A panel discusses the science presented during Oral Abstract Session B.
“The TACTICS trial clearly showed TACE in combination with sorafenib is a treatment option to improve clinical outcome and may be a standard of care in patients with intermediate-stage HCC,” presenter Masatoshi Kudo, MD, PhD, of Kindai University, in Japan, said.
It makes sense to use sorafenib in the management of unresectable HCC. First, TACE increases hypoxia within the liver, provoking upregulation of VEGFR and IGFR-2, both of which promote metastasis after TACE.4 Inhibition of VEGFR with sorafenib might be able to quell the angiogenic effects associated with a surge in VEGFR expression. Second, both TACE and sorafenib, when used individually, prolong survival in patients with unresectable HCC. When used together, their effects may be additive or even synergistic, which may be a windfall for individuals who are not candidates for resection or ablation.
To be eligible for the phase II trial, patients had to have unresectable HCC, a Child-Pugh score of 7 or less, no more than two prior TACE treatments, no macrovascular invasion, no extrahepatic spread, no more than 10 tumors, and tumors not exceeding 10 cm in size. Patients were then stratified by study site, Milan criteria, and the number of prior TACE treatments before being randomly assigned to on-demand conventional TACE plus sorafenib or to on-demand conventional TACE alone. Individuals assigned to the experimental arm received 400 mg of sorafenib once daily for 2 to 3 weeks prior to TACE and then 800 mg once daily after TACE was started. Sorafenib was paused 2 days before and 3 days after each TACE session.
TACTICS may have succeeded where other trials failed based on a unique aspect of the trial design. Patients continued to receive TACE and sorafenib until they either (1) became refractory to TACE or (2) developed untreatable progression, which was defined as a state when TACE continuation was not possible because of untreatable intrahepatic tumor progression, deterioration of liver function to Child-Pugh C, or the appearance of major vascular invasion or extrahepatic spread—a state referred to as “unTACEable.”
“In this trial, intrahepatic new lesions were not regarded as progressive disease since it is the natural tumor biology of HCC and does not imply treatment failure or moving to the next line of treatment,” Dr. Kudo said.
TACTICS evaluated two coprimary endpoints: PFS and overall survival (OS). Carrying through the unique design feature, PFS was defined as the time to unTACEable (untreatable) progression, TACE failure, or death.
A total of 156 patients participated in the trial. Most patients were male (approximately 76%), had an Eastern Cooperative Oncology Group performance status of 0 (approximately 89%), had serum alpha-fetoprotein levels below 200 ng/mL (approximately 79%), and had never before received TACE (approximately 89%).
TACTICS met one of the coprimary endpoints. Median PFS reached 13.5 months with TACE and 25.2 months with TACE plus sorafenib, translating into a 41% reduction in the risk of progression with the addition of the targeted therapy (HR 0.59, 95% CI [0.41, 0.87]; p = 0.006). Trends toward improved PFS were evident across all subgroups evaluated. The OS data are not yet mature since only 74% of the targeted number of events have been observed.
The median time to unTACEable (untreatable) progression was significantly longer with TACE plus sorafenib versus sorafenib alone (26.7 vs. 20.6 months; HR 0.57, 95% CI [0.36, 0.92]; p = 0.02), as was the median time to progression (26.7 vs. 16.4 months; HR 0.54, 95% CI [0.35, 0.83]; p = 0.005), which included both unTACEable progression and TACE failure.
Dr. Kudo said that no unexpected toxicities emerged during the trial. The increased incidence of hand-foot skin reaction, hypertension, lipase elevations, fatigue, diarrhea, erythema multiforme, weight loss, and hoarseness observed in the combined-modality arm were all consistent with the known tolerability profile of sorafenib. The majority of these additional events were grade 1/2 in severity.
Notably, patients in TACTICS assigned to the experimental arm received sorafenib for a median of 38.7 weeks. In comparison, in prior TACE-sorafenib trials, the median sorafenib duration ranged from 17.0 to 21.0 weeks. Treating patients until unTACEable progression and not until standard progression, certainly contributed to the longer sorafenib duration.
Discussant Jordi Bruix, MD, PhD, of the University of Barcelona, in Spain, favors the new unTACEable-based endpoint used in TACTICS. “The endpoint used in the trial is a good attempt to do something new that may be affirmative for activity of combinations in the field of chemoembolization,” he said. However, Dr. Bruix noted that this novel endpoint requires validation to determine whether it is a suitable surrogate for survival.
Dr. Bruix went on to state that it is too soon to use systemic sorafenib in combination with TACE in the clinic, and it will be important to see what the mature survival outcomes of TACTICS reveal. If positive, he then thinks it prudent to conduct a confirmatory study in the West with a large sample size.
– Kara Nyberg, PhD