Everolimus Safety in RCC Maintained With Expanded Access

Becky McCall

February 28, 2012

February 28, 2012 (Paris, France) — Under an expanded-access program, everolimus (Afinitor, Novartis) has a safety profile and tumor response consistent with those seen in RECORD-1 (Cancer. 2010;116:4256-4265), the registration study of patients with metastatic renal cell carcinoma (RCC), Italian researchers announced here at the European Association of Urology 27th Annual Congress.

"The phase 3 RECORD-1 trial established everolimus, a mammalian target of rapamycin (mTOR) inhibitor, as an agent able to provide clinical benefit to patients with metastatic RCC" after the failure of an initial vascular endothelial growth-factor receptor tyrosine kinase inhibitor (VEGFr-TKI) therapy, the authors explain.

This recommends everolimus as a standard of care when VEGFr-TKI therapy has failed in metastatic RCC, according to Sergio Bracarda, MD, director of medical oncology at the Istituto Toscano Tumori, Arezzo, Italy, who presented his team's findings.

Dr. Bracarda led the subanalysis of everolimus in European patients with metastatic RCC in the RAD001 Expanded Access Clinical Trial in RCC (REACT).

REACT was an evaluation of safety and tolerability of everolimus in a patient population broader than the previous placebo-controlled RECORD-1 trial. Patients were able to receive everolimus because no other treatment option existed.

"We found that the data were similar between the European and the international REACT populations. This is evidence that the use of this drug in a larger population does not show increased toxicity. Efficacy is also maintained," he reported.

"This information is derived from a patient population that is more similar to the everyday population than to the patients selected for registration studies," Dr. Bracarda told Medscape Medical News.

In REACT, 1367 patients from 34 countries received everolimus after VEGFr-TKI therapy failed. The focus of Dr. Bracarda's team was on the 900 patients in Europe. Patients received everolimus 10 mg once daily; the dose was reduced to 5 mg if toxicity was unacceptable.

In RECORD-1, median progression-free survival with everolimus was more than twice that of placebo (4.9 vs 1.9 months; hazard ratio, 0.33; < .001).

Tumor responses to everolimus were similar in the European population of REACT, the overall REACT population, and the RECORD-1 population.

In the European population, 51.4% of patients had stable disease and 1.1% had a partial response.

Grades 3 and 4 toxic events reported in the European REACT population included anemia (9.2% and 2.5%, respectively), stomatitis (5.6% and 0.1%, respectively), hyperglycemia (4.7% and 0.6%, respectively), pneumonia (2.4% and 0.4%, respectively), and pneumonitis (2.2% and 0.3%, respectively).

The overall incidence of grades 3 and 4 adverse events was 50.7% and 11.3%, respectively, which is comparable to that seen in the overall REACT population (48.8% and 12.8%, respectively).

Dr. Bracarda explained that "these are expected, class-specific side effects of mTOR inhibitors, linked to the metabolic and immunosuppressive, not only the antiangiogenic, effects of these drugs in advanced renal cancer."

"We have provided this drug to a larger population without evidence of increased toxicity but with maintenance of activity," Dr. Bracarda reported.

"We cannot cure kidney cancer, but we can extend survival with active and effective drugs," he said. "We can provide a safe drug with evidence of efficacy and the possibility to use this drug in the clinic with broader limits, beyond the rigid selection criteria linked to the registration study."

"There are a lot of new drugs in first- and second-line use; these need experts in the field to use selectively at the right time and for the right patient. The drug safety and efficacy need to be considered alongside patient comorbidities," Dr. Bracarda pointed out.

Session moderator Gero Kramer, MD, from the University of Vienna, Austria, explained that an "ongoing discussion is who should provide and prescribe these drugs — urologists or medical oncologists? It is so important that these people have the data to deal with these side effects. We need to know what the drugs are doing and when they are indicated."

Also commenting on the results, Martin Spahn, MD, from the Department of Urology and Pediatric Urology, University Hospital Wuerzburg, Germany, said that these results will add to our understanding of sequential treatments.

At the moment, we don't know "the sequence of therapies after failed prior therapy in metastatic kidney cancer. There are no standards right now to say what should follow first-line treatment," Dr. Spahn told Medscape Medical News.

"This study looked at the use of an mTOR inhibitor after the failure of a VEGFr-TKI. It is quite impressive that 51% of the patients had stable disease after about 6 to 8 weeks of treatment. But we need longer follow-up and a substratification of these patients so we know which patients best benefit from mTOR inhibitors and which might benefit from a second tyrosine kinase inhibitor or other drug," he added.

Everolimus is recommended as the standard of care for patients with VEGFr-TKI-refractory metastatic RCC, according to clinical practice guidelines released by the European Association of Urology, the European Society for Medical Oncology, the European Organisation for Research and Treatment of Cancer, and the National Comprehensive Cancer Network.

This study was sponsored by Novartis. Dr. Bracarda reports being been consultant to Novartis, Pfizer, Bayer, GSK, and Astellas. Dr. Spahn has disclosed no relevant financial relationships.

European Association of Urology (EAU) 27th Annual Congress. Presented February 24, 2012.


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