Background
Sitra, a spectrum-selective tyrosine kinase inhibitor, may enhance the efficacy of programmed cell death protein 1 (PD-1) inhibition. TIS, an anti-PD-1 antibody, has demonstrated efficacy in multiple advanced solid tumors. SAFFRON-104 is a multi-cohort Ph 1/2 study investigating sitra +/- TIS in patients (pts) with advanced HCC or GC/GEJC (NCT03941873).
Methods
Eligible pts had histologically/cytologically confirmed unresectable locally advanced or metastatic HCC or GC/GEJC. Pts enrolled in Ph 1 (dose escalation) received free base sitra (80 or 120 mg orally once daily) alone or combined with TIS (200 mg IV once every 3 weeks); Ph 1 determined the recommended Ph 2 dose (RP2D). Ph 2 evaluated sitra alone in pts with HCC who were naïve or refractory/resistant (R/R) to anti-PD-(L)1 therapy and sitra + TIS in pts with anti-PD-1/programmed death-ligand 1 (PD-L1)-naïve HCC, anti-PD-(L)1 R/R HCC, and anti-PD-(L)1-naïve GC/GEJC. Primary endpoints were safety/tolerability (Ph 1) and objective response rate (ORR) by RECIST v1.1 (Ph 2). Secondary endpoints included disease control rate (DCR), duration of response (DoR), and progression-free survival (PFS).
Results
As of Jan 4, 2023, 111 pts were enrolled, of whom 102 were efficacy-evaluable (median study follow-up 9.1 months [range 0.7-34.0]). The RP2D of sitra determined in Ph 1 was 120 mg orally once daily. In pts receiving sitra +/- TIS, respectively, any-grade treatment-related adverse events (TRAEs) were reported in 74 (89.2%) and 24 (100%); ≥grade 3 TRAEs in 37 (44.6%) and 13 (54.2%); and serious TRAEs in 19 (22.9%) and 6 (25.0%). TRAEs leading to treatment discontinuation were reported in 10 (12.0%) pts and 1 (4.2%) pt receiving sitra +/- TIS, respectively. Pooled efficacy data from Ph 1 and 2 by indication are shown in the Table.
Conclusions
Sitra +/- TIS was generally well tolerated and showed preliminary antitumor activity in pts with advanced HCC and GC/GEJC.
Table: 948P
| HCC | GC/GEJCa |
| Treatment | Sitra | Sitra + TIS | Sitra + TIS |
| Prior anti-PD-(L)1 treatment | Naïve or R/R (n=20) | Naïve (n=26) | R/R (n=21) | Naïve (n=31) |
| ORR, n (%) | 5 (25.0) | 3 (11.5) | 2 (9.5) | 5 (16.1) |
| DCR, n (%) | 18 (90.0) | 22 (84.6) | 17 (81.0) | 22 (71.0) |
| Median DoR, mo (95% CI) | 7.7 (2.8, NE) | 5.7 (4.1, NE) | NR (5.4, NE) | 5.5 (2.7, NE) |
| Median PFS, mo (95% CI) | 6.8 (4.0, 7.4) | 6.8 (2.8, 8.3) | 4.2 (2.7, 6.8) | 3.6 (2.8, 4.7) |
Efficacy analysis set. aFour patients with GC/GEJC enrolled in Ph 1 were not included in the efficacy or safety analysis by indication because they were either anti-PD-(L)1 R/R or received sitra monotherapy. CI, confidence interval; mo, months; NE, not estimable; NR, not reached.
Clinical trial identification
NCT03941873 (first posted July 05, 2018).
Editorial acknowledgement
This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Emily Finn, MSc, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd.
Legal entity responsible for the study
BeiGene, Ltd.
Funding
BeiGene, Ltd.
Disclosure
J. Li: Non-Financial Interests, Member: ASCO, CSCO. F. Yu, J. Zhang, Z. Zhang: Financial Interests, Full or part-time Employment: BeiGene. All other authors have declared no conflicts of interest.
