At the ASCO-GI in San Francisco, hepatocellular carcinoma was one of the focal points. How can therapy be optimized and what are the options for patients who are progressive during or after sorafenib treatment or who cannot tolerate the drug at all? A recent phase III study showed that everolimus did not induce a benefit in overall survival.
(ag) According to Andrew X. Zhu, MD, Boston, the following conclusion can be drawn from the development to date of the multi-kinase inhibitor sorafenib in the treatment of hepatocellular carcinoma (HCC):
- Moderate efficacy in advanced HCC with so-called Child A cirrhosis.
- Toxicity and dose management critical
- Large variability in outcomes depending on geographic region, etiology, and severity of cirrhosis
- Unknown mechanism of action of sorafenib with respect to clinical benefit and resistance.
- No valid predictive biomarkers for sorafenib in HCC.
Even after the failure of sorafenib, there is still no effective therapeutic option for advanced HCC. “The Phase III EVOLVE-1 trial now evaluated the efficacy and safety of everolimus in this patient population.”
A total of 546 patients were enrolled in the study, of whom 362 received everolimus (at a dose of 7.5 mg/d) and 184 received placebo. Participants suffered from stage B or C HCC (according to the so-called BCLC classification) at the time of study entry. They were progressive during or after sorafenib treatment (80.8%) or did not tolerate such therapy (19%). The drug in question was administered continuously until progression. In addition, intolerable toxicity was a reason for discontinuation.
Primary Endpoint: Overall survival was determined as the primary endpoint.
Secondary Endpoints: Time to progression, extent of disease control, and safety constituted the secondary endpoints.
Results: Median overall survival was 7.56 months on everolimus and 7.33 months on placebo. Thus, the difference was not significant (p=0.675). Median time to progression was 2.96 months (everolimus) and 2.6 months (placebo), and disease control rates were 56.1% and 45.1%, respectively (p=0.010). The most common grade 3/4 side effects were anemia, asthenia, loss of appetite, and increase in viral hepatitis B load.
“The results show that everolimus cannot improve overall survival in this patient population. The safety profile was consistent with previous studies,” Zhu concluded. “Similarly, another phase III study concluded that brivanib, compared with placebo, also did not significantly improve overall survival in the second-line setting [1]. Furthermore, several other studies failed to demonstrate the superiority of certain agents such as sunitinib, brivanib, and linifanib (tyrosine kinase inhibitors) over sorafenib in the first-line setting. In fact, the safety profile of the compared compounds was mostly worse. In light of these results, research into new molecular agents for the advanced form of HCC becomes all the more important.”
What can we learn from failed studies?
According to Zhu, there are several issues to consider if one wants to learn from the Phase III trials that have failed so far:
- Phase II data for efficacy assessments need to become more robust.
- Endpoints such as overall response rate, time to progression, and progression-free survival have their limitations.
- Safety and tolerability of the tested agents/regimens are important.
- The clinical and biological heterogeneity of HCC influences the efficacy of targeted therapies.
Promising new active ingredients
Several agents that inhibit pathways of hepatocarcinogenesis are in clinical development:
Antiangiogenic agents: HCC are vascular tumors with elevated levels of the so-called “vascular endothelial growth factor” (VEGF), which is one of the most important factors for liver tumor angiogenesis and is associated with poorer survival. Inhibition of angiogenesis is a potential therapeutic strategy that has long been the subject of intense research in HCC. Currently, for example, pazopanib, lenvatinib, axitinib, and ramucirumab are in clinical development (Table 1).
mTOR inhibitors: While preclinical data show that mTOR inhibitors are effective in inhibiting cell growth and tumor vascularity, everolimus, for example, failed in the Phase III trial mentioned above. However, other mTOR inhibitors such as temsirolimus and sirolimus are also in development.
MET inhibitors: in a phase II study, tivantinib was able to delay progression in second-line patients with HCC compared with placebo, especially in tumors with high MET levels [2]. Therefore, the compound is currently in Phase III.
“Ultimately, there is an urgent need to find new ways of therapy. The failures of some agents in Phase III should not obscure the fact that many new drugs are currently in development and intensive research is being conducted in this area. This raises hope that we are in for further advances in the treatment of HCC,” Zhu concluded his presentation. “However, sorafenib remains the only systemic agent approved for HCC. It’s important that we try to find new pathways of action and use predictive biomarkers and molecular classifications to predict response to each treatment.”
Source: “Advances in the Management of Liver Cancer,” General Session 4 at ASCO-GI – Gastrointestinal Cancers Symposium, January 16-18, 2014, San Francisco.
Literature:
- Llovet JM, et al: Brivanib in Patients With Advanced Hepatocellular Carcinoma Who Were Intolerant to Sorafenib or for Whom Sorafenib Failed: Results From the Randomized Phase III BRISK-PS Study. J Clin Oncol 2013; 31: 3509-3516.
- Santoro A, et al: Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol 2013; 14: 55-63.
InFo Oncology & Hematology 2014; 2(3): 33-34.
