Anti-programmed death-1 antibody SHR-1210 (S) combined with apatinib (A) for advanced hepatocellular carcinoma (HCC), gastric cancer (GC) or esophagogastric junction (EGJ) cancer refractory to standard therapy: A phase 1 trial.

Abstract

4075 Background: A phase 1 (P1) study to assess the safety and efficacy of combination of S, a fully human IgG4 monoclonal antibody against PD-1 with PD-L1/PD-L2 plus Apatinib (A), a VEGFR2 inhibitor in patients (pts) with advanced HCC, GC, EGJ cancer. Methods: In P 1a dose escalation, pts received A (125, 250, 500mg, QD, 5 pts per cohort) and S (200 mg, Q2W) until unacceptable toxicity, disease progression. In phase 1b cohort expansion, pts received A at recommended P2 dose (RP2D) + S (200 mg, Q2W). Response was evaluated by RECIST v1.1. Results: At the cut-off data (Feb. 2. 2018), 42 pts (P 1a, n = 15; P 1b, n = 27) were enrolled. Median prior lines of therapy in HCC and GC were 1 and 2, respectively. In P1a stage, 3 DLTs (all grade 3 pneumonia) were observed in A 500mg cohort. The RP2D was A 250mg + S. In P 1b stage, the median treatment duration was 19 wks (range, 2-57 wks). 19 pts (58%) had ≥ grade 3 treatment-related adverse events (TRAEs). The ≥10% grade 3 TRAEs were hypertension (18%), increased AST (15%) and ALT (12%). These AEs were manageable, only 1 pt discontinued treatment due to TR grade 3 hyperbilirubinemia. There were no TR- deaths. The ORR and DCR in 36 evaluable pts in all 3 cohorts were 30.6% (n = 11) and 83.3% (n = 30), respectively. All 11 responses occurred in A 125mg (n = 1) and 250mg (n = 10) cohorts. Among 18 HCC pts (14 evaluable: A 125mg cohort, n = 4; A 250mg cohort, n = 9, A 500mg cohort, n = 1), all infected with HBV. The ORR and DCR were 50.0% and 85.7%, respectively. Notably, 2 pts in A 125mg cohort had initial SD at best response, and achieved PR after escalating A dose to 250 mg, therefore the ORR at A 250 mg dose level was 54.5% (6/11). The median progression-free survival (PFS) was not reached. All 7 pts with PR were still on treatment, 5 lasted for 47 weeks+. Of 24 GC or EGJ cancer pts (22 evaluable: A cohort, 250mg n = 20; 500mg, n = 2), the ORR in A 250mg cohort was 20.0% and DCR was 80.0%. The median PFS was 3.0 months. Conclusions: S + A at RP2D demonstrated manageable toxicity in HCC, GC or EGJ cancer pts. Particularly encouraging clinical activity (PR rate 54.5%) was observed in pts with pretreated, advanced HCC. Clinical trial information: NCT02942329.