Post hoc analysis in patients with unresectable hepatocellular carcinoma who progressed to Child-Pugh B liver function in the phase 3 REFLECT study of lenvatinib vs sorafenib

Background The treatment landscape for patients with unresectable hepatocellular carcinoma (uHCC) has recently expanded. However, there is an unmet need for effective treatment options in patients with Child-Pugh (CP) B liver function. Lenvatinib is approved first-line in uHCC based on the REFLECT study results, which evaluated lenvatinib versus sorafenib (patients with CPA liver function were allowed, per inclusion criteria). In a prior analysis of REFLECT, patients treated with lenvatinib benefited irrespective of baseline liver function (ALBI grade 1 or 2; CP score 5 or 6). To determine outcomes in patients with reduced liver function, we conducted a post hoc analysis of patients from REFLECT who progressed to CPB (“CPB patients”) and those who did not (“CPA patients”) within the first 8 weeks of treatment. Methods In REFLECT, patients with uHCC were randomly assigned 1:1 to lenvatinib (per bodyweight: 12 mg/day for ≥60 kg; 8 mg/day for < 60 kg) or sorafenib (400 mg twice daily) in 28-day cycles. Here, we assessed objective response rate (ORR) along with landmark analyses (starting at week 8) of progession-free survival (PFS) and overall survival (OS) in CPB patients and in those who remained CPA, 8 weeks postrandomization. Tumors were assessed by mRECIST by independent imaging review. Safety was assessed from baseline, and adjusted by treatment duration. Results This analysis included patients in the lenvatinib arm (CPB, n=60 and CPA, n=413) and the sorafenib arm (CPB, n=47 and CPA, n=427). In the lenvatinib arm, ORR was 28.3% (95% CI 16.9-39.7) for CPB patients and 42.9% (95% CI 38.1-47.6) for CPA patients; in the sorafenib arm, ORR was 8.5% (95% CI 0.5-16.5) for CPB patients and 12.9% (95% CI 9.7-16.1) for CPA patients. A landmark analysis (starting at week 8) in the lenvatinib arm showed a median PFS of 3.7 months (95% CI 1.8-7.4) and 6.5 months (95% CI 5.6-7.4) for CPB and CPA patients, respectively; in the sorafenib arm, median PFS was 0.5 months (95% CI 0.1-3.6) and 3.6 months (95% CI 2.7-3.7) for CPB and CPA patients, respectively. In a landmark OS analysis, median OS was 6.8 months (95% CI 2.6-10.3) for CPB patients and 13.3 months (95% CI 11.6-16.1) for CPA patients in the lenvatinib arm; in the sorafenib arm, median OS was 4.5 months (95% CI 2.9-6.1) for CPB patients and 12.0 months (95% CI 10.2-14.0) for CPA patients. In CPB and CPA patients, median durations of treatment were 3.2 months and 6.9 months in the lenvatinib arm, respectively; and 1.9 months and 3.7 months in the sorafenib arm, respectively. Among CPB and CPA patients, the adverse event (AE) rates (number of AE episodes per patient-year) for grade ≥3 treatment-related AE episodes in the lenvatinib arm were 3.65 and 1.41, respectively; and 3.38 and 1.71, respectively, in the sorafenib arm. Conclusions This post hoc analysis is limited by its descriptive nature; however, the results indicate that patients with uHCC whose liver function deteriorates to CPB after initiation of therapy may continue to receive lenvatinib, and further study of lenvatinib in CPB patients with uHCC is warranted. Clinical trial identification ClinicalTrials.gov number: NCT01761266. Editorial acknowledgement Medical writing support was provided by Oxford PharmaGenesis Inc., Newtown, PA, USA, and was funded by Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding This study was sponsored by Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure M. Cho: Advisory / Consultancy: Eisai, Bayer; Travel / Accommodation / Expenses: Eisai. E. Kim: Speaker Bureau / Expert testimony: Eisai. M. Ren: Full / Part-time employment: Eisai Inc. C. Amaya-Chanaga: Full / Part-time employment: Eisai, Inc. A. Vogel: Honoraria (self): Daiichi Sankyo, AstraZeneca; Advisory / Consultancy: Daiichi Sankyo, AstraZeneca. The other author has declared no conflicts of interest.