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Master of Public Health

NCI10066: a Phase 1/2 study of olaparib in combination with ramucirumab in previously treated metastatic gastric and gastroesophageal junction adenocarcinoma

AUTHORS

Cecchini M , Cleary JM , Shyr Y , Chao J , Uboha N , Cho M , Shields A , Pant S , Goff L , Spencer K , Kim E , Stein S , Kortmansky JS , Canosa S , Sklar J , Swisher EM , Radke M , Ivy P , Boerner S , Durecki DE , Hsu CY , LoRusso P , Lacy J , . British journal of cancer. 2023 12 22; ().

ABSTRACT

BACKGROUND: Our preclinical work revealed tumour hypoxia induces homologous recombination deficiency (HRD), increasing sensitivity to Poly (ADP-ribose) polymerase inhibitors. We aimed to induce tumour hypoxia with ramucirumab thereby sensitising tumours to olaparib.

PATIENTS AND METHODS: This multi-institution single-arm Phase 1/2 trial enrolled patients with metastatic gastroesophageal adenocarcinoma refractory to ≥1 systemic treatment. In dose escalation, olaparib was evaluated at escalating dose levels with ramucirumab 8 mg/kg day 1 in 14-day cycles. The primary endpoint of Phase 1 was the recommended Phase 2 dose (RP2D), and in Phase 2 the primary endpoint was the overall response rate (ORR).

RESULTS: Fifty-one patients received ramucirumab and olaparib. The RP2D was olaparib 300 mg twice daily with ramucirumab 8 mg/kg. In evaluable patients at the RP2D the ORR was 6/43 (14%) (95% CI 4.7-25.6). The median progression-free survival (PFS) was 2.8 months (95% CI 2.3-4.2) and median overall survival (OS) was 7.3 months (95% CI 5.7-13.0). Non-statistically significant improvements in PFS and OS were observed for patients with tumours with mutations in HRD genes.

CONCLUSIONS: Olaparib and ramucirumab is well-tolerated with efficacy that exceeds historical controls with ramucirumab single agent for gastric cancer in a heavily pre-treated patient population.

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