Tuma, Rabiya S. PhD
ORLANDO, FL—A report last year showed that sorafenib prolonged overall survival in patients with liver cancer, but it left open the question of whether the drug was safe and effective in liver cancer patients with hepatitis. Now, though, results from a subgroup analysis show that sorafenib does work in these patients as well.
The data were reported here at the Gastrointestinal Cancers Symposium, a meeting cosponsored by the American Society of Clinical Oncology, the American Gastroenterology Association Institute, the American Society for Therapeutic Radiology and Oncology, and the Society of Surgical Oncology.
Additionally, a Phase II study suggests that a combination of doxorubicin and sorafenib may be synergistic in liver cancer patients.
The previously reported SHARP (Sorafenib HCC Assessment Randomized Protocol) trial randomized approximately 600 patients with advanced liver cancer to receive either sorafenib or placebo. The end result, presented at the most recent ASCO Annual Meeting, showed that sorafenib prolonged overall survival from a median of 7.9 months in the placebo arm to 10.7 months in the active drug group.
The patients in the SHARP trial, though, were highly selected, with more than 900 individuals screened for the trial and enrollment restricted to those with a Child-Pugh A score. “So these were very fit patients with excellent hepatic function,” said Alan Venook, MD, Professor of Medicine and Hematology/Oncology at the University of California, San Francisco.
“Indeed when I first saw the SHARP results and the nature of the patients—the lack of underlying hepatitis in many of these patients, the Child-Pugh A score—I thought we were dealing with Olympic athletes. These seemed to be extremely fit patients who may not reflect the rest of the population. We've got some clarity now, at least in some subsets.
“In the 30 percent of patients [in the SHARP trial] with hepatitis C, the benefit of sorafenib was every bit as robust, if not more robust, than we've seen in the general group of patients treated on the study,” Dr. Venook said during his discussion of the abstract.
Sorafenib in Patients with HCV
Although more than 50% of the liver cancer patients in the United States and Europe have underlying hepatitis C (HCV) infection, fewer than one-third of those in the SHARP trial did. To learn how the infection affected the safety and activity of sorafenib, Fabio Piscaglia, MD, of the S. Orsola-Malpighi Hospital at the University of Bologna in Italy, and colleagues examined the clinical outcomes of the 29% of patients in the sorafenib arm and 27% in the placebo arm who were infected with HCV.
In this subgroup analysis, the median overall survival was 14.0 months in the sorafenib arm and 7.9 months in the placebo arm, which was a statistically significant difference. The time to progression also appeared to be longer in the active drug arm at 7.6 months vs 2.8 months in the placebo arm.
As with the total patient population in the trial, few HCV-infected patients showed tumor shrinkage by Response Evaluation Criteria for Solid Tumors (RECIST), but many did benefit in terms of disease stability. The drug appeared to be well tolerated in this patient subgroup. Eight patients (9%) had Grade 3 diarrhea, 12 (13%) had Grade 3 hand-foot syndrome, and three (3%) had Grade 3 fatigue. No Grade 3 toxicities were reported in the placebo arm.
Additionally, the overall rates of serious adverse events were similar in the two arms, with 50% of patients in the sorafenib and 55% in the placebo arm affected. The serious adverse events were mainly cirrhosis related, and the similar rates in the two arms indicate that sorafenib does not increase the risk of this complication.
“The safety and efficacy analysis of this subgroup were consistent with the overall SHARP population,” Dr. Piscaglia said. “The drug-related adverse events were generally mild to moderate in severity, and this is very important in a setting where you have two diseases. Sorafenib was effective in patients with hepatocellular carcinoma regardless of the HCV status. It was effective in patients [like those] that we meet in our every day life in our unit.”
In his concluding remarks, Dr. Venook noted that the patients in these trials are still healthier than many who come into the typical clinic. Yet the observation that sorafenib with doxorubicin is effective in advanced liver cancer with underlying hepatitis C infection reinforces the value of sorafenib in the disease and “represents a huge step forward.”
Doxorubicin May Boost Sorafenib's Anti-cancer Activity
Meanwhile, Ghassan Abou-Alfa, MD, Assistant Attending Physician at Memorial Sloan-Kettering Cancer Center, reported in the same session at the meeting that a combination of doxorubicin and sorafenib was better than doxorubicin alone in liver cancer patients.
The randomized Phase II study was underway when the SHARP trial results were released. Based on the positive outcome from that trial, the data safety monitoring committee responsible for the doxorubicin-sorafenib Phase II trial requested an unplanned interim analysis.
“The results of the phase II trials, though immature, indicated that patients randomized to doxorubicin alone were at a disadvantage,” Dr. Abou-Alfa said. “As such the data monitoring committee recommended that the study be discontinued.”
The study was not designed for a statistical comparison between the arms, but rather was exploratory in nature. That said, the arms were different in their outcomes. The median time to progression for the 47 patients in the combination arm was 8.6 months and for the 49 patients in the doxorubicin plus placebo arm, was 4.8 months. Overall survival was 13.8 and 6.5 months in the two arms.
As in the SHARP trial there were few objective responses by RECIST criteria, with two (4%) in the doxorubicin-sorafenib arm and one (2%) in the doxorubicin-placebo arm. Stable disease was common in both arms, with 77% of the patients in the combination arm and 55% in the placebo arm showing disease control. A waterfall plot demonstrated that 62% of patients in the combination arm and 29% in the doxorubicin-placebo arm had some measure of tumor shrinkage, however.
The safety of the combination appeared to be generally good, with the side effect profile resembling what is seen for each of the drugs when administered alone. In terms of Grade 3 or 4 toxicity, the rate of fatigue was the same in the combination arm and the doxorubicin-placebo arm (15%), abdominal pain was similar (10% vs 8%), the rate of neutropenia was somewhat higher with the combination (55% and 46%), diarrhea was similar (11% and 10%), and bilirubin elevation occurred in both arms (11% and 6%).
The one adverse event about which Dr. Abou-Alfa expressed concern was alteration in left ventricular function. One (2%) patient in the combination arm had a Grade 3 reduction in left ventricular function and nine (19%) individuals had Grade 1 or 2 reduction.
One patient (2%)in the doxorubicin-placebo arm had Grade 1/2 reduction in left ventricular function. This side effect “requires careful further investigation,” he said.
Still Has Place?
Following his presentation, an audience member asked if doxorubicin still has a place in the treatment of hepatocellular carcinoma in light of the SHARP results. Dr. Abou-Alfa responded that while that was an important question, it is one that can only be answered with a head-to-head trial comparing the combination of doxorubicin plus sorafenib to sorafenib alone. Such a trial is already in the works.
During his comments, Dr. Venook came back to this point, noting that if the same results, which he described as “profound,” were seen with sorafenib and a second targeted agent, everybody would be excited. “We have become so enamored with targeted agents that we tend to dismiss results that make use of our conventional agents,” Dr. Venook said.
The Phase II results may suggest synergy or interaction between doxorubicin and sorafenib. The underlying mechanism behind the interaction is not clear, particularly because the patients on the combination arm received only three rounds of doxorubicin, which is less than the regimen given in other settings.
The authors of both studies reported significant research funding and consulting or leadership roles with Bayer, the maker of sorafenib.
© 2008 Lippincott Williams & Wilkins, Inc.