36 oe VOL. 12, NO. 4, NOVEMBER 2013 Report from CAGMO Renal cell carcinoma IS PAZOPANIB THE PREFERRED FIRST-LINE TREATMENT FOR METASTATIC RENAL CELL CARCINOMA? Eric Winquist, MD, FRCPC, FACP, Consultant Medical Oncologist, London Health Sciences Centre COMMENTARY: Highlights of the 8 th Annual Meeting of the Canadian Association of Genitourinary Medical Oncol- ogists included a debate between Dr. Kylea Potvin from the London Health Sciences Centre and Dr. Piotr Czaykowski of CancerCare Manitoba in Winnipeg on the optimal treat- ment for metastatic renal cell carcinoma. Sunitinib is an oral small molecule multikinase inhibitor considered the de facto standard of care in first-line treat- ment for patients with metastatic clear cell renal cell cancer. Pazopanib is another multikinase inhibitor active in renal cell cancer. Although both agents are believed to exert their clinical effects through inhibition of vascular endothelial growth factor receptors (VEGFR), pazopanib has been proposed as an equally efficacious but less-toxic alternative to sunitinib. At the time of the debate, results of a first-line open-label randomized trial comparing sunitinib with pazo- panib using a noninferiority design had been presented at the 2012 European Society of Medical Oncology (ESMO) Annual Meeting. More recently, the results of the trial have been formally published. 1 The debaters provided a spirited and entertaining debate that identified the most important issues when reviewing these results and considering their application in clinical practice. The motion proposed for debate was: “Pazopanib is the preferred first-line treatment for metastatic renal cell carcinoma.” Dr. Czaykowski argued the affirmative and Dr. Potvin the negative. SUMMARY: Yes, pazopanib is the preferred first- line treatment for metastatic renal cell carcinoma Piotr Czaykowski, MD, MSc, FRCPC, Medical Oncologist, Cancer- Care Manitoba, Internal Medicine and Community Health Sciences, University of Manitoba, Winnipeg. Metastatic renal cell carcinoma (mRCC) can be an unpre- dictable disease, but in most patients it is relentlessly pro- gressive and leads to substantial morbidity and, ultimately, death. With 6 new agents licensed in Canada for the man- agement of advanced renal cell carcinoma (RCC), we are now in an era when we can select the most appropriate treat- ment based on published efficacy and toxicity data. For patients with metastatic clear cell renal cell carcinoma (mCCRCC) who have good- or intermediate-prognosis dis- ease based on Memorial Sloan-Kettering Cancer Center (MSKCC) or Heng criteria, the standard first-line therapy has been the oral agent sunitinib, which doubles the pro- gression-free survival (PFS) duration compared to interferon- alpha. 2-4 However, sunitinib therapy is often accompanied by bothersome toxicity, necessitating dose and schedule adjustments. Although a number of studies have postulated that the standard dose and schedule of sunitinib are not optimal and underplay this agent’s true benefit and tolera- bility, there are no data from randomized trials to support this contention. The highest quality evidence suggests that the standard approved dosing of sunitinib is often difficult to tolerate. 5 A well-designed randomized controlled trial (RCT) of first-line pazopanib vs sunitinib has now been published. 1 The COMPARZ trial included 1,110 patients with mCCRCC. The subjects had received no prior systemic therapy and had measurable disease with a good perfor- mance status and adequate organ function. Subjects were randomized to pazopanib 800 mg once daily vs sunitinib in standard dosing (50 mg daily for 4 weeks on, followed by 2 weeks off). The study was powered to demonstrate the noninferiority of pazopanib in regard to PFS. The results of the COMPARZ study are clear. Pazopanib is noninferior to sunitinib, with a hazard ratio (HR) of 1.05 and a 95% confidence interval (CI) of 0.90 to 1.22. In numeri- cal terms, this translates to a median PFS of 8.4 months for pazopanib vs 9.5 months with sunitinib. Visually inspecting the PFS Kaplan-Meier curves demonstrates that they are essentially superimposable. Median overall survival (OS) is 28.4 months with pazopanib and 29.3 months with sunitinib (HR actually favours pazopanib at 0.91, 95% CI 0.76–1.08; p=0.28), and pazopanib is also numerically superior in terms of independently verified partial and complete responses (31% vs 25%; p=0.03). There were no significant differences in the need for treatment interruption, dose reduction or treatment dis- continuation. More fatal adverse events (AEs) were reported for sunitinib (19 events) than for pazopanib (13 events). Pazopanib use was associated with a higher incidence of hepatic toxicity, namely rises in transaminases and bilirubin (17% grade 3–4 ALT elevation), but this led to discontinu- ation in only 6% of patients. Of great interest is the fact that pazopanib is clearly better tolerated than sunitinib. The COMPARZ study did a commendable job of tracking health-related quality of life (HRQOL) using 4 validated tools. Assessments were per- formed at baseline, on day 28 of cycles 1 through 9 and on day 42 of subsequent cycles. Changes in mean scores over LANDMARKS