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AASLD 2012: Brivanib Fails to Match Sorafenib for Liver Cancer, but Tivatinib Looks Promising

The investigational cancer drug brivanib did not significantly increase overall survival for patients with hepatocellular carcinoma compared with existing standard therapy, researchers reported at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012) this month in Boston. But another drug, tivatinib, did appear beneficial for a subset of patients.

Over years or decades, chronic hepatitis B or C, heavy alcohol consumption, and other causes can lead to severe liver disease including cirrhosis and hepatocellular carcinoma (HCC), a form of primary liver cancer. Although HCC is one of the most common cancers worldwide -- being especially common in Asia -- it is often not detected until advanced stages and is therefore difficult to treat.

The multikinase inhibitor sorafenib (Nexavar) is currently the only drug shown to extend survival for liver cancer patients who are not eligible for resection, or surgical removal. Like many cancer drugs, however, it can be difficult to tolerate.

Phillip Johnson from the University of Birmingham in the U.K. and an international team of colleaguesconducted the Phase 3 BRISK-FL trial to evaluate the efficacy of sorafenib versus brivanib, a selective inhibitor of receptors for vascular endothelial growth factor and fibroblast growth factor, which play a role in liver cancer development. In previous trials brivanib demonstrated anti-tumor activity, though it did not extend overall survival compared with placebo.

BRISK-FL trial enrolled 1155 patients with advanced HCC who had received no prior systemic treatment. Most (84%) were men, about two-thirds were Asian, and the median age was 60 years. About 45% had hepatitis B, about 20% had hepatitis C, and about 15% had alcoholic liver disease. More than 90% were Child-Pugh stage A. Half had distant metastasis, or spread beyond the liver, and just over one-quarter had regional lymph node metastasis.

Participants were randomly assigned (1:1) to receive 800 mg oral brivanib once-daily or 400 mg oral sorafenib twice-daily. They were followed until they experienced disease progression or unacceptable toxicity. The researchers looked at overall survival as a primary endpoint, as well as time to progression, objective response rate, disease control rate, and quality of life.

Results

• Median duration of treatment was 3.2 months in the brivanib arm and 4.1 months in the sorafenib arm.
• Median survival was 9.5 months in the brivanib arm compared with 9.9 months in the sorafenib arm, not a statistically significant difference.
• No significant survival differences were seen in subgroups based on geographic region, cause of HCC, or disease severity.
• The median time to progression was 4.2 months in the brivanib arm compared with 4.1 months in the sorafenib arm, again not a significant difference.
• The best response in the brivanib and sorafenib groups was as follows:

o   Complete response: 0.3% vs 0.9%, respectively;

o   Partial response: 11.6% vs 8.0%, respectively;

o   Stable disease: 53.6% vs 55.9%, respectively;

o   Progressive disease: 16.3% vs 23.9%, respectively;

o   Unable to assess: 18.2% vs 11.4%, respectively.

• Objective response rates were 12.0% in the brivanib arm and 8.8% in the sorafenib arm, which fell just short of statistical significance.
• 46% of participants in the brivanib arm and 53% in the sorafenib arm discontinued the study early due to disease progression.
• Both brivanib and sorafenib were difficult to tolerate:

o   Serious adverse events: 59% vs 52%, respectively;

o   Adverse events leading to treatment discontinuation: 43% vs 33%, respectively;

o   Deaths attributed to drug toxicity: 1.6% vs 0.3%, respectively;

• Loss of appetite, fatigue, nausea, vomiting, high blood pressure, and low blood sodium were at least 10% more common in the brivanib arm.
• Hair loss, rash, and hand or foot skin reactions were at least 10% more common in the sorafenib arm.
• Half of patients in both arms had their drug doses reduced.
• Quality of life declined considerably in both arms by week 12 after starting treatment, slightly by significantly more so in the brivanib arm.

Based on these findings, the researchers concluded, "The primary endpoint of non-inferiority in overall survival for brivanib vs sorafenib was not met." However, they added, "Brivanib had antitumor activity similar to sorafenib," based on time to progression, objective response rate, and disease control rate.

"Brivanib had an acceptable safety profile," they continued, but was "generally less well-tolerated than sorafenib."

At a conference overview for the media, AASLD president GuadalupeGarcia-Tsao said that since brivanib showed no improvement in survival over sorafenib, but was less well-tolerated, "therefore sorafenib will continue to be the standard of care for these patients."

Tivantinib

Another liver cancer study looked at tivantinib, a selective oral tyrosine kinase inhibitorof the hepatocyte growth factor receptor known as MET. In Phase 1 studies it showed promise alone and in combination with sorafenib.

Ivan Borbath from Cliniques Universitaires Saint-Luc in Brussels and colleagues conducted a Phase 2 multicenter clinical trial of patients with un-resectable (not surgically removable) HCC who either experienced disease progression after first-line therapy or were unable to tolerate first-line treatment, which was usually sorafenib.

A total of 107 participants were randomly assigned (2:1) to receive 360 mg or 240 mg twice-daily tivantinib, or else placebo; the initial 360 mg dose was lowered to 240 mg after the first set of patients developed neutropenia, or low white blood cell count.

In an intent-to-treat analysis, the median time to progression was 1.7 months for the tivantinib arm compared with 1.5 months for the placebo arm. This difference was not statistically significant, nor was the difference in overall survival.

Benefits were greater, however, for the subset of participants with high MET expression. For this subgroup, time to progression was 2.7 months with tivantinibvs 1.4 months with placebo. Overall survival durations were 7.2 vs 3.8 months, respectively. Adverse events included fatigue, weakness, loss of appetite, and blood cell deficiencies.

In the absence of treatment, HCC patients with high MET expression have a higher risk of disease progression and death. The researchers saw no relation between MET expression and blood biomarkers or hepatitis B or C status, noting that it must be determined by liver biopsy.

These results should be interpreted cautiously, as they rely on a subgroup analysis, but a growing body of evidence in various types of cancer indicates that individual genetic factors play a key role in determining treatment response.

"Tivantinib demonstrated a nearly doubling of progression free and overall survival in the MET high group compared to placebo in a Phase 2 study in patients with advanced HCC as second-line treatment," Jörg Trojan and Stefan Zeuzem from Johann-Wolfgang Goethe-Universität summarized in a review in the November 21, 2012, advance online edition of Expert Opinion on Investigational Drugs. "The activity of tivantinib in combination with sorafenib is also promising."

Larger studies of tivantinib are being planned specifically for high MET HCC patients.

11/30/12

References

P Johnson, S Qin, J-W Park, et al. Brivanib (BRI) versus Sorafenib (SOR) as First-line Therapy in Patients with Unresectable, Advanced Hepatocellular Carcinoma (HCC): Results from the Phase 3 BRISK-FL Study. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract LB-6.

I Borbath, C Porta, L Rimassa, et al. Randomized Controlled Phase 2 Study (RCT) with Tivantinib in pre-treated hepatocellular carcinoma (HCC): Efficacy, Safety, and MET-analysis. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 114.

J Trojan and S Zeuzem. Tivantinib in hepatocellular carcinoma. Expert Opinionon Investigational Drugs. November 21, 2012 (Epub ahead of print).