NCI10066: a Phase 1/2 study of olaparib in combination with ramucirumab in previously treated metastatic gastric and gastroesophageal junction adenocarcinoma
Mené sur 51 patients atteints d'un adénocarcinome gastro-oesophagien de stade métastatique, cet essai de phase I/II détermine la dose maximale tolérée de l'olaparib en combinaison avec le ramucirumab puis évalue l'efficacité, du point de vue du taux de réponse globale, de cette combinaison après l'échec d'au moins une ligne thérapeutique
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.