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.
Highlights
Hepatocellular carcinoma (HCC) is characterized by clinical and biological heterogeneity [1,2].In addition, most cases of hepatocellular carcinoma (HCC) have a dismal prognosis that is strictly linked to the stage of cirrhosis [3].more than half of all cases of HCC are diagnosed at a stage with no potentially curative treatment options
At a threshold of 1000 patients per sequence, the simulated estimates of median overall survival (OS) were significantly higher for Lenvatinib followed by Nivolumab, compared to Lenvatinib followed by Pembrolizumab (p = 0.002) and Atezolizumab plus Bevacizumab followed by Nivolumab (p = 0.035) (Supplementary Table S1)
PS 1 simultaneously, Lenvatinib followed by Nivolumab, and Atezolizumab plus Bevacizumab followed by Nivolumab, were more effective than Sorafenib followed by Nivolumab in 100% and
Summary
Hepatocellular carcinoma (HCC) is characterized by clinical and biological heterogeneity [1,2].In addition, most cases of HCC have a dismal prognosis that is strictly linked to the stage of cirrhosis [3].more than half of all cases of HCC are diagnosed at a stage with no potentially curative treatment options. Until 2018, Sorafenib was the only systemic treatment which was found to significantly improve overall survival (OS) as a first-line therapy for advanced HCC [11]. 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. 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%). The net health benefit assessed by ISER favored Lenvatinib followed by Nivolumab, compared to Atezolizumab plus Bevacizumab, followed by Nivolumab in 52% of cases.
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