Sorafenib Has Ushered in an Era of Hope for Liver Cancer Patients

Zosia Chustecka

December 23, 2008

December 22, 2008 —Although there has been some hype associated with it, sorafenib (Nexavar, Onyx/Bayer) has "ushered in an era of hope for patients with hepatocellular carcinoma," declares an editorial in the December 20 issue of the Journal of Clinical Oncology.

This is a lethal and invasive cancer, and until sorafenib, no systemic treatment had been shown to confer a survival advantage in a randomized clinical trial, write the editorialists, Robin Kelley, MD, and Alan Venook, MD, from the University of California, San Francisco. "The flurry of activity surrounding sorafenib is an exciting development," they comment.

The study showing that sorafenib prolonged survival compared with placebo in advanced liver cancer was first reported at the American Society of Clinical Oncology (ASCO) meeting in June 2007. On the basis of these results, the drug was approved in both Europe and the United States a few months later. And at the end of 2007, this trial was listed as one of the major clinical advances in cancer in 2007 in the ASCO annual review.

Pivotal Trial Now Published

The full report of this trial, Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP), was recently published (Llovet JM et al. N Engl J Med 2008;359:378-390). Conducted in 602 patients, it showed that sorafenib prolonged overall survival to 10.7 months, vs 7.9 months on placebo (hazard ratio, 0.69; P < .001).

"This study offers the first hope for life prolongation for the more 600,000 patients who die each year from hepatocellular carcinoma worldwide," Drs. Kelley and Venook comment. But they add: "With the first hope of an active therapy in a grim disease, there is a natural tendency toward expansiveness — the hype." They say that clinicians need to question whether the patients who took part in the trial are similar to the patients they see in their office and how far the results can be generalized.

Differences in Viral Hepatitides

There are several key differences between the patients in the SHARP trial and the majority of patients with hepatocellular carcinoma, the editorialists point out. Foremost among them is the proportion of patients with viral hepatitides. About half of the trial participants had a viral cause of the disease, hepatitis C in approximately 30% and hepatitis B in another 20%. In contrast, more than 70% of patients with hepatocellular carcinoma in the United States and Western Europe test positive for hepatitis C virus (HCV), and worldwide, hepatitis B (HBV) infection accounts for 60% to 80% of liver-cancer cases and ranks second only to tobacco as a human carcinogen.

Recently, sophisticated genetic analyses of liver-cancer tissue have detected underlying differences between HCV- and HBV-associated liver cancers, the editorialists point out, and they speculate that these and liver cancers of other etiologies may turn out to have different natural histories and different responses to targeted therapies.

Corroborating but Different Results from Asian Trial

Corroborating but different results have since been reported from an Asian trial, in which more than 70% of the 226 patients were positive for hepatitis B, the editorialists comment. Results from that trial were reported at this year's ASCO meeting and were welcomed as providing confirmation that sorafenib is effective also in that patient population. The full report of that trial, led by Ann-Lii Cheng, MD, from the National Taiwan University Hospital, in Taipei, has just been published (Cheng ALet al. Lancet Oncol. Published online December 16, 2008).

This Asian trial also showed a significantly longer survival in patients on sorafenib, 6.2 months, vs 4.1 months on placebo (hazard ratio, 0.67; P = .0155). However, although this benefit is of the same relative magnitude as was seen in the SHARP trial, the patients in both cohorts of the Asian trial did appreciably worse than the patients in the SHARP trial, the editorialists point out. The Asian patients had poorer performance status, more prior therapies, and more severe liver disease, but "it is unclear what factors account for the differential outcomes," they write.

Differences in Underlying Liver Dysfunction

Another important point for the clinician to note is that, in contrast with most patients with hepatocellular carcinoma, the majority of participants in the SHARP trial had a limited extent of underlying liver dysfunction. The editorialists point out that 97% of the study population was classified as Child-Pugh class A (CPA) cirrhosis.

Thus, the SHARP trial, by definition, did not explore safety or efficacy of the drug in patients with greater degrees of liver compromise, but 2 smaller studies have suggested that sorafenib may have less clinical benefit and significant toxicity in such patients, they point out.

The Food and Drug Administration (FDA) approval for sorafenib applies to any patient with hepatocellular carcinoma, but the National Comprehensive Cancer Network (NCCN) practice guidelines point out that the data so far are inadequate to define dosing or safety in patients with CPB or worse liver function, and they also advise extreme caution in patients with elevated bilirubin. "As a cancer drug with an FDA label more permissive than the algorithm of the NCCN, sorafenib is an exception to the rule," the editorialists comment.

Sorafenib "Offers Real Hope"

"In summary, the SHARP results can at this point be applied to a minority of patients with advanced hepatocellular carcinoma," the editorialists conclude. "Nonetheless, sorafenib offers real hope of efficacious treatment for patients with advanced hepatocellular carcinoma and preserved liver function."

Further trials are planned, they add, and data from the soon-to-be-launched registry Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib may provide a clearer profile on risk and benefit in patients treated outside the clinical-trial setting.

In addition, combinations and new products are being investigated. The combination of sorafenib plus doxorubicin is being studied in an ongoing trial, while another plans to test the combination of sorafenib with erlotinib (Tarceva, Roche), with the comparator in both cases being sorafenib monotherapy. In addition, sunitinib (Sutent, Pfizer) has also demonstrated modest activity in liver cancer, prompting Pfizer to support a head-to-head comparator trial of sunitinib against sorafenib. "A new era of research in liver cancer has dawned," Drs. Kelley and Venook proclaim.

"The SHARP trial is pivotal in the systemic treatment of hepatocellular carcinoma because it puts an end to the time of no belief in therapy for patients with advanced disease," says another editorial. "It has defined a standard that other new therapies have to match with or have to be added onto," editorialist Peter Galle, MD, from the University of Mainz, in Germany, writes in the November issue of the Journal of Hepatology.

We have won the battle but not the war

However, Dr. Galle also adds some words of caution and points out that this is just the beginning of systemic treatment of advanced hepatocellular carcinoma. "Survival improvement of 3 months is great — but the problem is far from being solved." Further options include teaming sorafenib with other drugs and maybe using it after resection or ablation. "We have won the battle but not the war," he writes.

Dr. Kelley reports no conflicts of interest. Dr. Venook reports receiving research funding from Amgen, Genentech, Novartis, Pfizer, GlaxoSmithKline, and Bristol-Myers Squibb. Dr. Galle reports having received lecture and consultancy fees from Bayer.

J Clin Oncol. 2008:36;5845-5848.
J Hepatol. 2008;49:871-878. Abstract

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