ctDNA analysis of patients (pts) with unresectable hepatocellular carcinoma (uHCC) treated with lenvatinib (LEN) or sorafenib (SOR) as 1L therapy.

4094 Background: In REFLECT, LEN had superior ORR and PFS versus SOR in pts with uHCC ( P<0.0001); OS was noninferior. In this post-hoc analysis, we determined baseline mutation (MUT) status by plasma ctDNA and analyzed its association with clinical outcomes. Methods: In REFLECT, pts with untreated uHCC received either LEN 8 or 12 mg daily or SOR 400 mg twice daily. Tumor responses were measured per mRECIST by independent review. Baseline MUT status in ctDNA was measured by a PGDx elio Plasma Complete panel. We explored associations between ctDNA MUT status and ORR via Fisher's exact test or PFS/OS via Cox regression/log rank test. Results: 167 Pts enrolled to LEN and 86 pts enrolled to SOR had evaluable baseline ctDNA. The ctDNA population had a lower % of Asian pts (27% vs 67%) and pts with HBV etiology (27% vs 53%), and a higher % of Western pts (73% vs 33%) and pts with alcohol etiology (14% vs 6%) than the intention to treat (ITT) population. In the ctDNA population, a lower % of pts treated with LEN versus SOR had an AFP of <200 ng/mL (57% vs 70%) and HCV etiology (27% vs 44%); a higher % with LEN versus SOR had HBV etiology (32% vs 17%). In SOR-treated pts, slight differences in the median (m) PFS/mOS were observed between the ITT and ctDNA populations (Table). Among the ctDNA population (n=253), the most frequent MUT genes were TERT(48%), TP53(38%), and CTNNB1(27%). TERT/ CTNNB1MUT rates were higher in SOR-treated pts (56%/40%) than in LEN-treated pts (44%/20%). Gene MUT status was generally not associated with ORR in either arm. Similarly, MUT status was not associated with PFS with LEN; with SOR, pts with TP53 and TERT MUT showed shorter trends in PFS. OS with LEN was shorter in pts with TP53 MUT than WT; OS with SOR was shorter in pts with TERT, TP53,and CTNNB1 MUT. Results of LEN versus SOR by MUT subgroups will be presented. Conclusions: TERT, TP53, and CTNNB1 MUT had little effect on tumor response in either treatment arm; TP53 MUT appeared to be a factor for poor OS prognosis in both arms. Further analysis is needed due to the differences in baseline characteristics between ctDNA and ITT pts, and the difference in sample size between arms. Clinical trial information: NCT01761266 . [Table: see text]