Sorafenib New First-Line Option for Advanced Liver Cancer

Allison Gandey

June 11, 2007

June 11, 2007 (Chicago) — Onyx Pharmaceuticals' sorafenib (Nexavar) is the first effective systemic treatment for advanced liver cancer. Presenting here at the 43rd annual meeting of the American Society of Clinical Oncology, researchers showed that the targeted multikinase inhibitor extends survival by 44%. "This improvement is dramatic," Philip Johnson, MD, from the Institute for Cancer Studies at the University of Birmingham, in the United Kingdom, said during a discussion period following the presentation. "This is the dawn of a new era for hepatocellular carcinoma therapy," he said, but he also cautioned that just like at the dawn of a new day, "we can't necessarily see everything until the light shines."

During a press briefing outlining the findings, session moderator William Blackstock, MD, from the Wake Forest University School of Medicine, in Winston-Salem, North Carolina, was very enthusiastic about the new trial. "This is an example of a study that couldn't have been done in the United States," Dr. Blackstock told Medscape. "Cancer patients here would never have accepted a placebo arm like the one in this trial. They expect to be treated."

He said that in addition to providing a first-line option for difficult-to-treat patients, these findings out of Spain will revolutionize future liver cancer clinical trials. "I can't tell you what the design will be for these trials," Dr. Blackstock said, "but I can tell you what the control will be — sorafenib."

New Reference Standard for Future Clinical Trials

Lead investigator Josep Llovet, MD, from the Mount Sinai School of Medicine, in New York, and the Institut d'Investigacions Biomediques August Pi i Sunyer Hospital Clinic, in Barcelona, Spain, told delegates at the meeting that sorafenib is the new reference standard for systemic therapy of hepatocellular carcinoma patients.

"What Dr. Llovet has done for us establishes a baseline, a platform," Dr. Blackstock told reporters. "Now we can move forward in hepatocellular carcinoma in a way that was not possible before."

There is currently no widely accepted standard of care for advanced liver cancer. Doxorubicin is reportedly the most widely used agent, despite the fact that only 1 randomized controlled trial of 60 patients has supported its use and the drug is said to have a 25% rate of fatal complications. Mitoxantrone is licensed for hepatocellular carcinoma but is not considered a gold standard.

In this international phase 3, double blind, randomized, placebo-controlled trial, investigators studied 602 patients. The trial, known as the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP), looked at the primary end points of overall survival and time to symptomatic progression. Patients received oral sorafenib 400 mg twice daily or placebo for 6 months, but the trial was stopped early because the findings were so positive.

Response Evaluation Criteria in Solid Tumors

Outcome Sorafenib (n=299) Placebo (n=303)
Complete response 0 0
Partial response, n (%) 7 (2.3) 2 (0.7)
Stable disease, n (%) 211 (71) 204 (67)
Progressive disease, n (%) 54 (18) 73 (24)
Progression-free rate at 4 months 62% 42%
Duration of treatment (median) 23 weeks 19 weeks

Toxicity

Outcome Sorafenib (n=299) Placebo (n=303)
Serious adverse events 52 54
Diarrhea 11 2
Hand-foot skin reactions 8 1
Bleeding 6 9

Dr. Llovet reported that the median time to progression was 24 weeks vs 12 weeks (hazard ratio, 0.58; = 0.000007). This represented a 73% prolongation in time to progression.

During the discussion period following the presentation of the findings, Dr. Johnson noted that the incidence of hepatocellular carcinoma is rising in the United States. Risk factors for hepatocellular carcinoma include chronic viral hepatitis types B and C. Worldwide, hepatitis B is said to be responsible for 60% to 80% of all hepatocellular carcinoma cases. Because it is preventable by immunization at birth and antiviral treatment, Dr. Johnson pointed out that scarce resources should be focused on prevention.

But for those requiring treatment, Dr. Llovet said sorafenib costs $5000 per month, roughly the same as it costs in the European Union. Dr. Johnson noted that cost will be a barrier in many parts of the world. Dr. Blackstock was less concerned about the price point: "Given that there are no alternatives at this time, I don't see cost as a major barrier."

Because sorafenib was so well tolerated, Dr. Blackstock proposed that it be studied in patients with more compromised liver function. Other targeted agents in the wings for liver cancer include bevacizumab, erlotinib, and sunitinib.

ASCO 43rd Annual Meeting. Late-breaking abstract 1. Presented June 4, 2007.

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