Abstract CT170: A phase 1/2 study of olaparib in combination with ramucirumab in metastatic gastric and gastroesophageal junction adenocarcinoma (GEJ)
Authors: Cecchini Michael , Chao Joseph , Shyr Yu , Cleary James , Uboha Nataliya , Cho May , Shields Anthony , Pant Shubham , Goff Laura , Spencer Kristin , Kim Edward , Hsu Chih-Yuan , Stein Stacey , Thumar Jaykumar , Kortmansky Jeremy , Kunstman John , LoRusso Patricia , Ivy Percy , Lacy Jill 
Published: June 2022

Abstract
Background: Ramucirumab is a monoclonal antibody that binds to the vascular endothelial growth factor receptor 2, increasing hypoxia in the tumor microenvironment. In advanced gastric cancer, single agent ramucirumab is well tolerated and improves overall survival (OS) compared to placebo although it is largely cytostatic with a response rate ≤3%. Preclinical in vitro and in vivo experiments reveal that hypoxia induces homologous recombination deficiency (HRD) in tumors, which may be exploited by the addition of inhibitors of poly (ADP-ribose) polymerase (PARPi). We thus designed NCI10066 for metastatic gastric cancer with the hypothesis that ramucirumab would sensitize tumors to the PARPi olaparib.
Methods: NCI 10066 (NCT03008278) was a phase 1/2, multicenter, open-label clinical trial sponsored by the Cancer Therapy Evaluation Program. Eligible patients had histologically confirmed metastatic gastric or GEJ adenocarcinoma with measurable disease refractory to ≥ 1 prior therapy that did not contain ramucirumab. Patients were treated with escalating doses of olaparib with ramucirumab 8 mg/kg every 2 weeks in a 3+3 design. Dose escalation evaluated two dose levels: olaparib 200 mg twice daily with ramucirumab 8 mg/kg every 2 weeks (dose level 1) and olaparib 300 mg twice daily with ramucirumab 8 mg/kg every 2 weeks (dose level 2). The primary objective of dose escalation was to assess safety and measure dose limiting toxicities (DLT) to determine the recommended phase 2 dose (RP2D). The primary objective in phase 2 was to evaluate clinical activity at the RP2D in a 40-patient expansion cohort.
Results: From 2/8/18 - 9/17/21, 51 patients were enrolled at 10 centers throughout the Experimental Therapeutics Clinical Trials Network and 28/51 (55%) patients had ≥2 prior lines of therapy. In dose escalation 3 patients were treated at dose level 1 and 8 at dose level 2. No DLTs were observed at dose level 1 and at dose level 2 there was 1 DLT (fatigue) in 6 evaluable patients. The RP2D was determined to be olaparib 300 mg twice daily and ramucirumab 8 mg/kg every 2 weeks. Forty patients were treated in dose expansion at the RP2D. Of 46 patients evaluable for a response there were 5/46 (11%) partial responses (PR) and the disease control rate (PR/SD) was 29/46 (63%) at 6 weeks. The median progression free survival (PFS) was 2.8 months (95% CI 2.3 - 4.2) and the median OS was 7.3 months (95% CI 5.6 - 13.0). Grade ≥ 3 treatment related adverse events were seen in 13 (25%) of patients and there were no treatment related deaths.
Conclusions: The combination of olaparib and ramucirumab is well tolerated with a RP2D of olaparib 300 mg twice daily and ramucirumab 8 mg/kg every 2 weeks. The ORR, PFS, and OS exceed the historical control with ramucirumab monotherapy, suggesting that the combination is clinically active. Biomarkers are critical to defining patient subsets more likely to benefit from the combination and HRD biomarker analysis is ongoing.
Citation Format: Michael Cecchini, Joseph Chao, Yu Shyr, James Cleary, Nataliya Uboha, May Cho, Anthony Shields, Shubham Pant, Laura Goff, Kristin Spencer, Edward Kim, Chih-Yuan Hsu, Stacey Stein, Jaykumar Thumar, Jeremy Kortmansky, John Kunstman, Patricia LoRusso, Percy Ivy, Jill Lacy. A phase 1/2 study of olaparib in combination with ramucirumab in metastatic gastric and gastroesophageal junction adenocarcinoma (GEJ) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT170.