The phase 2 ACTION trial, which evaluated the safety of second-line cabozantinib in patients with hepatocellular carcinoma who were intolerant to first-line sorafenib or who received agents other than sorafenib in the first line, did not meet its safety futility criteria, allowing the trial to continue.
The phase 2 ACTION trial (NCT04316182), which evaluated the safety of second-line cabozantinib (Cabometyx) in patients with hepatocellular carcinoma (HCC) who were intolerant to first-line sorafenib (Nexavar) or who received agents other than sorafenib in the first line, did not meet its safety futility criteria, allowing the trial to continue, according to findings presented during the 2023 International Liver Cancer Association Conference.1
“Here, we present the results of the interim analysis of [this] trial that was performed in November 2021, and [updates] in recruitment at the end of the study,” lead study author, Marco Sanduzzi Zamparelli, of the Fundació Clinic per a la Recerca Biomèdica – IDIBAPs, in Barcelona, Spain, and colleagues, wrote in a poster of the data.
Previously, the phase 3 CELESTIAL trial (NCT01908426) showed that cabozantinib generated longer overall survival and progression-free survival outcomes vs placebo in patients with previously treated, advanced HCC.2 However, the outcomes of patients with HCC who received cabozantinib in the second line because of sorafenib intolerance or after intolerance to first-line sorafenib have only been described retrospectively.
The open-label, investigator-initiated ACTION trial is investigating the safety of second-line cabozantinib in patients with HCC who received and were intolerant to first-line sorafenib or who received other first-line treatments.1 In this trial, safety was measured by the rates of adverse effects (AEs), treatment-related AEs, and death.
Patients eligible for enrollment in ACTION include those with HCC who were intolerant to sorafenib per the sorafenib intolerance definition outlined in the phase 3 RESORCE trial (NCT01774344) or those who discontinued first-line lenvatinib (Lenvima) or atezolizumab (Tecentriq)/bevacizumab (Avastin).
Patients in ACTION received cabozantinib at 60 mg daily. Cabozantinib dosing was modified upon AE development, with a minimum permitted dose of 20 mg every 72 hours. Patients received treatment until unacceptable AEs, symptomatic tumor progression, patient withdrawal, or death.
The interim analysis of this trial was planned for when 14 patients had a minimum follow-up of 30 days. The trial would be stopped because of futility if 8 or more patients developed critical AEs per investigator assessment. Critical AEs were defined as grade 3 or higher AEs, excluding hand-foot skin reaction.
As of the end of trial enrollment in July 2022, 29 patients had been enrolled in ACTION, 4 of whom had screening failure. Of the 25 patients included in the trial, 19 ended treatment, 15 because of progressive disease, 2 because of patient decision, and 1 each because of a suspected unexpected serious adverse reaction of intestinal ischemia and grade 3 hand-foot skin reaction. Additionally, 5 patients continued the study treatment after the last trial patient’s last visit, and 1 patient did not receive the study treatment.
Of the 14 patients included in the interim analysis of ACTION, the median age was 61 years, 10 patients were over the age of 65 years, and most patients were male. Of the 10 patients evaluable for Child-Pugh score, 7 had a score of A5 and 3 had a score of A6. Twelve patients had an ECOG performance score (PS) of 0, and 2 patients had an ECOG PS of 1. Four patients each had extra-hepatic disease and vascular invasion. Eight patients had Barcelona Clinic Liver Cancer (BCLC) stage B disease, and 6 patients had Barcelona Clinic Liver Cancer stage C disease. Twelve patients had received sorafenib in the first line, and 1 patient each had received lenvatinib and atezolizumab/bevacizumab.
In total, 7 patients experienced grade 3 or higher AEs, excluding hand-foot skin reaction. One patient experienced grade 3 hypokalemia (a serious AE), grade 3 hypocalcemia, 2 instances of grade 4 hypomagnesemia, and 2 instances of grade 3 gastrointestinal (GI) bleeding (1 of which was considered a serious AE), all of which were treatment related. This patient interrupted cabozantinib for the hypokalemia and the first instance of GI bleeding and eventually died. One patient experienced grade 3 ano-rectal hemorrhage, which was determined to be treatment related, and grade 3 spontaneous bacterial peritonitis, both of which were serious AEs. This patient died. One patient experienced grade 3 treatment-related intestinal ischemia, for which they interrupted cabozantinib. One patient had treatment-related grade 4 elevated bilirubin levels, for which they interrupted cabozantinib. This patient died. One patient experienced grade 3 fever (a serious AE). One patient experienced grade 3 elevated blood pressure that was possibly treatment related, for which they interrupted cabozantinib. One patient experienced grade 3 asthenia that was possibly treatment related and grade 3 acute cholecystitis (a serious AE). This patient withdrew cabozantinib treatment because of the asthenia and eventually died.
“The Data and Safety Monitoring Board concluded that the ACTION trial could continue, since it did not meet the safety futility criteria,” Zamparelli and colleagues concluded.