SAFFRON-104: a phase Ib/II study of sitravatinib alone or with tislelizumab in advanced hepatocellular carcinoma and gastric cancer/gastroesophageal junction cancer

Abstract

Background: Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC).

Methods: Eligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1-naïve or -treated HCC and anti-PD-(L)1-naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II).

Results: At data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7-36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7-49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4-30.2) with anti-PD-(L)1-naïve HCC, 9.5% (95% CI 1.2-30.4) with anti-PD-(L)1-treated HCC, and 16.1% (95% CI 5.5-33.7) in patients with anti-PD-(L)1-naïve GC/GEJC.

Conclusions: Sitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC.

Keywords: Clinical trials; Combination therapy; Drug therapy; Immune checkpoint inhibitors; Immunotherapy; Phase II.

Fig. 1

Patient flow. ^aAfter the study was terminated by the sponsor, all patients who were still on treatment were transferred to the long-term extension study to continue treatment as assigned

Fig. 2

Best percent change from baseline in target lesion sum of diameters by best confirmed overall response (efficacy-evaluable population from phase I and phase II). Best percent change from baseline in target lesion sum of diameters in A sitravatinib-treated patients with anti-PD-(L)1–naïve or –treated HCC; B sitravatinib with tislelizumab–treated patients with anti-PD-(L)1–naïve HCC; C sitravatinib with tislelizumab–treated patients with anti-PD-(L)1–treated HCC; D sitravatinib with tislelizumab–treated patients with anti-PD-(L)1–naïve GC/GEJC. Responses are investigator-assessed based on RECIST v1.1. GC/GEJC gastric cancer/gastroesophageal junction cancer, HCC hepatocellular carcinoma, PD-1 programmed cell death protein 1, PD-L1 programmed death-ligand 1, RECIST Response Evaluation Criteria in Solid Tumors

Fig. 3

Progression-free survival (safety analysis set from phase I and phase II). KM plot of PFS in A sitravatinib-treated patients with anti-PD-(L)1–naïve or –treated HCC; B sitravatinib with tislelizumab–treated patients with anti-PD-(L)1–naïve and –treated HCC; C sitravatinib with tislelizumab–treated patients with anti-PD-(L)1–naïve GC/GEJC. Four patients with GC/GEJC cancer in phase I were excluded, either due to unknown prior anti-PD-(L)1 treatment status or because they received sitravatinib monotherapy. CI confidence interval, GC/GEJC gastric cancer/gastroesophageal junction cancer, HCC hepatocellular carcinoma, KM Kaplan–Meier, PD-1 programmed cell death protein 1, PD-L1 programmed death-ligand 1, PFS progression-free survival, Sitra sitravatinib, Tisle tislelizumab

Fig. 4

Overall survival (safety analysis set from phase II only). KM plot of OS in A sitravatinib-treated patients with anti-PD-(L)1–naïve or –treated HCC; B sitravatinib with tislelizumab–treated patients with anti-PD-(L)1–naïve and –treated HCC; C sitravatinib with tislelizumab–treated patients with anti-PD-(L)1–naïve GC/GEJC. CI confidence interval, GC/GEJC gastric cancer/gastroesophageal junction cancer, HCC hepatocellular carcinoma, KM Kaplan–Meier, NE not estimable, OS overall survival, PD-1 programmed cell death protein 1, PD-L1 programmed death-ligand 1, Sitra sitravatinib, Tisle tislelizumab