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New Standards for VEGF-Resistant Metastatic Renal Cell Carcinoma

Goodwin, Peter M.

doi: 10.1097/01.COT.0000516156.02376.34
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renal cell carcinoma

renal cell carcinoma

MILAN, Italy—The first choice of therapy for patients with metastatic kidney cancer who have failed vascular endothelial growth factor (VEGF) therapy has changed according to experts at the 8th European Multidisciplinary Meeting on Urological Cancers who assessed phase III study data on two different agents—each of which showed clinically meaningful improvements to outcomes.

“There is a new treatment algorithm for individuals who have failed VEGF-targeted therapy,” said Thomas Powles, MBBS, MRCP, MD, Director of Barts Cancer Centre at St. Bartholemew's Hospital in London.

“Both the ESMO and EAU guidelines are [now] supporting nivolumab and cabozantinib rather than—[as] previously—supporting axitinib and everolimus.”

He based his comments on observations from the METEOR and CheckMate 025 studies, which found that therapy with cabozantinib or nivolumab improved overall survival (OS) compared to everolimus.

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Tyrosine Kinase

The METEOR study randomized 658 patients who had failed VEGF-targeted therapy either to cabozantinib—a VEGF AXL and MET tyrosine kinase inhibitor—or to the mTOR inhibitor everolimus (Lancet Oncol 2016;17(7):917-927). Patients in the cabozantinib arm had longer median OS (21.4 months compared with 16.5 months—hazard ratio (HR) 0.66), better response rates (17% compared with 3%), and a nearly doubled median progression-free survival (HR 0.51).

“What we have shown in this trial is [that] cabozantinib outperforms everolimus irrespective of prognostic risk groups that patients fall in. It can be used in patients who have failed multiple lines of VEGF-targeted therapy,” explained Powles.

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Immunotherapy

The CheckMate 025 study randomized 821 patients who had progression of their advanced renal cell carcinoma to treatment with the immune checkpoint inhibitor nivolumab or to everolimus (N Engl J Med 2015;373:1803-1813). Median OS in the nivolumab arm was significantly longer (25.0 months) than among patients treated with everolimus (19.6 months). The objective response rate was greater (25% compared with 5%) and nivolumab showed fewer serious adverse events. Nineteen percent of patients treated with nivolumab had grade 3 or 4 toxicities compared to 37 percent of patients treated with everolimus.

CheckMate 025 also found longer median OS with nivolumab in all subgroups, including those defined by region, MSKCC prognostic score, and number of previous regimens of antiangiogenic therapy.

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New Paradigm

“The goal posts have shifted here and now,” Powles said. “We have a choice between an immune therapy and a VEGF-targeted therapy. The immune therapy is well-tolerated, has a significant survival advantage, and has better quality of life. Living longer and feeling better is a really powerful goal for patients with cancer.

“The hazard ratio [for both carbozantinib and nivolumab] suggests delay of death in approximately a quarter to a third of patients—which is significant. We haven't seen those benefits before,” he continued. “This is an exciting time in kidney cancer. [But] we need to identify biomarkers.”

Phillip M. Pierorazio, MD, Assistant Professor of Urology and Oncology at Johns Hopkins University, Baltimore, agreed the emerging clinical options for treating metastatic kidney cancer were promising.

“We're at a dramatic and exciting time for kidney cancer—especially advanced kidney cancer,” he said. “For 30 years we've had minimal options for curative therapies and so we're basically managing patient expectations, managing progression-free survival while trying to delay metastasis and give patients good quality of life.

“In the past year or so—with the introduction of checkpoint inhibitors and [other] new exciting therapies—the time is very hopeful for kidney cancer patients. Not all patients are responding, but for some patients who do there's a wonderful chance [of] a long-term, more durable survival.

“Importantly—for some of these drugs—there are patients we call ‘exceptional responders’ who are having long-term durable responses that are not necessarily seen in the curves for the entire study. So that's the very exciting and intriguing thing for some patients who have advanced disease,” Pierorazio concluded.

Peter M. Goodwin is a contributing writer.

Wolters Kluwer Health, Inc. All rights reserved.
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