The trial design did not differ much from the original REACH trial except for restricting enrollment to patients with AFP levels 400 ng/mL and including gross vascular invasion as a stratification factor. sorafenib. A recent phase III trial (IMbrave150) showed that combination immunotherapy with atezolizumab plus bevacizumab increases overall survival compared with sorafenib therapy; Food and Drug Agency already approved this combination therapy, and worldwide approval is expected soon. This review describes the recent advances in systemic therapy and the use of tyrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib, and cabozantinib), monoclonal antibodies (ramucirumab and bevacizumab), and immune checkpoint inhibitors (nivolumab, pembrolizumab, and atezolizumab) in elderly patients and the similarity of their efficacy and safety Asapiprant profiles to those in the general population. = 185) and the propensity-matched cohort (= 48). Ziogas et al. [40] reported similar results, showing that the safety and efficacy of sorafenib did not differ between elderly patients (75 years) (= 39) and nonelderly patients ( 75 years) (= 151). In a propensity-matched study, Nishikawa et al. [41] reported that OS in elderly patients (80 years) Mouse monoclonal to CD3/HLA-DR (FITC/PE) (= 132) was similar to that in nonelderly patients ( 80 years) (= 132) (9.3 and 8.8 months, respectively; = 0.8247). PFS in elderly patients was also similar to that in nonelderly patients (3.8 [95% CI: 2.2C5.4] and 3.4 [95% CI: 3.1C3.7] months, respectively, = 0.668). DCR and ORR were also similar in both age subgroups. Treatment-related grade 3 or higher serious AEs were observed in 28.5% of elderly patients and 24.7% of nonelderly patients (= 0.385). Therefore, the authors concluded that there were no significant differences in efficacy and safety between elderly and nonelderly patients. However, Williet et al. [42] reported that tolerability to sorafenib is low in elderly patients (80 years) and OS is poor in elderly patients (85 years). Similarly, Morimoto et al. [43] reported higher discontinuation rates and lower OS in elderly patients (75 years) (= 24) than in nonelderly patients (= 52) with a starting dose of sorafenib of Asapiprant 800 mg. However, safety and efficacy were comparable between the elderly and nonelderly populations treated with a half-dose regimen, which is consistent with the results reported by Montella et al. [44]. Lenvatinib: Overview of the REFLECT Trial Results The REFLECT trial was the first positive phase III clinical trial in the first-line setting undertaken during a 10-year period in which 8 other trials were negative. Lenvatinib is an oral kinase inhibitor that selectively inhibits receptor tyrosine kinases involved in tumor angiogenesis and malignant transformation (e.g., VEGFR1, VEGFR2, VEGFR3, fibroblast growth factor receptor [FGFR]1, FGFR2, FGFR3, FGFR4, PDGFR, KIT, and RET). Because it is a particularly strong inhibitor of FGFR4, it is useful for treating high malignancy grade or poorly differentiated HCC. A single-arm phase II trial of lenvatinib in advanced HCC showed excellent results: the time to progression (TTP) was 7.4 months and OS was 18.7 months [45]. This was followed by the phase III REFLECT trial comparing sorafenib and lenvatinib [16]. The REFLECT trial was a global phase III trial assessing the noninferiority of lenvatinib to sorafenib. Patients were randomized to a lenvatinib or a sorafenib arm at a 1:1 ratio and stratified by ethnicity (Asian or non-Asian), vascular invasion and/or EHS (presence or absence), Eastern Cooperative Oncology Group performance status (ECOG PS; 0 or 1), and body weight ( 60 or 60 kg). Noninferiority of OS was set as the primary endpoint, and the noninferiority margin was set at 1.08. PFS, TTP, ORR, and safety were evaluated as secondary endpoints. Asapiprant The proportion of patients with HCC caused by hepatitis C was balanced in favor of the sorafenib arm (27 vs. 19% in the lenvatinib arm) [16]. Conversely, the proportion of patients in the lenvatinib arm with HCC caused by hepatitis B was 53% compared with 48% in the sorafenib arm. The proportion of patients with alpha-fetoprotein (AFP) levels 200 ng/mL was also balanced favorably toward the sorafenib arm (39 vs. 46% in the lenvatinib arm). The primary endpoint for OS was 13.6 months in the lenvatinib arm and 12.3 months in the sorafenib arm. The upper limit of the 95% CI of the HR was 0.92 (0.79C1.06) and was below the prespecified noninferiority margin of 1 1.08, which demonstrated statistically the noninferiority of lenvatinib with respect to OS [16]. PFS (7.4 months in the lenvatinib arm vs. 3.7 months in the sorafenib arm), TTP (8.9 vs. 3.7 months), and ORR (24.1 vs. 9.2%) per investigator assessment using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) were better in the lenvatinib arm than in the sorafenib arm (odds ratio [OR].