Clinical impact of relative dose intensity of cabozantinib during the first 8 weeks and of subsequent dose reductions in patients with unresectable hepatocellular carcinoma

Background Cabozantinib is a second-third line agent for sorafenib-experienced HCC patients. Therefore, it can be prescribed as part of a lenvatinib-sorafenib-cabozantinib or atezo/bev-sorafenib-cabozantinib sequence. Tolerability and safety are key concerns, especially for patients reaching a third-line treatment. However, dose reductions to manage adverse events (AEs) may induce fears of reduced efficacy. Methods Analysis of the MULTICABO cohort (96 patients from 15 Italian centers). We evaluated the relative dose-intensity of cabozantinib during the first 8 weeks (8W-DI; expressed a ratio between the cumulative dose actually received and the maximum theoretical dose). The 8W-DI was correlated with disease control at the first imaging, progression-free survival (PFS), and overall survival (OS). To assess the effects of dose reductions after the first 8 weeks on the OS, multivariable time-dependent Cox regressions were carried out. Results Disease control rate was 63%. The median PFS and OS were and 5.2 and 11.3 months, respectively. The majority of patients (n=45) received the full 60mg daily dose during the first 8 weeks (median 8W-DI 100%, IQR 70-100%). A 90% 8W-DI (equating to a mean 54 mg/daily dose) was chosen for further analysis. A high 8W-DI did not correlate with worse radiological response (OR 1.72, 95% CI 0.72-4.15), PFS (HR 1.39, 95% CI 0.87-2.22), or OS (HR 1.06, 95% CI 0.61-1.83). Sixty-one (63.5%) and 19 (19.8%) patients permanently reduced cabozantinib to 40 and 20 mg/day to manage AEs. In the time-dependent analyses, reduction to 40 mg and 20 mg were associated with increased OS (HR 0.47, 95% CI 0.29-0.76; HR 0.41 95% CI 0.21-0.80, respectively]. Conclusions Our results underline the importance of tailored dosing of cabozantinib. Dose adjustements to manage AEs should not automatically induce fears of reduced efficacy, as higher 8W-DI were not related to better outcomes while dose reductions to manage AEs were associated with increased OS. Cabozantinib is a second-third line agent for sorafenib-experienced HCC patients. Therefore, it can be prescribed as part of a lenvatinib-sorafenib-cabozantinib or atezo/bev-sorafenib-cabozantinib sequence. Tolerability and safety are key concerns, especially for patients reaching a third-line treatment. However, dose reductions to manage adverse events (AEs) may induce fears of reduced efficacy. Analysis of the MULTICABO cohort (96 patients from 15 Italian centers). We evaluated the relative dose-intensity of cabozantinib during the first 8 weeks (8W-DI; expressed a ratio between the cumulative dose actually received and the maximum theoretical dose). The 8W-DI was correlated with disease control at the first imaging, progression-free survival (PFS), and overall survival (OS). To assess the effects of dose reductions after the first 8 weeks on the OS, multivariable time-dependent Cox regressions were carried out. Disease control rate was 63%. The median PFS and OS were and 5.2 and 11.3 months, respectively. The majority of patients (n=45) received the full 60mg daily dose during the first 8 weeks (median 8W-DI 100%, IQR 70-100%). A 90% 8W-DI (equating to a mean 54 mg/daily dose) was chosen for further analysis. A high 8W-DI did not correlate with worse radiological response (OR 1.72, 95% CI 0.72-4.15), PFS (HR 1.39, 95% CI 0.87-2.22), or OS (HR 1.06, 95% CI 0.61-1.83). Sixty-one (63.5%) and 19 (19.8%) patients permanently reduced cabozantinib to 40 and 20 mg/day to manage AEs. In the time-dependent analyses, reduction to 40 mg and 20 mg were associated with increased OS (HR 0.47, 95% CI 0.29-0.76; HR 0.41 95% CI 0.21-0.80, respectively]. Our results underline the importance of tailored dosing of cabozantinib. Dose adjustements to manage AEs should not automatically induce fears of reduced efficacy, as higher 8W-DI were not related to better outcomes while dose reductions to manage AEs were associated with increased OS.