Comparing the efficacy and safety of second-line therapies for advanced hepatocellular carcinoma: a network meta-analysis of phase III trials

Abstract

Background: The prospect for targeted therapies in advanced hepatocellular carcinoma (HCC) has dramatically changed since several recent clinical trials have yielded promising results. The number of second-line therapies is increasing, though the consequent challenge is to consider differences between these interventions. This is a comparative investigation of presently approved second-line drugs for HCC based on findings from phase III randomized controlled trials. Methods: Data related to treatment efficacy including overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were extracted and compared using a Bayesian approach. Adverse events (AEs) and the rate of discontinuation due to AEs were assessed and compared with provide a more complete understanding. OS and PFS in patients with alpha fetoprotein (AFP) values greater than 400 were compared and ranked as a subgroup. Results: A total of five trials involving 2571 patients were included. The comparison suggests that regorafenib and cabozantinib significantly prolong OS compared with placebo. The rate of AEs and treatment discontinuation did not significantly differ, although the types of AEs varied substantially. Subgroup analysis did not highlight a significant OS difference between regorafenib [hazard ratio (HR) 0.68; 95% confidence interval (CI) 0.50–0.92], cabozantinib (HR 0.71; CI 0.54–0.94) and ramucirumab (HR 0.69; CI 0.57–0.84). Conclusion: Among the four second-line HCC therapies compared, regorafenib and cabozantinib appear to be better choices in terms of OS. Cabozantinib, regorafenib and ramucirumab have similar levels of efficacy for those with AFP >400, although ramucirumab has fewer side effects. No significant difference was observed in AEs, but some AEs related to each of these interventions should be given further consideration.

Comparative Efficacy of Cabozantinib and Ramucirumab After Sorafenib for Patients with Hepatocellular Carcinoma and Alpha-fetoprotein ≥ 400 ng/mL: A Matching-Adjusted Indirect Comparison

“…The results reinforce and build on those of a recent ITC that reported clinical equivalence of cabozantinib, ramucirumab and regorafenib with respect to OS in patients with serum AFP levels of 400 ng/mL or above [33] and of an NMA of available phase 3 trials of 2L agents for advanced HCC [34]. The NMA subgroup analysis of patients with AFP [ 400 ng/mL suggested that cabozantinib may significantly prolong PFS compared with ramucirumab (HR [95% CI], 0.59 [0.40, 0.88]), but it found no significant differences in OS estimates for cabozantinib, ramucirumab or regorafenib for patients with AFP [ 400 ng/mL.…”

“…Diarrhea was the most common AE reported for cabozantinib (54% of patients compared with 18% for ramucirumab), and peripheral edema was the most common for ramucirumab (36% of patients compared with 0% for cabozantinib). Overall, the authors considered the AEs in patients treated with ramucirumab to be relatively mild, with 36% of patients experiencing grade 3 or 4 AE rates compared with 68% of those treated with cabozantinib [ 34 ].…”

Regorafenib Combined with PD-1 Blockade Immunotherapy versus Regorafenib as Second-Line Treatment for Advanced Hepatocellular Carcinoma: A Multicenter Retrospective Study

“…Among the current standard second-line HCC therapies, regorafenib appears to be the best choice in terms of OS. 7 However, given the low ORR and modest improvement in OS, a more effective second-line treatment is needed.…”

Long-term survival of 11 years with multidisciplinary therapy for hepatocellular carcinoma metastasis to the ovary and peritoneum: a case report

“…Regarding treatment-related adverse effects, good tolerance even in elderly patients was also reported with improvement of overall survival and quality of life [46]. In a network meta-analysis, Wang et al found that the efficacy of ramucirumab was comparable to regorafenib and cabozantinib in patients with AFP levels above 400 ng/mL, although the adverse effects were fewer with ramucirumab compared to regorafenib and cabozantinib [47]. In the present case, ramucirumab did not decrease tumor volume but dramatically reduced AFP level, and the tolerance was better for ramucirumab than for sorafenib and lenvatinib.…”