1. Carlson, Robert H.

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BARCELONA, Spain-Since sorafenib was approved in 2007 by the FDA for first-line treatment of unresectable hepatocellular carcinoma, there have been no new agents successfully tested in either first- or second-line.

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It now appears the oral multikinase inhibitor regorafenib may take that second-line role.


Results from the randomized phase III RESORCE trial of regorafenib in second-line treatment show improved overall survival compared with placebo in patients with intermediate or advanced disease who had progressed after or during treatment with sorafenib.


The results were presented at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer by Jordi Bruix, MD, Head of the Hepatic Oncology Unit at Hospital Clinic, University of Barcelona.


Bruix reported an overall survival of 10.6 months for 379 patients taking regorafenib versus 7.8 months for 194 patients on placebo (hazard ratio 0.62). "That represents a 38 percent reduction in the risk of death," Bruix said in an oral presentation.


Hepatocellular carcinoma is the most common form of liver cancer. Regorafenib is a multikinase inhibitor that blocks a variety of kinases known to promote angiogenesis (including VEGF receptor tyrosine kinases), oncogenesis (c-kit, BRAF, BRAFV600), and the tumor microenvironment (PDGFR, FGFR).


RESORCE (REgorafenib after SORafenib in hepatocellular CArcinoma) was conducted in 152 centers in 21 countries. Median age for all patients was 63 years; 88 percent were male. All patients were tolerant of sorafenib, defined as being able to receive sorafenib 400 mg or more daily for at least 20 of the last 28 days of treatment.


Patients in RESORCE were randomly assigned to regorafenib 160 mg or placebo once daily for the first 3 weeks in a 4-week cycle. All received best supportive care. Treatment continued until disease progression, death, or unacceptable toxicity.


Bruix reported that the disease control rate, comprising complete and partial responses and stable disease by mRECIST criteria, was 65.2 percent for regorafenib versus 36.1 percent for placebo.


Overall response rates (complete and partial responses) were 10.6 percent versus 4.1 percent, respectively. And median progression-free survival was 3.1 months for regorafenib versus 1.5 months for placebo.



Rates of grade 3 or higher adverse events were 79.7 percent for regorafenib versus and 58.5 percent for placebo.


Most of the common grade 3 or higher adverse events occurred more frequently with regorafenib, Bruix reported, including hypertension (15.2% for regorafenib versus 4.7% for placebo), hand-foot skin reaction (12.6% versus 0.5% respectively), fatigue (9.1% versus 4.7%), and diarrhea (3.2% versus 0%).


Bruix speculated that the toxicity might have been higher if patients on this trial had not tolerated the earlier treatment with sorafenib. He also suggested a timely start of systemic therapy in unresectable liver cancer may be important in improving patients' treatment outcomes by providing patients with the opportunity of receiving both sorafenib and regorafenib.


Earlier Failed Trials

The discussant for this presentation, Jean-Luc Raoul, MD, Team Leader for Translational Medicine in Digestive Cancers, Institute Paoli-Calmettes, Marseille, France, began by describing failures of prior phase III trials, which he called "phase III trial disillusion."


He listed five phase III trials in liver cancer tested regimens against single-agent sorafenib in first-line (sunitinib, brivanib, linifanib, sorafenib plus erlotinib, and sorafenib plus doxorubicin), and four phase III trials tested new drugs (brivanib, everolimus, ramucirumab, and ADI-PEG 20) versus best supportive care in second-line.


"And all failed!" Raoul said. There was a whole host of reasons for the second-line failures, he said, from lack of efficacy to toxicity to flaws in trial design.


Better results were expected for regorafenib in liver cancer because it had demonstrated efficacy in previously treated metastatic colorectal cancers as well as in GIST after imatinib and sunitinib failure.


Raoul noted special inclusion criteria for RESORCE: the trial accrued only patients who were truly resistant to sorafenib, with documented radiological progression, with progression either during or after sorafenib treatment; and only patients who tolerated sorafenib.


There are questions to be answered, Raoul noted: How do the toxicities of sorafenib and regorafenib compare; does tolerance to regorafenib correlate with tolerance to sorafenib; and will there be a reliable predictive biomarker for either drug.


There was no major safety issue, but a quality-of-life analysis is awaited. In conclusion, Raoul declared that regorafenib is the gold standard in second-line post-sorafenib in patients who tolerate sorafenib, with real and meaningful benefit in overall survival, time to progression, and overall response rate.


Robert H. Carlson is a contributing writer.