PD-010A multi-cohort phase 1 study of ramucirumab plus durvalumab: Preliminary safety and clinical activity in patients with locally advanced and unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma

Introduction: Hallmarks of tumor growth include angiogenesis and immunosuppression. Simultaneously blocking VEGFR-2 and the PD-1/PD-L1 pathway demonstrates a synergistic antitumor effect in preclinical cancer models. This global phase 1 trial evaluates the combination of ramucirumab (R; anti-vascular endothelial growth factor receptor 2 antibody) and durvalumab (D; anti-programmed death ligand-1 antibody) in patients with locally advanced and unresectable or metastatic gastrointestinal or thoracic malignancies. Methods: This ongoing, multi-cohort, phase 1a/b trial (NCT02572687) is enrolling patients with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma following progression on 1 – 2 lines of prior systemic therapy. Eligibility requires measurable disease, ECOG PS 0-1, and baseline tumor tissue. Enrolled patients received R (8 mg/kg IV) and D (750 mg IV) every two weeks on a 28-day cycle, and were treated to confirmed progression. The primary objective is to assess the safety and tolerability of R in combination with D. Preliminary efficacy and PD-L1 expression will also be examined. Results: As of 12-Dec-2016, 26 G/GEJ patients were treated, of whom 5 patients initiated treatment less than 12 weeks prior to the data cut-off date. Median age was 55 years, 73% were male, 65% had an ECOG PS of 1, and 73% received study treatment as second line for advanced disease. Median duration on treatment was 2.3 months for R and 2.4 months for D, with treatment ongoing in 13 patients. Treatment-emergent adverse events (TEAEs) occurred in 23 (88%) patients; 12 (46%) patients experienced grade 3/4 TEAEs. Treatment-related adverse events (TRAEs) occurred in 17 (65%) patients; 5 (19%) patients experienced grade 3 TRAEs with no grade 4 or 5 TRAEs reported. All grade TRAEs occurring in ≥ 10% of patients were hypertension (35%), headache (27%), diarrhea (23%), fatigue (23%), and pyrexia (12%). Grade 3 TRAEs included hypertension (n = 4) and proteinuria (n = 1), which was also a serious adverse event (SAE). One additional treatment-related SAE, a grade 2 diarrhea, was also reported. Preliminary efficacy data showed 4/26 patients had confirmed partial response, 8/26 patients had stable disease, and 11/26 patients had progressive disease as their best response. Three patients were not evaluable for response at the time of analysis. The median time to response was 1.5 months and three of the four responders remain on treatment. As of data cut-off, 13 patients discontinued (all due to progressive disease). Conclusion: The combination of R+D generated no new safety signals and demonstrated antitumor activity in patients with previously treated advanced G/GEJ adenocarcinoma.