A phase Ib study of sEphB4-HSA combined with first-line chemotherapy in patients (pts) with advanced pancreatic (PC) and biliary cancers (BC).

Abstract

4640 Background: EphB4, a receptor kinase expressed in most epithelial tumors, binds EphrinB2 to affect cancer cell growth, apoptosis and angiogenesis. EphB4 overexpression is associated with advanced stage and shorter survival in multiple cancers. sEphB4-HSA, the albumin-bound extracellular fragment of EphB4, is a first-in-class inhibitor which blocks EphB4-EphrinB2 bidirectional signaling and results in downstream suppression of KRAS, PI3K, and promotes recruitment of CD3 and CD8 T cells into the tumor. The RP2D of sEphB4-HSA is 10 mg/Kg IV q week. Here, we report on sEphB4-HSA in combination with standard first-line chemotherapy. Methods: Pts with advanced PC or BC and no prior therapy for metastatic disease were eligible and enrolled into separate cohorts. Pts with PC received gemcitabine 1,000 mg/m2 + nab-paclitaxel 125 mg/m2 on Days 1, 8, 15 of a 28-day cycle. Pts with BC received gemcitabine 1,000 mg/m2 + cisplatin 25 mg/m2 on Days 1, 8 of a 21-day cycle. sEphB4-HSA 10 mg/kg IV was given weekly starting in Cycle 2. Response was assessed every 2 cycles. Primary endpoint was safety and tolerability; secondary endpoints were objective response rate (ORR) by RECIST 1.1, PFS, OS. Expression of EphrinB2 and EphB4 in tumor was examined by IHC and classified as 1+ (weak staining); 2+ (moderate staining); 3+ (strong, uniform staining). Results: A total of 44 pts with advanced PC (n = 21) and BC (n = 23; 70% gallbladder cancer) were enrolled. Median age 66 yrs; ECOG 1 (70%), 52% male. Median number of cycles received were 5 (PC) and 7 (BC). Median PFS was 5.6 mo in PC and 5.8 mo in BC (95% CI: 3.1-8.1 [PC]; 2.7-7.0 [BC]). Median OS was 7.9 mo in PC and 9.1 mo in BC (95% CI: 6.5-15.0 [PC]; 5.4-15.0 [BC]). In response evaluable pts (20 PC, 22 BC), ORR was 40% in PC (95% CI: 21%, 63%) and 23% in BC (95% CI: 9%, 45%). Stable disease was noted in 48% of PC and 61% of BC pts. The most common grade 3 or 4 treatment-related AEs in ≥10% of pts in both cohorts combined were hypertension (n = 16; 36%), neutropenia (n = 15; 34%), anemia (n = 14; 32%), thrombocytopenia (n = 7, 16%), fatigue (n = 7, 16%). In the PC cohort, there was an association between EphB4 expression and objective response (p = 0.009). Conclusions: sEphB4-HSA has a manageable safety profile in combination with chemotherapy in pts with PC and BC. Clinical activity is manifested by a high disease control rate in both cohorts and a promising RR in PC. Additional biomarker analyses will be presented. Future studies combining chemoimmunotherapy with sEphB4-HSA in pancreatic cancer are planned. Clinical trial information: NCT02495896 .