior therapy for incurable, advanced disease. Patients were required to have adequate end-organ function, measurable disease by RECIST 1.1, and a PD-L1 CPS > 1. Patients received OBP-301 at 2x1012 viral particles via direct tumor injection every two weeks x 4 injections as well as pembrolizumab 200 mg IV every 3 weeks. The primary endpoint was objective response rate (ORR). The null hypothesis that the ORR is < 15% was tested against the Ha ORR > 30%. We used a Simon two-stage design, requiring 3 or more responses in 18 patients in the first stage to proceed to stage two. The study was closed after successfully completing stage one of the Simon’s two stage design to formally examine OBP-301 + pembrolizumab in an immunotherapy (IO) refractory GEA population. Tissue was collected for single cell RNA Sequencing to examine the tumor immune microenvironment pre- and post-OBP-301 injections. Results: From May 2019 to Oct 2022, we enrolled 16 patients, median age 65 (range 43-81), male n = 13. OBP-301 direct tumor injection was well tolerated, median OBP-301 injections 3 (range 1-5). Toxicity attributed to OBP-301 included grade 2 fatigue/weakness (25%), grade 2 fever (18.7%), and a single incidence each of grade 2 nausea, anemia, grade 3 melena, and grade 4 diabetes mellitus (6.25%). We observed 3 patients (19%) with a partial response (PR), thereby meeting the Simon two-stage threshold. The responses were durable; two patients with PR are currently without evidence of disease (one completed 2 years of pembrolizumab, one underwent resection of primary tumor after 15 months), and the 3rd patient is now in month 12 of treatment. Further, one patient with brain metastases demonstrated regression of metastatic disease following progression on immunotherapy alone. All patients were mismatch repair proficient. Conclusions: OBP-301 viral particle injection into the tumor is feasible and safe. OBP-301 with pembrolizumab has encouraging activity in GEA, with durable responses and demonstration of activity in immunotherapy refractory disease. Single Cell RNA Sequencing data of the pre- and post-injection immune effects of OBP-301 will be presented. A formal phase II study of OBP-301 + pembrolizumab in IO refractory GEA patients is underway. Clinical trial information: NCT03921021 .