First-Line Treatments for Metastatic Renal-Cell Carcinoma Are Evolving

August 2012 Vol 5, No 5, Special Issue ASCO 2012 Payers' Perspective - Renal-Cell Carcinoma

Chicago, IL—The list of choices for first-line pharmacologic therapy of metastatic renal-cell carcinoma (mRCC) is ever increasing. There are now 7 approved targeted therapies against the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways, said Daniel Y.C. Heng, MD, MPH, Clinical Associate Professor, Tom Baker Cancer Center, University of Calgary, Alberta, Canada, at ASCO 2012.

Oral VEGF tyrosine kinase in­hibitors (TKIs), such as sunitinib and pazopanib, and intravenous (IV) anti-VEGF antibodies, such as bevacizu­mab (in combination with interferon [IFN]-alpha), used as first-line agents, have extended progression-free survival (PFS) in patients with a favorable or intermediate prognosis in mRCC, said Dr Heng. Sorafenib is another option, and axitinib has been used as a second-line therapy after treatment with a cytokine or a VEGF inhibitor.

In patients with a poor prognosis, the mTOR inhibitor temsirolimus plus IFN-alpha has been shown to improve overall survival (OS) compared with IFN-alpha alone. Everolimus was approved by the US Food and Drug Administration (FDA) in 2011, al­though it is used as second-line therapy after a VEGF inhibitor.

However, no predictors of response to targeted therapy are available; therefore, the choice of therapy is usually based on the patient’s prognostic profile, physician preference, route of delivery (IV or oral), physician experience, and drug efficacy and toxicity profiles.

For example, a patient with poor pulmonary function “might not be the best mTOR candidate, simply because of the risk of noninfectious pneumonitis,” Dr Heng said. Patients with refractory diabetes are also not good candidates for mTOR inhibitors, because of the risk for hyperglycemia, and those with refractory hypertension who are taking several antihypertensive medications would not be good candidates for a VEGF inhibitor, he noted.

Recent and Emerging Comparative Clinical Trials
“Probably, the most important consideration is efficacy,” but no evidence from head-to-head efficacy trials exists so far, said Dr Heng, although some are emerging. Retrospective comparison analyses show that PFS is approximately 7.2 months with sunitinib as first-line therapy, 7.3 months with sorafenib, and 6.0 months with bevacizumab.

“What this means is that it’s unclear if there is a difference in efficacy with first-line therapy, and clinical trial results are greatly anticipated,” he said.

PISCES was a head-to-head clinical trial, but its primary end point was patient preference at 22 weeks, not treatment efficacy. PISCES compared the tolerability and toxicity level of sunitinib followed by pazopanib versus pazopanib followed by sunitinib in patients with mRCC, focusing on whether the differences in tolerability were significant enough to determine patient preference, a measure that is increasingly being included in the decision-making paradigm of treatment selection. Pazopanib was preferred by 70% of patients, sunitinib was preferred by 22% of patients, and 8% did not have a preference.

Results from the phase 3, head-to-head clinical trial COMPARZ are highly anticipated. COMPARZ is an open-label study comparing sunitinib with pazopanib as first-line therapy for patients with mRCC, with a primary end point of PFS duration and secondary end points include OS and quality of life.

The potent and specific TKI tivozanib, which is not yet FDA approved for mRCC, demonstrated an improvement in PFS as first-line targeted treatment compared with sorafenib in clear-cell mRCC (see article on page 21). “Pending FDA approval, tivozanib will probably be incorporated into the treatment algorithm,” said Dr Heng.

The RECORD-3 clinical trial is comparing 2 treatment sequences—sunitinib followed by everolimus versus everolimus followed by sunitinib in patients with mRCC; the primary end point is PFS duration associated with the first-line therapy. “This gives an indication of first-line VEGF versus mTOR efficacy and sequencing,” Dr Heng said.

Indicators of Treatment Response
Although there are externally validated predictive biomarkers in mRCC, recent studies have demonstrated that the development of hypertension during the first cycle of sunitinib therapy, as well as other therapy-related toxicities (eg, hand-foot syndrome, hypothyroidism) are associated with improved outcomes, but these are only helpful once therapy is initiated; these effects do not help guide the choice of therapy.

The presence of certain single- nucleotide polymorphisms (SNPs) can serve as a biomarker that may indicate improved patient outcomes, but SNPs, too, require validation. In addition, results obtained by examining genetic profiles are currently restricted to the Caucasian population, because there are substantial racial differences in SNPs.

Immunotherapy on the Horizon?
Immunotherapy with a programmed death 1 (PD-1) inhibitor could also be on the horizon, but clinical trials are in their early stages. Higher PD-1 ligand levels in patients with RCC have been associated with larger tumors, advanced-stage tumors, higher-grade tumors, and tumors with necrosis.

In a trial that included 18 patients with RCC, the overall objective response rate in the 16 patients who were treated with a 10-mg/kg dose of the investigational PD-1 inhibitor BMS-936558 was 31.2%, and the median duration of response was 4.0 months.

An autologous dendritic-cell im­mun­otherapy (AGS-003) was studied with sunitinib in 21 patients with RCC, with an overall response rate of 38% and a median PFS of 11.2 months; this is encouraging, because almost half of these patients had poor prognostic profiles.

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Last modified: August 30, 2012
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