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33rd Congress of the European Society for Medical Oncology

Stockholm, Sweden / September 12-16, 2008

According to Dr. Peter Mulders, Radboud University Nijmegen Medical Centre, The Netherlands, in a 1999 study of 154 clinically important management decisions/interventions across 14 tumour types, only 24% were supported by level 1 evidence, suggesting the need to consider other kinds of evidence beyond phase III clinical trials. Dr. Mulders described how earlier this year, a panel of 12 experts met to assess which factors should be considered when choosing optimal treatment for specific patients with advanced renal cell carcinoma (RCC). The panel proposed a simple, patient-focused schema to assist clinical decision-making; the usefulness of this schema was assessed by a second separate panel using sorafenib data. The schema was based on primary and subgroup analyses of phase III clinical trials and expanded–access programs in Europe and North America such as ARCCS (Advanced Renal Cell Carcinoma Sorafenib) that included a broad range of patients not included in clinical trials as well as single-centre studies in particular patient subgroups.

The panel recommendations were based on specific disease-, patient- and treatment-related characteristics, Dr. Mulders explained. “The panel determined that sorafenib is effective in a broad range of patients with RCC, including those with multiple metastases, elderly patients with comorbidities, patients previously treated with cytokines, and patients on other targeted therapies,” he told delegates.

The tyrosine kinase inhibitor (TKI) sorafenib was strongly recommended for good- and intermediate-risk patients with clear cell histology and zero to three metastases in the lymph nodes, liver, lung, and bone. It was also recommended for younger and older patients with performance status 0-2 and with hematologic comorbidities, controlled hypertension, cirrhosis and renal illness; and for patients regardless of whether they had previous cytokine therapy, with the goal of prolonged survival, disease stabilization, and maintaining quality of life.

Cardiovascular Safety in Clinical Trials

Targeted therapies used in the treatment of RCC have been associated with cardiovascular (CV) events such as myocardial infarction (MI), hypertension and congestive heart failure (CHF). In order to determine the CV safety profile of sorafenib monotherapy, investigators compiled CV adverse-event data from 19 phase I, II and III clinical trials involving a total of 2276 patients with renal cell, breast, colorectal, hepatocellular, or non-small cell lung cancer.

Most adverse events were clinically manageable. Hypertension was the most common adverse event, and the majority of cases were mild to moderately severe and responded to standard antihypertensive therapy. While adverse CV events have been presumed to be a class effect of TKIs, it was suggested that sorafenib might be an exception.

CHF was reported in 43 patients (1.89%) and was serious in 31 (1.36%). One patient experienced a decrease in left ventricular ejection fraction (LVEF). MI occurred in 28 patients (1.23%) and was a serious adverse event in 27 patients (1.19%). Treatment-emergent hypertension was found in 438 patients (19.24%) and was considered serious in 12 patients (0.53%). Most cases of hypertension were grade 2 or 3. Severe hypertension described as hypertensive crisis occurred in five patients, investigators reported.

Cardiovascular Safety in a Real-world Population

In patients with advanced RCC, hypertension is likely to be present as a comorbid condition. Data have suggested that some antiangiogenic therapies are known to increase the rate of hypertension and some have been associated with a reduction in LVEF or an increase in arterial thromboembolic events. Since patients with clinical CV diseases (CCDs) treated with a TKI could be at an increased risk of CV adverse events, a subset analysis of the large expanded European (EU)-ARCCS trial was conducted to address these concerns, explained lead author Prof. Tim Eisen, Cancer Research UK, Cambridge Research Institute.

EU-ARCCS enrolled 1159 patients recruited from 11 European countries. Of the 1148 evaluable patients, 490 had CCD and 658 had no evidence of CCD. CCD was defined as coronary heart disease, stroke, hypertension or CHF. Clinical benefit, progression-free survival (PFS), safety and treatment duration were assessed for between-group differences.

PFS and clinical benefit of treatment were similar in both groups. Median PFS was 6.9 months overall, 6.8 months for those with CV disease and 6.9 months for those without. More than three-quarters of patients in both groups derived clinical benefit from sorafenib (i.e. complete or partial response and stabilized disease for 12 weeks or longer).

Among 978 patients evaluable for safety, the frequency and types of grade 3 or higher adverse events were similar for patients with and without CCDs. Notably, there were no differences in LVEF. Grade 3 or higher drug-related cardiac adverse events were similar between the two groups, with the exception of hypertension, which was seen more frequently in patients with CCD (7.7%) vs. 2.1% in patients without (Table 1). Baseline hypertension was an inclusion criterion for the group with CCDs, so it was not surprising to see elevated systolic blood pressure (BP) in this group compared with their counterparts.

According to the authors, in advanced RCC patients with a baseline CCD status, treatment with sorafenib 400 mg b.i.d. does not affect clinical benefit or safety.

Table 1. Grade <u>></u>3 Drug-related Cardiac Adverse Events* (%)

Left Ventricular Ejection Fraction

In targeting angiogenic pathways, anti-vascular endothelial growth factor therapies may increase CV adverse events due to effects on the vasculature and cardiac tissues. A decline in LVEF and the development of CHF have been reported with other TKIs, but have been uncommon in studies with sorafenib. To that end, a small open-label, two-centre, phase I study assessed the cardiac effects of chronic sorafenib monotherapy. The study enrolled 53 cancer patients with advanced solid tumours or lymphoma who received sorafenib 400 mg b.i.d. for up to five cycles (one cycle=28 days). LVEF was assessed by multigated acquisition (MUGA) scan at baseline, day 1 of cycles 3 and 5, and at study discontinuation. Treatment was continued until disease progression or unacceptable toxicity.

At baseline, all patients had a LVEF <u>></u>45%, systolic BP <u><</u>170 mm Hg or diastolic BP <u><</u>100 mm Hg, and QTc <500 msec. Exclusion criteria were a history of CHF greater than New York Heart Association class II, cardiac arrhythmias requiring therapy other than beta blockers or digoxin, uncontrolled hypertension, and prior anthracycline use. Active coronary artery disease or MI more than six months prior to study entry was allowed as long as LVEF <u>></u>45%.

Overall, little or no change in mean LVEF from baseline was seen on day 1 of cycle 3 and cycle 5, and at study discontinuation. However, some isolated patients experienced <u>></u>10% decrease in LVEF on serial MUGA scans. Minimal prolongation of mean changes in QTc intervals were seen (9 msec for Fridericia-corrected QTc and 4 msec for Bazett-corrected QTc) following sorafenib. Mean increases from baseline of 12 mm Hg and 11 mm Hg were seen for systolic and diastolic BP, respectively. Most patients had BP <u><</u>150/90 mm Hg. Minimal decreases in heart rate were observed on day 1 of cycle 2.

Summary

As no specific therapy is applicable to all patients, a patient-focused schema can facilitate treatment decisions in the real-world clinical setting. The parameters to consider for treatment choices are disease, patient and treatment-related characteristics. While clinical trials have demonstrated the efficacy of targeted therapies in RCC, hepatocellular carcinoma and other tumour types, specific analyses of trials with sorafenib have demonstrated its relative cardiac safety in patients with or without CCD and have demonstrated safety and efficacy in a broad range of patients.