Page 193 - ebook HCC

190 PROGRAMME AND ABSTRACTS GENEVA, SWITZERLAND EASL HCC SUMMIT 191
FEBRUARY 13 - 16, 2014

SECOND LINE DRUG TREATMENT FOR
HEPATOCELLULAR CARCINOMA (HCC)

Markus Peck-Radosavljevic 1 If successful, this would be the first drug for treatment of HCC to use a molecular marker
1 Department of Gastroenterology and Hepatology, as predictive biomarker for drug selection. In addition to Tivantinib, other c-met inhibitors
Medizinische Universität Wien, Vienna, Austria are undergoing clinical development in earlier phase trials at the moment. Likewise,
Refametinib, a MEK-inhibitor, is undergoing phase-II testing in ras-mutated HCC
Corresponding author’s e-mail: markus@peck.at (NCT01655693), highlighting the potential importance of molecular testing for a more
personalized approach to drug treatment of HCC.Furthermore Regorafenib, a multikinase
inhibitor similar but more potent than Sorafenib (NCT01774344) and a nanoparticle
linked Doxorubicin (NCT01655693) are also undergoing phase III testing in patients that
According to Globocan 2012, over 62000 deaths per year have to be attributed to primary failed Sorafenib with advanced stage HCC. Several other targeted agents are currently
liver cancer, which makes it the 7th most common cause of cancer related death in undergoing second line phase II testing in advanced HCC to explore the possibility of
Europe (http://globocan.iarc.fr). Almost 70% of patients are diagnosed in a non-curatively development in this indication. Until one of these drugs yields a positive result we will
treatable disease stage and many of those will end up getting first line drug treatment not have an evidenced based suggestion of what to do with patients that fail Sorafenib
with Sorafenib, which will prolong the time to radiologic progression to 5,5 months from treatment. While patients that are intolerant to Sorafenib can sometimes be treated with
the initiation of treatment. So far, no clear answer can be given to the question of what to a reduced dose of sorafenib, many investigators at the moment consider treatment
do upon progression under Sorafenib treatment or intolerance to it. So, development of with Sorafenib beyond progression as a reasonable alternative to no treatment at all. In
drugs for second line treatment of HCC are currently the major focus in drug development the end, in the second line setting, a more personalized approach might be needed to
for liver cancer. The first drug with definitive data from a prospective controlled phase III confer a survival advantage to these patients. This would require an improved molecular
trial was Brivanib. In a trial with 2:1 randomization into Brivanib (800 mg per day) versus understanding of liver cancer as well as rapid and reliable testing for key driver mutations
Placebo until disease progression or unescapable toxicity in patients that had failed in an individual cancer and effective treatments to counter them. c-met inhibition and ras-
prior Sorafenib treatment, no survival benefit for Brivanib (median OS 9,4 month) versus inhibition might be an initial step to more sophisticated use of molecularly targeted agents.
CLINICAL SPEAKERS ABSTRACTS well as disease control rate was significantly better in the Brivanib group. The second trial References CLINICAL SPEAKERS ABSTRACTS
placebo (median OS 8,2 month) could be demonstrated [1]. While subgroup analysis for
OS didn’t show any signal for survival benefit in a specific subgroup, time to progression as
1. Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, et al. Brivanib versus
to report definitive phase III results just recently was the randomized Placebo controlled
Placebo in Patients with Advanced Hepatocellular Carcinoma (HCC) Who Failed or
Everolimus study, where 546 patients were 2:1 randomized into the Everolimus versus
Were Intolerant to Sorafenib: Results from the Phase 3 BRISK-PS Study. J Hepatol
Placebo group. Again, Everolimus (7,6 month) was not able to confer a survival benefit
2012;56: A1398.
over Placebo (7,3 month median) and neither the subgroup analysis for OS nor the time
to progression was significantly improved by Everolimus. Only the disease control rate
Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a
was significantly better for Everolimus (56%) compared to Placebo (45%; p=0,01) [4].
randomised, placebo-controlled phase 2 study. Lancet Oncol 2013;14(1): 55-63.
The monoclonal VEGFR2 antibody Ramucirumab is undergoing phase III testing in the 2. Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, et al.
3. Zhu AX, Finn RS, Mulcahy M, Gurtler J, Sun W, Schwartz JD, et al. A Phase II and
second line setting in HCC (www.clinicaltrials.gov NCT01140347) after successful first Biomarker Study of Ramucirumab, a Human Monoclonal Antibody Targeting the VEGF
line phase II data were obtained [3]. This Placebo-controlled second line trial has stopped Receptor-2, as First-Line Monotherapy in Patients with Advanced Hepatocellular
recruiting patients and they follow up for survival is ongoing. One very interesting second- Cancer. Clin Cancer Res 2013;19(23): 6614-6623.
line phase III trial currently ongoing is the Placebo- controlled evaluation of Tivantinib, 4. Zhu AX, Kudo M, Assenat E, Cattan S, Kang Y-KL, Ho Yeong , Poon RT, et al.
a c-met inhibitor. Tivantinib was shown in a Placebo controlled phase II trial to improve EVOLVE-1: Phase 3 Study of Everolimus for Advanced HCC that Progressed During
survival in advanced stage HCC patients with high c-met expression in the tumor tissue, or After Sorafenib. J Clin Oncol 2014: ASCO-GI.
well patients with low expression did not benefit from Tivantinib treatment [2].