Reports

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14th European Cancer Conference (ECCO-14)

Barcelona, Spain / September 23-27, 2007

As reported by Dr. Josep Llovet, Associate Professor of Medicine, and Director, Liver Cancer Research, Mount Sinai School of Medicine, New York, New York, sorafenib, a Raf kinase, VEGFR and PDGFR inhibitor which targets enzymes involved in proliferation and angiogenesis, is the first agent to show a statistically significant improvement in overall survival for patients with advanced hepatocellular carcinoma (HCC).

The SHARP Trial

SHARP (Sorafenib HCC Assessment Randomized Protocol) was a randomized, double-blind trial carried out to continuously evaluate the efficacy and safety of sorafenib 400 mg b.i.d. vs. placebo. It involved 602 European and North American patients (87% male) whose median age was 65 to 66 years and who had advanced HCC. About a fifth had undergone surgery and 40% loco-regional therapies but none had prior exposure to systemic therapy.

Dr. Llovet reported that the trial was halted prematurely because a planned interim analysis disclosed that the 297 actively-treated patients had a highly statistically significant increase (44%) in the primary end point of median overall survival that was 2.8 months longer (10.7 months) than in the 302 placebo-control cohort (7.9 months). This allowed the trial to be unblinded so that the surviving placebo recipients (n=125) could cross over to active therapy (n=156). The hazard ratio favouring active treatment was 0.69 (P=0.00058). Median time to progression was nearly double (5.5 vs. 2.8 months (P=0.000007), which Dr. Llovet characterized as “an outstanding result.”

The rates of serious treatment-emergent adverse effects were similar in the actively treated group vs. placebo (52% vs. 54%, respectively) and the most common grade 3-4 events were diarrhea (11% vs. 2%), hand-foot skin reaction (8% vs. 1%), fatigue (10% vs. 15%) and bleeding (6% vs. 9%).

“The SHARP trial clearly shows that sorafenib’s effect is clinically meaningful,” Dr Llovet stated. “It represents a breakthrough in the management of HCC because this is the first time we have had an effective systemic treatment for this highly aggressive disease, the third leading cause of cancer death worldwide. Now, however, after 30 years of research and more than 100 randomized controlled trials, the SHARP trial establishes sorafenib as a first-line treatment. And because there are no therapies that significantly improve survival for the thousands who have liver cancer, we can regard it as the new reference standard for first-line systemic therapy of HCC patients. What is more, the data suggest that it is well tolerated with manageable side effects.”

New Directions for Future Research in HCC

Dr. Llovet emphasized that the success of sorafenib in the SHARP trial was just a first stage. The drug should also be studied as adjuvant therapy, to reduce relapse after resection/ablation or chemoembolization, and in combination with other drugs. It could also be used as a comparator in trials of other new therapeutic agents.

Dr. Jordi Bruix, senior consultant, Hepatology Unit, Hospital Clinic of Barcelona, Spain, concurred that the results of the SHARP trial are likely to influence the development of new ways to treat HCC. “Treatment strategies will change for many patients with advanced HCC for whom the only currently available intervention is best supportive care. That is of paramount importance. It is likely to have a big impact on future advances and research protocols.”

The SHARP trial confirmed that targeted therapeutic interventions now have an important role. It highlights the need to test other agents that block different signalling pathways, either in combination with sorafenib or alone. “That will require major and long-term research but eventually will provide substantial benefit to many HCC patients and prove well worthwhile,” Dr. Bruix told delegates.

This is good news for patients with advanced HCC, he added, but the future should see targeted therapies for the less seriously ill too. Researchers are also investigating targeted agents that might reduce or delay recurrence of the disease after effective first-line sorafenib treatment. “Clearly, this is an area we must explore and develop. There are lots of signalling pathways to investigate.”

Combination Therapy in HCC

Preliminary results were presented at this meeting of a phase II double-blind study of doxorubicin/sorafenib combination therapy in patients with advanced HCC. The trial involved 96 patients randomized to the combination of intravenous doxorubicin 60 mg/m2 every 21 days for a maximum of 18 weeks plus sorafenib 400 mg orally b.i.d. (n=47) or to doxorubicin plus placebo (n=49). Patients in the active-treatment arm had an overall survival of 13.7 months vs. 6.5 months in the placebo group. Progression-free survival was 6.9 vs. 2.8 months, respectively. According to investigator Dr. Ghassan Abou-Alfa, Memorial Sloan-Kettering Cancer Center, New York, New York, these outcomes were “encouraging” and in line with the results of the SHARP trial.

Treatment of Melanoma

Although previous experience with sorafenib alone in melanoma has not been promising, encouraging results were reported in previous phase I/II trials with the combination dacarbazine/sorafenib. To that end, Dr. David McDermott, Beth Israel Deaconess Medical Center, Boston, Massachusetts, reported on a phase II, randomized, placebo-controlled, multicentre study with the combination vs. dacarbazine/placebo in 101 patients with unresectable stage III or IV melanoma who had not received prior cytotoxic chemotherapy. Researchers concluded that the active combination treatment regimen was well tolerated in these chemotherapy-naïve patients with advanced melanoma, with a strong efficacy trend vs. dacarbazine/placebo in progression-free survival, progression-free survival at six months and overall response rate. Investigators concluded that these results warrant further evaluation of this regimen in larger clinical trials.

Rethinking Clinical Trial Design

Although advances in HCC treatment are now no longer hindered by the absence of any active agent, progress nevertheless may still be hampered by conventional clinical trial designs unsuitable for assessing potential HCC therapies. For example, a key question that arose from the SHARP trial, and which has important implications for future studies, is determining which end points are now most appropriate in trials of anti-cancer agents. In some instances, tumour response, the standard primary end point, might not reflect the activity of a targeted agent as accurately as time to tumour progression. “It is no longer a valid end point,” according to Dr. Bruix.

He explained that one issue is that because most patients have cirrhosis or chronic liver disease as well as cancer, it is difficult to assess the effect on survival of a putative new agent. Another concern is that whereas conventional assessment of response requires at least a halving of tumour volume, a much smaller effect might be clinically important. Also, true tumour response can be obscured by variability among HCC patients due to the multiple etiologies of the disease. These are all obstacles to a better understanding of the key molecular changes that lead to HCC development.

As stated by Dr. Bruix, present end points should be supplanted by more realistic ones such as longer survival, symptom palliation and improved or maintained quality of life. Trial designs should include stratification of patients according to a clinical prognostic scoring system, such as the Child-Pugh classification of liver insufficiency, and by disease etiology—HBV-related or HCV-related, for example. Patients who might benefit from systemic therapy could then be better identified, he concluded.