Background: Inhibition of the vascular endothelial growth factor receptor-2 (VEGFR-2) blocks angiogenesis and attenuates tumor growth, but cancers may evade this effect through activation of MET, the hepatocyte growth factor (HGF) receptor. Preclinical data suggest that co-targeting VEGFR and MET/HGF leads to greater tumor shrinkage when compared to a VEGFR blockade alone. Here we report the safety and clinical activity observed during dose escalation and tumor-specific expansion cohorts for the combination of the anti-VEGFR-2 antibody ramucirumab (R) and emibetuzumab (E), a bivalent monoclonal anti-MET antibody that inhibits ligand-dependent and ligand-independent MET signaling (NCT02082210).
Methods: Patients (pts) with advanced solid tumors, measurable disease, and a fresh pretreatment tumor biopsy were enrolled in a Phase 1b/2 study receiving either 750 or 2000 mg E in combination with 8 mg/kg R, both intravenously administered every two weeks (Q2W). Following dose escalation, pts were assigned to tumor-specific expansion cohorts including gastric/gastroesophageal junction adenocarcinoma (G/GEJ), renal cell cancer (RCC), and non-small cell lung cancer (NSCLC). The primary objective was to determine the dose range of E that can be safely given in combination with R. Additional objectives included evaluation of anti-tumor activity by RECIST v1.1, pharmacokinetic (PK) parameters, immunogenicity, and biomarkers for MET/HGF and VEGF pathways.
Results: As of Sept 2016, 6 pts were treated in the dose escalation and 45 pts in the cohort expansions (n=17 G/GEJ, n=15 RCC, n=13 NSCLC) with a median of 2 prior systemic therapies (range 1-7). No dose-limiting toxicities were observed in the dose escalation, and 750 mg E and 8 mg/kg R were recommended for the tumor expansion in line with the recommended phase 2 dose in other ongoing E phase 2 studies. Common possibly related AEs of all grades included fatigue (33%), nausea (20%), and dyspnea (16%). Grade 3 or higher AEs observed in more than 1 patient were fatigue (n=3) and pulmonary embolism (n=3). Disease control rates in the cohort expansions for G/GEJ, RCC, and NSCLC pts were 53%, 47%, and 85%, respectively. Unconfirmed partial responses were observed in an ovarian and a gastric pt. The median progression-free survival was: 2.73 months (95% CI: 1.35, 4.60) in the G/GEJ cohort, 4.17 months (95% CI: 1.18, 7.39) in the RCC cohort, and 6.57 months (95% CI: 2.76, 10.61) in the NSCLC cohort. Pretreatment tumoral MET expression and other biomarker analyses are ongoing and will be presented at the meeting.
Conclusions: Treatment with E at a dose of 750 or 2000 mg can be safely administered with 8 mg/kg R Q2W with minimal toxicity and shows a potential to stabilize disease in G/GEJ, RCC, and NSCLC pts.
Citation Format: Johanna Bendell, Charles Fuchs, Martin Voss, Todd M. Bauer, Toni K. Choueiri, Alexander Drilon, Katharine Thorn, Sameera Wijayawardana, Brian Moser, Arantxa Uruñuela, Volker Wacheck, James J. Harding. A phase 1b/2 study of ramucirumab in combination with emibetuzumab in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT090. doi:10.1158/1538-7445.AM2017-CT090