Regorafenib or Cabozantinib in second or subsequent lines after Sorafenib in advanced hepatocellular carcinoma. Which way to chose?

The aim of this paper is to assess the cost-effectivess of regorafenib and cabozantib in the treatment of advanced hepatocellular carcinoma (HCC) after sorafenib. Pivotal phase III randomized controlled trials (RCTs) were considered. Incremental cost-effectiveness ratio (ICER) was calculated for both treatments. Two phase III RCTs, including 1274 patients, were considered. Regorafenib resulted the less expensive, with 2771 € per month overall survival (OS)-gained versus 5309 € of cabozantinib. Combining pharmacological costs of drugs with the measure of efficacy represented by the OS, regorafenib is a cost-effective for the treatment of advanced HCC after sorafenib.


Introduction
Recently, the introduction of cabozantinib, a tyrosine kinase inhibitor, offered a therapeutic possibility beyond the first or subsequentline for patients affected by advanced hepatocellular carcinoma (HCC) in progression after sorafenib, with the improvement in clinical outcomes and prolonged survival [1]. This therapeutical option in this setting of advanced HCC adds to regorafenib, a small-molecule multikinase inhibitor, that improved overall survival (OS) in the pivotal phase III randomized controlled trial (RCT) [2]. The introduction of these active new agents raises the main problem of pharmacy costs increase. The aim of this paper is to assess the cost-effectiveness of regorafenib and cabozantib in the treatment of advanced HCC.

Materials and methods
Pivotal phase III RCTs of regorafenib and cabozantinib in the treatment of advanced HCC after sorafenib in second or subsequent lines were considered. Incremental cost-effectiveness ratio (ICER) was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (OS). The costs of drugs are at the Pharmacy of our Hospital and are expressed in euros (€), updated to June 2020. Calculations were based on an "ideal patient" (BSA 1.8 sqm; weight 70 Kg). The dosage of drugs were considered according to those reported in each RCT. We assumed the following costs for each month of therapy: regorafenib= 1940 € (at the dose of 160 mg/daily for the first 3 weeks of each 4-week cycle), cabozantinib= 2920 € (same price for 60 mg, 40 mg and 20 mg). European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) [3] was applied to the above RCTs to derive a relative ranking of clinical benefit [4].

Results
Two phase III RCTs, including 1274 patients, were considered. The main reported outcomes of the analyzed phase III RCTs are reported in  [2] and grade 2 for the CELESTIAL trial [2]. Regorafenib resulted the less expensive, with 2771 € per month OS-gained (Table 1).

Discussion
Two main variables are able to condition pharmacy costs: the efficacy of treatment and the price of drugs. The first variable is related to the patient's inclusions criteria and we know that results from RCTs could be not representative of daily clinical practice (that is of patients treated outside such trials). The price of drugs is the second strong variable [5,6].
In addition, the annual perspective of the annual cost of treatment wit regorafenib (33 252 €) is in line with those reported in literature, that found a favored implementing intervention for thresholds of less than $61,500 (57 138 €) per life-year gained [7], differently from cabozantinib (63 708 €).
However, to our knowledge, this is the first time an analysis of the pharmacological costs of advanced HCC treated with regorafenib or cabozantinib after sorafenib is linked to OS.
The results become even more interesting if we consider that 51% of patients in the RESORCE trial [3] and 62% in the CELESTIAL trial [2] have reduced the full dose of regorafenib and cabozantinib, respectively. In facts, while in the case of cabozantinib the dose reduction does not impact on pharmacy costs (flat price, that means the same price for the different dosages), in the case of regorafenib it implies for a reduction on pharmacy costs of 25% and 50% if we consider the dose reduction at 120 mg/daily and 80 mg/daily, respectively (Table 1).
In addition, we have to consider that the scenario in the advanced HCC is changing, with the recently introduction in first-line of Lenvatinib [8] and the combination of atezolizumab and bevacizumab [9]. So, regorafenib and cabozantinib will be placed in third line (about 30% of patients treated with cabozantinib in pivotal phase III RCT where already in third line [1]. Ramucirumab was not considered in our analysis because it was approved by Food and Drug Administration (FDA) in 2019, but not by European Medical Agency (EMA) [10].
In conclusion, based on ICER, regorafenib is a cost-effective for the treatment of advanced HCC after sorafenib. The price of newly