SORAFENIB (Nexavar) added to transarterial chemoembolization (TACE) doubled the median progression-free survival over TACE alone in patients with unresectable hepatocellular carcinoma, Japanese investigators reported at the 2018 Gastrointestinal Cancers Symposium.1 The results of the randomized, open-label, multicenter, phase II TACTICS trial were presented by Masatoshi Kudo, MD, of Kindai University Faculty of Medicine in Osaka.
Masatoshi Kudo, MD
“The TACTICS trial clearly showed that TACE in combination with sorafenib is a treatment option to improve clinical outcomes and may be a standard of care in patients with intermediate-stage hepatocellular carcinoma,” Dr. Kudo said.
Study Rationale
The rationale for this combination is based on the observation that TACE may produce a spike in the intratumoral concentration of vascular endothelial growth factor (VEGF); blockade of the VEGF receptor might prevent the surge in proangiogenic factors that contribute to metastasis. Since TACE and sorafenib, individually, have been shown to prolong survival in patients with unresectable hepatocellular carcinoma, their combination may be additive or synergistic, he explained.
Three previous randomized trials, however, failed to show the combination was better than a single approach, including post-TACE,2 SPACE,3 and TACE 2.4 Dr. Kudo suggested: “Longer sorafenib treatment duration in the TACTICS trial (38.7 weeks) may be the key to the success of this trial, as compared with previous failed trials,” he said, noting the duration of sorafenib was 17 weeks in post-TACE, 21 weeks in SPACE, and 17 weeks in TACE 2.
The 156 patients in this trial were 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.
TACE PLUS SORAFENIB
- In contrast to three prior studies, the addition of sorafenib to TACE for unresectable hepatocellular carcinoma led to an improvement in progression-free survival over TACE alone in a Japanese study.
- The study introduced a unique primary endpoint: a state referred to as “unTACEable,” meaning that further TACE treatments would be futile. The new definition is necessary to capture the way in which TACE is different from other treatments.
- Median progression-free survival using this endpoint was 13.5 months with TACE and 25.2 months with TACE plus sorafenib, translating into a 41% reduction in the risk of disease progression (HR = 0.59; P = .006). Trends toward improvements were evident across all subgroups evaluated.
Unique Endpoint
THE STUDY introduced a unique primary endpoint that may prove to be a better way to evaluate treatment success: a state referred to as “unTACEable,” meaning further TACE treatments would be futile. The new definition is necessary to capture the way in which TACE is different from other treatments.
“In this trial, intrahepatic new lesions were not regarded as progressive disease, since it is the natural tumor biology of hepatocellular carcinoma and does not imply treatment failure or moving to the next line of treatment,” Dr. Kudo said.
The definition of progression-free survival was the time from randomization to either disease progression or death from any cause. Disease progression was defined as either untreatable (UnTACEable) disease progression (the inability of a patient to further receive or benefit from TACE) or disease progression that meets the TACE failure or refractoriness criteria by the Japan Society of Hepatology definition.
Median progression-free survival reached 13.5 months with TACE and 25.2 months with TACE plus sorafenib, translating into a 41% reduction in the risk of disease progression with the addition of the targeted therapy (hazard ratio [HR] = 0.59; P = .006). Trends toward improvements were evident across all subgroups evaluated.
A secondary endpoint, median time to unTACEable (untreatable) disease progression, was significantly longer with TACE plus sorafenib vs sorafenib alone, 26.7 vs 20.6 months (HR = 0.57; P = .02), as was the median time to disease progression, 26.7 vs 16.4 months (HR = 0.54, P = .005), which included both unTACEable disease progression and TACE failure. The overall survival data are not yet mature.
Overall response rates were not significantly different between the arms, 71.3% with the combination and 61.8% with TACE alone (P = .23), as was the disease control rate, 83.8% vs 77.6% (P = .42). No unexpected toxicities emerged during the trial. ■
DISCLOSURE: Dr. Kudo reported financial relationships with Ajinomoto, Bayer, Eisai, MSD, Bristol-Myers Squibb, Chugai Pharma, Kowa, and Taiho Pharmaceutical.
REFERENCES
1. Kudo M, et al: 2018 Gastrointestinal Cancers Symposium. Abstract 206. Presented January 19, 2018.
2. Kudo M, et al: Eur J Cancer 47:2117-2127, 2011.
3. Lencioni R, et al: J Hepatol 64:1090-1098, 2016.
4. Meyer T, et al: Lancet Gastroenterol Hepatol 2:565-575, 2017.
