Presenter: R.J. Motzer Presenter's Affiliation: Memorial Sloan Kettering Cancer Center, New York, NY Type of Session: Scientific
Treatment of metastatic renal cell carcinoma (RCC) has changed dramatically over the past several years with the availability of targeted agents.
As the role of angiogenesis and tumor proliferation in RCC has come to light, agents effective at multiple sites along these pathways have been developed and demonstrated to be efficacious in varying degrees. These agents include:
Sunitinib and sorafenib, multi-targeted, small molecule, tyrosine kinase inhibitors of the vascular endothelial growth factor receptor (VEGFr-TKI therapies).
Bevacizumab, a monoclonal antibody directed against VEGF
Axitinib, an oral and selective tyrosine kinase inhibitor
Temsirolimus, an inhibitor of the mammalian target of rapamycin (mTOR)
mTor is an intracellular kinase that regulates cell proliferation and angiogenesis. Everolimus (RAD001) is an oral inhibitor of mTOR, which has been shown in a single-arm phase II trial to have antitumor activity in pretreated metastatic RCC (Jac, ASCO, 2007).
This randomized, double-blind, multicenter, phase III study was carried out to compare efficacy of everolimus to placebo in treatment of metastatic RCC having progressed during VEGFr-TKI therapy with either sunitinib or sorafenib.
Materials and Methods
Patients with metastatic RCC who had progressed either during or less than six months after VEGFr-TKI therapy with sunitinib, sorafenib, or both, were randomized in a 2:1 fashion to receive everolimus (10 mg daily) to placebo, both in the setting of best supportive care.
Physicians and patients were blinded to the arm assigned.
Inclusion criteria included: diagnosis of metastatic RCC with a clear cell component; measurable disease; and progressive disease on VEGFr-TKI therapy. Patients were not excluded if they had also received previous treatment with bevacizumab and/ or cytokine-based treatment.
Patients were stratified according to Memorial Sloan Kettering Cancer Center (MSKCC) risk group criteria and prior VEGFr-TKI therapy.
Progression-free survival (PFS) was the primary endpoint. 290 events were required to achieve 90% power to detect a 33% risk reduction (hazard ratio 0.67).
At the time of progressive disease, patients and physicians were unblinded, and patients were permitted to cross over from the placebo arm to the everolimus arm.
Two interim analyses were planned during this study; at the time of the second interim analysis, an Independent Data Monitoring Committee recommended early cessation of the study to allow patients receiving placebo to receive everolimus. This recommendation was accepted, and the second interim analysis now serves as the final analysis.
During the period from September 2006 through October 2007, 272 patients were randomized to receive everolimus, and 138 to placebo.
Previous treatment included sunitinib in 45% of patients, sorafenib in 29%, and both in 25%.
Differences in baseline patient characteristics between the two arms were not significant.
At the time of final analysis, 51% of patients receiving everolimus continued on treatment, versus 22% of those receiving placebo.
Treatment was discontinued because of progressive disease in 31% of patients receiving everolimus versus 73% receiving placebo.
Treatment was discontinued because of drug intolerance in 10% of patients receiving everolimus versus 1% receiving placebo.
Patients randomized to everolimus continued treatment for a median time of 95 days, versus 57 days continued by patients taking placebo.
Median progression-free survival (PFS) was 4.0 months in the everolimus arm, versus 1.9 months in the placebo arm (hazard ratio 0.30, p < 0.001).
Improved PFS was seen across all subgroups randomized to receive everolimus.
Of patients classified as MSKCC favorable risk (n = 118), median PFS was 5.5 months versus 2.2 months with everolimus versus placebo, respectively (hazard ratio 0.35, p < 0.0001).
Of those classified as MSKCC intermediate risk (n = 231), median PFS was 3.9 months versus 1.8 months with everolimus versus placebo, respectively (hazard ratio 0.25, p < 0.0001).
Of those classified as MSKCC poor risk (n = 61), median PFS was 3.6 months versus 1.9 months with everolimus versus placebo, respectively (hazard ratio 0.36, p = 0.009).
Sixty percent of patients taking everolimus achieved stable disease, versus just 30% of those taking placebo. Disease progression occurred in 20% of patients taking everolimus versus 46% taking placebo.
Sixty-eight deaths have been observed, and this study will continue to assess the secondary endpoint of overall survival.
The most common treatment toxicities encountered were stomatitis (36% versus 0% with everolimus versus placebo, respectively), anemia (28% versus 15%), and aesthesia (28% versus 20%). A 3% incidence of grade 3-4 pneumonitis was encountered in the group receiving everolimus, as were a 3% incidence of hypercholesterolemia, and a 12% incidence of hyperglycemia. Ten percent of patients receiving everolimus experienced treatment discontinuation due to toxicity versus 4% of patients receiving placebo.
No significant difference in health-related quality of life was seen between the two groups.
The authors conclude that everolimus is associated with a 70% relative risk reduction in progressive disease/ death from metastatic RCC.
They note that this benefit is seen across all subgroups, with a favorable safety profile and no significant detriment to quality of life.
They go on to conclude that everolimus should be the standard of care for metastatic RCC progressing through VEGFr-TKI therapy.
This trial represents a well-planned, well-executed, phase III double-blinded randomized controlled trial assessing efficacy of everolimus versus placebo in the setting of metastatic RCC.
Although these treatments are described as second-line in this study, many patients had received several prior treatments and were in fact embarking on third- or fourth-line therapy.
The benefit of everolimus over placebo is clear from this study, and the authors’ conclusion that everolimus should be a standard of care in this setting seems valid, particularly given the fact that no other agent has been demonstrated to be as efficacious to date.
Having said this, with the recent advent of targeted agents available to treat metastatic RCC, the timing and sequence with which they will be ultimately used to achieve the best outcomes is as of yet undetermined.
Everolimus appears to be quite efficacious in this study; direct comparisons to VEGFr-TKI therapies in the form of further trials would be very interesting.
Additionally, use of these agents in combination with one another or with conventional chemotherapy could demonstrate even further benefit.
For current patients, however, everolimus represents a treatment option that is effective and seems tolerable, with little impact on quality of life. Certainly, this is a major addition to the current armory used to treat RCC, and should indeed be used to provide benefit to patients in this setting.
Jun 6, 2012 - Continuing use of bevacizumab (Avastin) in combination with second-line chemotherapy improves overall survival and progression-free survival in patients with metastatic colorectal cancer who have progressed after discontinuation of first-line bevacizumab and chemotherapy, according to the results of a phase III study presented at the annual meeting of the American Society of Clinical Oncology, held from June 1 to 5 in Chicago.