Mehta, Rutika Jitesh

356 Background: Autologous anti-claudin 18.2 (CLDN18.2) CAR T cell, satricabtagene autoleucel (satri-cel), was developed to treat solid tumors. We report the completed results of the Phase 1b ELIMYN18.2 study (Cohort A) in gastric/gastroesophageal junction (GC/GEJ) and pancreatic cancer (PC). Methods: This single-arm, open-label, Phase 1b/2 study (NCT04404595) evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced GC/GEJ or PC. Cohort A consisted of a modified 3+3 design. After a conditioning regimen of fludarabine, cyclophosphamide, and nab-paclitaxel, patients were administered 1-3 cycles of satri-cel. The primary objectives were safety and determination of the recommended Phase 2 dose (RP2D). Adverse Events (AEs) were graded per CTCAE 5.0, objective response rate (ORR), and clinical benefit rate (CBR) including CR, PR, and ≥6-month SD were assessed by the investigator per RECIST 1.1. Results: As of May 14, 2023, twenty-four patients underwent leukapheresis in Cohort A. Nineteen patients (7 GC/GEJ and 12 PC) with a median of 3 (range: 1-8) prior therapeutic lines had satri-cel at three dose levels (DLs) between 250×106 and 600×106 cells. Seven patients received a 2nd dose and two patients received a 3rd dose of satri-cel at a median of 113 and 259 days, respectively, post-first infusion. All 19 patients experienced at least one AE. No DLTs occurred and 17 patients experienced cytokine release syndrome (CRS). Two cases of Grade 3 CRS were reported, and all other CRS were Grade 1 or 2. Two Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred. All CRS and ICANS were resolved. No severe gastrointestinal-related AEs were found. No increased toxicities were reported after any reinfusion. No satri-cel treatment-related death occurred. For all patients, the best ORR was 26.3%, the median DOR was 3.7 months and the CBR was 42.1%. The median PFS was 5.2 months, and overall survival was 12.8 months (95% CI 5.7-NE) after leukapheresis, and the median PFS was 3.3 months, and overall survival was 8.9 months (95% CI 3.3-NE) after the first infusion. In the GC/GEJ group, the ORR was 42.9% (3/7), the median DOR was 6.9 months and the CBR was 57.1%. In the PC group, the ORR was 16.7% (2/12), the median DOR was 3.4 months and the CBR was 33.3%. An ORR of 42.9% (3/7) and a CBR of 71.4% were reported at the DL3 of 600×106 cells which was selected as RP2D. At DL3, one GC patient achieved a CR and two PC patients had PR, suggesting the PC group achieved an ORR of 40% (2/5) and the GC group achieved an ORR of 50% (1/2). In addition, tumor shrinkage was detected in 73.7 % (14/19) of patients. Conclusions: The safety profile and therapeutic efficacy of satri-cel were shown to be promising in heavily pretreated patients with CLDN18.2-positive advanced GC/GEJ and PC . In the Phase 2 study, the first patient with GC received satri-cel in May 2023. Clinical trial information: NCT04404595 .

TPS4149 Background: Patients with advanced gastric cancer experience a 5 year survival rate <10% even with multimodality therapy representing a clear unmet need for improved treatment. In advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma, ramucirumab (a monoclonal antibody against VEGFR2) has demonstrated clinical activity and has been approved as second line therapy in combination with paclitaxel with a response rate of 28% and absolute overall survival benefit of 8 weeks when compared to placebo. However, there are many patients that cannot tolerate paclitaxel due to prior exposure to oxaliplatin causing neuropathy. Therefore, novel combinations with ramucirumab, is highly desirable. TAS-102 is an oral cytotoxic agent with two active components; trifluridine (TFD) which inhibits tumor cell growth by being incorporated into DNA during DNA synthesis and tipiracil (TPI) which inhibits the metabolism of TFD, thereby prolonging its ability to exert effect. TPI also inhibits platelet derived endothelial cell growth factor which plays a key role with VEGF in tumor angiogenesis. The combination of a cytotoxic agent with an antiangiogenic agent has demonstrated a significant anticancer activity in multiple cancers. In a recent Phase III study, TAS-102 significantly prolonged overall survival as compared to best supportive care in patients with GEJ and gastric cancers that had received at least 2 prior lines of treatment. We hypothesize that a combination of TAS-102 and ramucirumab might increase efficacy without causing unmanageable toxicity. Methods: This is a single institutional phase II single arm two-stage design trial using the combination of TAS-102 and ramucirumab in advanced, refractory gastric or GEJ adenocarcinoma. Eligible patients include those with histologically confirmed gastric or GEJ adenocarcinoma that have received at least 1 prior line of treatment with performance status 0 or 1 and preserved organ function. Ramucirumab will be administered 8mg/kg every 2 weeks and TAS-102 at doses of 35 mg/m2 twice daily. Each cycle length will be 28 days. The primary endpoint is 6 month OS and secondary endpoints are safety, objective response rate and PFS. Fifteen patients will be enrolled in the first stage. If ≥ 7 of the 15 are alive at 6 months, an additional 10 patients will be enrolled in the second phase. Enrollment is currently ongoing. Clinical trial information: NCT03686488.