Efficacy of lenvatinib (LEN) vs sorafenib (SOR) in the first-line (1L) treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC): A post hoc analysis of patients with nonviral etiology from REFLECT.
Authors: Baron Ari David , López López Carlos , Chang Stephen Lam , Piscaglia Fabio , Ramji Zahra , Ren Min , Estenson Kasey , Vogel Arndt , Gholam Pierre 
Published: June 2023

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Background: The randomized phase 3 REFLECT trial demonstrated that LEN was non-inferior to SOR in overall survival (OS; primary endpoint) in 1L uHCC (median: 13.6 months [95% CI, 12.1–14.9] vs 12.3 months [95% CI, 10.4–13.9]) (HR, 0.92; 95% CI, 0.79–1.06). Median progression-free survival (PFS) by independent imaging review (IIR) per mRECIST was 7.3 months (95% CI, 5.6–7.5) for pts in the LEN arm and 3.6 months (95% CI, 3.6–3.7) for pts in the SOR arm (HR, 0.64; 95% CI, 0.55–0.75; p<0.0001). Objective response rate (ORR) by IIR per mRECIST was 40.6% for pts in the LEN arm and 12.4% for pts in the SOR arm (odds ratio, 5.01; 95% CI, 3.59–7.01; p<0.0001) [Kudo 2018, Lancet]. Since REFLECT, combination therapies with immunotherapy have become part of the therapeutic arsenal for the treatment of uHCC, and many studies are ongoing. Recent data suggest that viral/nonviral etiology may impact treatment outcomes [Pfister 2021, Nature; Rimini 2022, ESMO Open]. To add to the current body of evidence, this post hoc analysis evaluated efficacy in pts with nonviral etiology in REFLECT. Methods: In REFLECT, pts with uHCC who had not received treatment for advanced disease were randomized to LEN (12 mg/day for bodyweight ≥60 kg; 8 mg/day for bodyweight <60 kg) or SOR (400 mg twice-daily) in 28-day cycles. This post hoc analysis included pts without hepatitis B or C (based on medical history) who were randomized to receive LEN or SOR. PFS, ORR (by IIR per mRECIST), and OS were analyzed. OS and PFS were estimated with the Kaplan-Meier method. Results: Of 478 pts randomized to LEN and 476 pts randomized to SOR, 127 and 108 pts, respectively, had nonviral etiology. Among randomized pts with nonviral etiology, median OS was 13.8 mos (95% CI, 10.5–18.7) in the LEN arm and 13.9 months (95% CI, 11.7–17.5) in the SOR arm (HR, 1.03; 95% CI, 0.75–1.43). Median PFS was 7.4 months (95% CI, 5.5–8.7) in pts randomized to LEN with nonviral etiology and 4.0 months (95% CI, 3.6–5.5) in pts randomized to SOR with nonviral etiology (HR, 0.60; 95% CI, 0.42–0.87). ORR was 39.4% (95% CI 30.9–47.9) in pts randomized to LEN with nonviral etiology and 20.4% (95% CI 12.8–28.0) in pts randomized to SOR with nonviral etiology. Fewer (n=34 [26.8%]) pts with nonviral etiology randomized to LEN received anticancer medication during survival follow-up than those randomized to SOR (n=46 [42.6%]). Conclusions: In this post hoc analysis, OS, PFS, and ORR in pts randomized to LEN with nonviral etiology were consistent with the overall population of pts randomized to LEN. This post hoc analysis, along with the results of the primary analysis of REFLECT [Kudo 2018, Lancet], demonstrates the efficacy of LEN regardless of etiology in uHCC, and supports LEN as a standard of care option for pts with 1L uHCC. Treatment efficacy by etiology should be assessed prospectively in future uHCC trials. Clinical trial information: NCT01761266 .