Sorafenib in combination with hepatic arterial infusion chemotherapy demonstrated an improvement in overall survival compared with sorafenib alone for patients with hepatocellular carcinoma and portal vein invasion, according to the results of a randomized phase III trial.
Sorafenib (Nexavar) in combination with hepatic arterial infusion chemotherapy (HAIC) demonstrated an improvement in overall survival (OS) compared with sorafenib alone for patients with hepatocellular carcinoma (HCC) and portal vein invasion, according to the results of a randomized phase III trial.1The combination also had an acceptable toxicity profile.
The median OS with the combination was 13.37 months (95% CI, 10.27-16.46) compared with 7.13 months (95% CI, 6.28-7.98) with sorafenib alone, representing a significant reduction in the risk of death with added HAIC (HR, 0.35; 95% CI, 0.26-0.48;P<.001).
“Compared with sorafenib alone, the addition of HAIC of FOLFOX [leucovorin, fluorouracil (5-FU), and oxaliplatin] improved OS among patients with hepatocellular carcinoma and portal vein invasion. The safety results suggest that sorafenib plus HAIC has acceptable treatment-related toxic effects,” the study authors, led by MinKe He, MD, wrote in their report published inJAMA Oncology.“Future studies are warranted to evaluate molecular targeted agent plus HAIC for hepatocellular carcinoma without vascular invasion.”
Portal vein invasion is seen in approximately 13% to 32% of patients with HCC and is associated with a poor prognosis. Patients with HCC and portal vein invasion typically have a median survival of 2.7 to 4.0 months with supportive care, which is extended to 5.5 to 7.2 months with standard sorafenib treatment. Cisplatin-based HAIC is widely used in Japan as a treatment option for patients with HCC and portal vein invasion.
In the prior phase II trial,2the combination of oxaliplatin-based HAIC and sorafenib in patients with HCC and major portal vein invasion demonstrated a median progression-free survival (PFS) of 6.7 months and a median OS of 13.2 months. The objective response rate (ORR) with the combination was 40% and the disease control rate (DCR) was 77.1%. Additionally, the regimen had an acceptable safety profile and no treatment-related deaths occurred.
The open-label phase III trial was performed in 5 hospitals across China. A total of 818 patients were screened between April 1, 2016 and October 10, 2017, and 247 newly diagnosed patients with portal vein invasion were randomized 1:1 to either sorafenib monotherapy or sorafenib with HAIC of FOLFOX.
In the investigational arm (n = 125), patients received 400 mg sorafenib twice daily on days 1 through 21 plus oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU bolus 400 mg/m2on day 1, and 5-FU infusion 2400 mg/m2for 46 hours, every 3 weeks. Patients in the combination arm received femoral artery puncture and catheterization on day 1 of each cycle for HAIC. Treatment crossover to the investigational arm was allowed after confirmed disease progression.
Patients who underwent randomization had portal vein invasion, as confirmed with 2 imaging techniques; Child-Pugh class A; an ECOG performance status of 0 to 2; and adequate organ function. Those who had hepatic decompensation, central nervous system metastases, HIV infection history, or other invasive malignant disease were excluded from the trial.
Of the 247 patients included, the median age was 49 years (range, 18-75). The majority of patients were male (90.3%), had an ECOG performance status of 1 (65.6%), and had hepatitis B virus infection (80.6%).
Patients in the investigational arm received a median of 4 cycles of HAIC. Fifty-four percent of patients developed collateral branches in their hepatic-gastroduodenal collateral artery and needed re-embolization. Investigators noted that the mean and median durations of treatment with sorafenib were longer in the combination arm than in the monotherapy group, but the mean dose was not different between the 2 groups.
At 9 months, the OS rate was 65.6% in the group of patients treated with the sorafenib and HAIC regimen versus 24.6% in the sorafenib-monotherapy group.
A consistent benefit was seen for the combination arm even when median OS was stratified by portal vein invasion grade. In patients with a lower grade, the median OS was 18.17 months with added HAIC versus 10.87 months with sorafenib alone (P= .002), and in patients with grade 4 invasion, the median OS was 9.47 months and 5.5 months (P<.001), respectively.
The median PFS was 7.03 months (95% CI, 6.05-8.02) with sorafenib and HAIC compared with 2.6 months (95% CI, 2.15-3.05) with single-agent sorafenib (HR, 0.33; 95% CI, 0.25-0.43;P<.001). The median intrahepatic PFS was 8.07 months versus 3.1 months (HR, 0.28; 95% CI, 0.21-0.37;P<.001), respectively.
In the combination arm, the ORR was 40.8% compared with 2.46% in the monotherapy arm, comprising all partial responses in both arms (P<.001). An additional 43 patients (34.4%) achieved stable disease with the combination regimen and 57 (46.7%) had stable disease with sorafenib alone. The DCR was 75.2% with added HAIC versus 49.2% with sorafenib alone.
When looking specifically at intrahepatic responses, the ORR increased to 48.0% with sorafenib and HAIC compared with 3.3% with sorafenib alone, and the DCRs were 81.6% and 55.7%, respectively.
Thirty-five patients from the sorafenib group crossed over to receive the combination regimen. The median OS among these patients was 9.47 months (95% CI, 8.19-10.74).
The safety assessment included all patients who received at least 1 dose; 2 patients were not treated, 1 from each arm. Treatment-related adverse events (AEs) were observed at a slightly higher rate in the combination-treatment arm compared with the sorafenib-alone arm (any-grade, 95.16% vs 90.08%;P= .15; grade 3/4, 53.23% vs 42.15%;P= .10; serious AEs, 32.26% vs 34.71%;P= .69).
The most common any-grade AEs observed in the sorafenib plus HAIC treatment arm were hypoalbuminemia (81.45% vs 40.5%), elevated aspartate aminotransferase levels (80.65% vs 85.12%), nausea (79.84% vs 28.93%), fatigue (76.61% vs 37.19%), hyperbilirubinemia (73.39% vs 65.29%), elevated alanine aminotransferase levels (69.35% vs 66.12%), anemia (68.55% vs 62.81%), vomiting (59.68% vs 14.05%), and thrombocytopenia (55.65% vs 42.15%). Grade 3/4 neutropenia, thrombocytopenia, and vomiting were all observed more frequently with added HAIC.
Additionally, the study authors noted that 34 patients who received the combination regimen experienced abdominal pain from HAIC, which was usually relieved by slowing or stopping the infusion of oxaliplatin.
Three treatment-related deaths occurred within 30 days after treatment conclusion, 2 in the combination arm and 1 in the sorafenib group. None were attributed to disease progression.
The study authors suggested that the benefit may be partly due to the synergistic antitumor effects of sorafenib with FOLFOX chemotherapy. The investigators also believed that repetitive catheterization was more reliable than implanted port catheters for concentrating the chemotherapy dose to targeted areas of the body only.