SAFFRON-104: a phase Ib/II study of sitravatinib alone or with tislelizumab in advanced hepatocellular carcinoma and gastric cancer/gastroesophageal junction cancer
**Background:** Sitravatinib is a selective tyrosine kinase inhibitor that targets TAM receptors (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. The SAFFRON-104 trial (NCT03941873) was a multicohort phase Ib/II study evaluating sitravatinib, both alone and in combination with tislelizumab, an anti-PD-1 antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric/gastroesophageal junction cancer (GC/GEJC).
**Methods:** Eligible participants had histologically or cytologically confirmed advanced HCC or GC/GEJC. Phase I aimed to determine the recommended phase II dose (RP2D) of sitravatinib, with or without tislelizumab. In Phase II, sitravatinib monotherapy was evaluated in pretreated HCC patients, and the combination of sitravatinib and tislelizumab was assessed in anti-PD-(L)1-naïve or -treated HCC and anti-PD-(L)1-naïve GC/GEJC patients. The primary endpoints were safety and tolerability in Phase I, and the objective response rate (ORR) in Phase II.
**Results:** As of the data cutoff on March 31, 2023, 111 patients were enrolled, with 102 evaluable for efficacy (median follow-up of 9.1 months, ranging from 0.7 to 36.9 months). The RP2D for sitravatinib was established as 120 mg once daily. Among patients receiving sitravatinib monotherapy, 14 (51.9%) experienced grade ≥3 treatment-related adverse events, while 42 (50.0%) of those receiving the combination therapy had similar events. The ORR for sitravatinib monotherapy in pretreated HCC patients was 25% (95% confidence interval [CI]: 8.7-49.1). For patients treated with sitravatinib and tislelizumab, the ORR was 11.5% (95% CI: 2.4-30.2) in anti-PD-(L)1-naïve HCC, 9.5% (95% CI: 1.2-30.4) in anti-PD-(L)1-treated HCC, and 16.1% (95% CI: 5.5-33.7) in anti-PD-(L)1-naïve GC/GEJC.
**Conclusions:** Sitravatinib, with or without tislelizumab, was generally well tolerated and showed early signs of antitumor activity in patients with advanced HCC and GC/GEJC.