Optimizing Sequential Systemic Therapies for Advanced Hepatocellular Carcinoma: A Decision Analysis

Abstract

Background: An optimal sequential systemic therapy for advanced hepatocellular carcinoma (HCC) has not been discovered. We developed a decision model based on available clinical trials to identify an optimal risk/benefit strategy for sequences of novel systemic agents. Methods: A Markov model was built to simulate overall survival (OS) among patients with advanced HCC. Three first-line (single-agent Sorafenib or Lenvatinib, and combination of Atezolizumab plus Bevacizumab) followed by five second-line treatments (Regorafenib, Cabozantinib, Ramucirumab, Nivolumab, Pembrolizumab) were compared in fifteen sequential strategies. The likelihood of transition between states (initial treatment, cancer progression, death) was derived from clinical trials. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥grade 3) were calculated. The innovative measure, called incremental safety-effectiveness ratio (ISER), of the two best sequential treatments was calculated as the difference in probability of SAEs divided by LYG. Results: Lenvatinib followed by Nivolumab (median OS, 27 months) was the most effective sequence, producing a LYG of 0.75, while Atezolizumab plus Bevacizumab followed by Nivolumab was the safest sequence (SAEs 40%). Accordingly, the net health benefit assessed by ISER favored Lenvatinib followed by Nivolumab, compared to Atezolizumab plus Bevacizumab, followed by Nivolumab in 52% of cases. Conclusion: Further sequential clinical trials or large-scale real-world studies may prove useful to evaluate the net health benefit of the best sequential treatment for advanced HCC.

Nivolumab vesus Regorafenib in patients with hepatocellular carcinoma after Sorafenib failure

“…The current study compared the e cacy of nivolumab and regorafenib, the most frequently used ICI and TKI, for HCC patients with advanced stages who failed sorafenib. In a mathematical Markov model reported by Cabibbo et al that simulated treatment effect of sequential systemic therapies among patients with advanced HCC based on data of clinical trials, the simulated estimates of median OS were signi cantly higher for sofafenib followed by nivolumab compared to sorafenib followed by regorafenib (27 months vs 18 months) [22]. In the current study, we found that using nivolumab had a trend of better ORR and DCR than using regorafenib, but there was no statistical difference.…”

Progression-Free Survival Early Assessment Is a Robust Surrogate Endpoint of Overall Survival in Immunotherapy Trials of Hepatocellular Carcinoma

“…PFS is a composite endpoint not influenced by post-progression survival and that avoids crossover treatment bias. Modeling sequential treatments, PFS represents the primary endpoint for first-line therapy in ICI trials, as demonstrated by a recently published decision model [ 40 ]. Although efforts have been made to improve the surrogacy between PFS and OS in immunotherapy trials—by modifying the threshold percentage to define PFS or the response criteria with Immune Response Evaluation Criteria in Solid Tumors (iRECIST)—PFS surrogacy for OS remains weak both at trial and individual level [ 10 , 11 , 41 ].…”

Antiviral therapy in the palliative setting of HCC (BCLC-B and -C)

“…Indeed, the window of intervention before reaching the irreversibility time-point for BCLC-C and D patients is extremely small but should be considered during clinical decision making. This is particularly relevant now since there are several systemic therapeutic options available [46].…”