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MEDICAL FRONTIERS - 45th Annual Meeting of the American Society of Clinical Oncology

Orlando, Florida / May 29-June 2, 2009

Targeted therapies are providing rational and evidence-based choices in cancers for which there were few or no options previously. These targeted therapies include such multikinase inhibitors as sorafenib and sunitinib as well as extracellular receptor ligand inhibitors, such as those that target the receptor for vascular endothelial growth factor (VEGF) and those that act directly on VEGF. In both hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), new data have immediate clinical implications.

AP and SHARP Findings

A new phase III study with the tyrosine kinase inhibitor (TKI) sorafenib in HCC, called the AP (Asia-Pacific) trial, has reinforced the results of the first phase III study called SHARP (Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol) and increased the pool of efficacy and safety data. “Results of the phase III randomized, double-blind, placebo-controlled AP trial demonstrated that it is effective and safe for the treatment of advanced HCC. In our new data from this trial, we have shown that sorafenib is an effective treatment for HCC irrespective of baseline liver transaminases,” reported Dr. Shukui Qin, Nanjing 81 Hospital, Nanjing, China.

The recently published AP trial (Cheng et al. Lancet Oncology 2009;10:25-34) included 271 patients with advanced HCC from 23 centres in Asia. They were randomized in a 2:1 ratio to sorafenib 400 mg or placebo. The 2.3-month increase in survival generated a hazard ratio (HR) of 0.68 (95% CI, 0.50-0.93; P=0.014) in favour of the TKI.

In this substudy, the overall survival (OS) was reduced in patients with evidence of impaired liver function, but the relative survival advantage conferred by sorafenib was retained, producing consistent HRs for mortality across liver enzyme values. HRs for other outcomes favouring the agent, such as time to progression (TTP) and disease control rates (DCR), were also comparable across baseline liver transaminase and alpha-fetoprotein (AFP) levels.

The AP data substantially expand and enrich the evidence of efficacy that was generated by the landmark SHARP trial, which was published about six months earlier (Llovet et al. N Engl J Med 2008;359:378-90). This study randomized 602 patients with advanced HCC to sorafenib 400 mg or placebo twice daily. The study participants had not received previous systemic therapy for their malignancy. In this study, the improvement in survival was almost three months (10.7 vs. 7.9 months), generating a 31% relative advantage for the TKI (HR 0.69; 95% CI, 0.55-0.87; P<0.001). The mean interval to radiological progression was 5.5 months in the active-treatment group vs. 2.8 months in the group on placebo (P<0.001).

Analysis of Baseline Characteristics on Response

Data from AP and SHARP were analyzed by Dr. Jordi Bruix, Liver Clinic, IDIBAPS Hospital Clinic, Barcelona, Spain, in order to look for the effects on response of other baseline characteristics, particularly Eastern Cooperative Oncology Group (ECOG) performance status and presence or absence of macroscopic vascular invasion (MVI) or extrahepatic spread (EHS).

Again, HRs for OS remained in a relatively tight range between 0.45 and 0.77 favouring sorafenib in both data sets (Table 1). In addition, a subset analysis of response according to hepatic function in the AP trial demonstrated the TKI to be effective irrespective of baseline liver function (Table 2).

Table 1.

This consistency of results across baseline features is reassuring because of potential geographic variations with this malignancy, which is much more common in Asia due to high rates of hepatitis B. Not only were response rates similar across different baseline features and geographic regions, but so were side effects. “Overall, sorafenib was well tolerated. When compared to placebo, the most common grade 3 to 4 adverse events in both studies were hand-foot skin reaction (7.7%-10.0% vs. 0%-0.3%), diarrhea (6%-8.4% vs. 0%-1.7%) and fatigue (3.4%-3.7% vs. 1.3%-3.6%),” Dr. Bruix reported. “The results of our subgroup analysis support its utility in patients across geographic regions and with a variety of
actors.”

Table 2.

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Characteristics Influencing Treatment Patterns

The likelihood of receiving TKIs or any other therapy in HCC appears to be strongly influenced by the presence of comorbidities and patient age, according to an analysis of a US healthcare claims database. Claims for 4153 cases of identified HCC between 2002 and 2008 were stratified by baseline characteristics, including age, HCC risk factors, time to treatment and type of treatment.

When compared to younger patients, these patients received noncurative treatments sooner (58 days vs. 110 days; P<0.001) and were less likely to receive transplantation (2.2% vs. 10.7%; P<0.001), according to Dr. Arun Sanyal, Virginia Commonwealth University School of Medicine, Richmond. Transplantation and resection were performed earlier in younger patients. When TKIs were available, although not significant, data suggest older patients were less likely to receive them (2.8% vs. 3.2%).

Risk factors for HCC included non-alcoholic fatty liver disease, diabetes and hepatitis C and did not differ by age stratification, suggesting practice patterns are influenced by age.

RCC Data

In RCC, targeted therapies have also been associated with substantial improvements in meaningful measures of clinical benefit, including progression-free survival (PFS) and OS, but the order of first-line and subsequent therapies is less well established because a broad number of studies have compared several different types of targeted therapies to placebo or to cytokines but not to each other.

In addition to multikinase inhibitors such as sorafenib and sunitinib, well-controlled trials have associated the VEGF inhibitor bevacizumab and the mTOR inhibitor temsirolimus with activity in various treatment-experienced and treatment-naive patients with advanced RCC. The inhibitors of VEGF (bevacizumab, sorafenib, sunitinib) and mTOR (temsirolimus and everolimus) have led to a significant improvement in clinical outcome and are now commonplace for the treatment of metastatic RCC. However, despite these major advances, important questions remain about the sequence of such therapies, reported a team of investigators led by Dr. Daniel Heng, Tom Baker Cancer Centre, Calgary, Alberta.

In a study they described here at ASCO, the outcomes of second-line therapies were assessed in patients initially treated with sorafenib, sunitinib or bevacizumab at seven participating institutions in Canada and the US. Of the 645 patients treated with one of these agents, 216 (33%) received a second-line therapy. Among agents that work along the VEGF pathway, these were sunitinib in 93 patients, sorafenib in 80 patients, bevacizumab in 11 patients and axitinib in 8 patients. Of agents that work along the mTOR pathway, 21 received temsirolimus and three received everolimus.

In a multivariate analysis, the only predictor of receiving a second-line therapy was a Karnofsky Performance Status (KPS) score >80% prior to receiving the first-line therapy. “The median time to treatment failure of second-line therapy was 4.9 months for a VEGF-inhibiting agent and 2.5 months for mTOR inhibitors (P=0.014),” Dr. Heng and his co-investigators reported. This translated into a 48% reduction in risk (HR 0.52; 95% CI, 0.29-0.91; P=0.014). The relative advantage of the VEGF inhibitors persisted after adjusting for non-clear cell histology and sarcomatoid features, although an OS advantage did not reach significance (14.2 vs. 10.6 months, P=0.38).

However, the ability to even assess relative efficacy of a second-line therapy in metastatic RCC is indicative of major advances in a disease that had once been generally managed with palliative care. Several studies published over the past few years have changed clinical practice: one demonstrating a PFS benefit of sorafenib when compared to placebo in clear-cell RCC patients who had failed previous treatment (Escudier et al. N Engl J Med 2007;356:125-34); another demonstrating a PFS advantage of sunitinib over interferon (IFN) in first-line metastatic RCC (Motzer et al. N Engl J Med 2007; 356:115-24); and a third showing an added OS benefit of temsirolimus monotherapy over its combination with IFN or IFN alone in poor-risk metastatic RCC (Hudes et al. N Engl J Med 2007;356:2271-81). However, comparison studies of targeted therapies remain uncommon, making the relative risks and advantages difficult to assess.

Medical Claims Database Perspective

One retrospective study attempting to address this question observed dosing patterns for sorafenib and sunitinib in a US medical claims database. In this study, the database produced 189 RCC patients who had been prescribed sorafenib and 204 patients who had been prescribed sunitinib. There were no significant baseline characteristic differences in the two groups other than a higher incidence of stroke (7.9% vs. 3.8%; P=0.037) and a higher incidence of cancers at sites other than RCC (93.7% vs. 87.8%) in the sorafenib group.

When compared, fewer patients on sunitinib received the recommended dose (50 mg/day) than sorafenib (800 mg/day). “In the first three months of treatment, 65% of sunitinib patients vs. 25% of sorafenib patients had a dose reduction (P<0.001). After controlling for different lengths of exposure time to each drug, the proportion of patients with at least one dose reduction was up to six times greater in sunitinib-treated patients than in sorafenib patients, and this difference was statistically significant for the first three months and for the complete initial episode of treatment (P<0.001),” reported Dr. Stephen M. Keefe, Abramson Cancer Center, Philadelphia, Pennsylvania.

For the complete treatment comparison, dose reductions occurred in 35.5% of sunitinib patients vs. 16.9% of sorafenib patients (P<0.001). The mean time to dose reduction was 104.3 days in the sunitinib group vs. 161.6 days in the sorafenib group (P=0.003). Further prospective studies to identify the reason for these differences and to determine whether they affect treatment outcome are warranted.

Treatment Effect on Time to Progression

In comparing treatments for advanced RCC, whether conventional chemotherapy agents, targeted agents or a combination of therapies, it is reasonable to employ time to disease progression or PFS as meaningful outcomes, according to a study designed to evaluate this premise.

In this study, 28 published trials assessing 39 potential treatment comparisons in 8770 participating metastatic RCC patients were evaluated. These included trials with cytokines such as IFN and interleukin-2, chemotherapies such as vinblastine, small-molecule inhibitors such as sorafenib and sunitinib, mTOR inhibitors such as temsirolimus and everolimus, and bevacizumab were included. “Results of this study suggest that treatment effects on measures of time to progression, especially PFS, are predictive of treatment effect on OS in patients with metastatic RCC,” reported Dr. Thomas E. Delea, Policy Analysis Inc., Brookline, Massachusetts. “The usage of PFS and time to progression end points for OS may be appropriate in clinical trials of novel treatments for metastatic RCC.”

This is a potentially important finding, because trials that employ survival as a primary end point take more time to complete and are more expensive. With the recent proliferation of new therapies for advanced and metastatic RCC, shorter and more efficient comparisons are needed to more rapidly sort out the relative benefits and risks of the available agents that have shown activity in this disease. Identification of the relative benefits of these agents will not only allow patients to be guided to the therapy most likely to improve control of their disease but will also facilitate efforts to build further on activity by combining the most effective proven agents with novel treatments in clinical studies.

Summary

The activity of targeted agents in advanced HCC and advanced or metastatic RCC represents a profound evolution in the approach to these malignancies. These therapies are providing new opportunities to offer patients modest but meaningful improvements in outcome. While the recent AP trial has contributed new evidence for the efficacy and safety of sorafenib as a first-line therapy in advanced HCC, there has been progress in sorting out the relative efficacy of a variety of different types of targeted therapies in RCC, including which therapies might work best as second-line options in patients who have already received a first-line targeted drug. It is hoped that this progress is a first step toward the ultimate goal of long-term disease control.