By Will Boggs, MD
NEW YORK (Reuters Health) – Temsirolimus does not improve progression-free survival in metastatic renal cell carcinoma (RCC) compared to standard treatment, according to results from two randomized controlled trials.
“While an improvement was hoped for, this is why large randomized trials need to be conducted so we can adequately test whether a new therapy is an improvement over a standard therapy,” Dr. Brian I. Rini from Cleveland Clinic Taussig Cancer Institute in Cleveland, Ohio, told Reuters Health by email.
Because temsirolimus, an mTOR inhibitor, and bevacizumab, a monoclonal antibody against VEGF, target different mechanisms of RCC pathogenesis, researchers hoped a combination of the two would be more effective.
Dr. Rini and colleagues in the phase III INTORACT trial compared combination treatment with temsirolimus/bevacizumab against standard combination therapy of interferon alfa (IFN)/bevacizumab as first-line treatment for advanced RCC.
Four hundred patients were assigned to temsirolimus/bevacizumab (393 actually received treatment) and 391 were assigned to IFN/bevacizumab (all received treatment), as reported December 2 online in the Journal of Clinical Oncology.
Median progression-free survival (PFS) did not differ significantly between temsirolimus/bevacizumab and IFN/bevacizumab (9.1 vs 9.3 months).
Objective response rates were also similar for temsirolimus/bevacizumab (27.0%) and IFN/bevacizumab (27.4%), as was median overall survival (25.8 vs. 25.5 months).
Temsirolimus/bevacizumab patients reported better quality of life scores, but the differences were not considered clinically meaningful.
Dose reductions and treatment delays owing to adverse events affected similar proportions of patients in both treatment groups, and the primary cause of death in both groups was disease progression.
“IFN/bevacizumab remains the only combination regimen with demonstrated benefit for first-line treatment of advanced RCC,” the researchers conclude.
“There is a role for Torisel (temsirolimus) in poor risk patients and everolimus in refractory patients,” Dr. Rini said. “We still need to conduct further trials and explore novel agents to continue to make improvements in the lives of patients with metastatic RCC.”
“At the present time, the combinations of mTOR inhibitors have no place, but these drugs are still essential monotherapies in several settings, such as the poor-risk patient as well as patients who progress on prior VEGF tyrosine kinase inhibitors (TKIs),” Dr. Toni K. Choueiri from Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts, told Reuters Health in an email.
“Efforts are ongoing to define optimal predictive markers of benefit to these drugs. Also, there is an ongoing large adjuvant study with the mTOR inhibitor everolimus in high-risk RCC patients and this study is accruing,” Dr. Choueiri said.
“The most important message is that targeted sequential rather than combinatorial approaches remain standard in metastatic RCC,” he concluded.
Dr. Frank Stenner from University Hospital Zurich in Zurich, Switzerland, has also studied treatments for metastatic RCC. He told Reuters Health by email, “The established roles of temsirolimus in first line for poor risk patients and for everolimus for patients who have failed one or two TKI therapies remain. Clinicians will continue to use mTOR inhibitors in these situations. However, I do not see mTOR inhibitors as promising combination partners for TKI therapy.”
“TKIs are the mainstay of therapy in metastatic RCC,” Dr. Stenner said. “Don’t use mTOR inhibitors outside their approved indication.”
Dr. Stenner added, “New combinational trials of drugs already in the clinic for RCC are not very promising. Integrating immunotherapy into the therapeutic sequence of RCC is a more rational way to advance patients’ care in metastatic RCC.”
In a second article published concurrently, Dr. Thomas E. Hutson from Baylor University Medical Center in Dallas, Texas, and colleagues in the INTORSECT trial report similarly disappointing results for temsirolimus versus sorafenib in the second-line treatment after sunitinib of 512 patients with metastatic RCC.
Median PFS in this study was 4.3 months for temsirolimus and 3.9 months for sorafenib (P=0.19), and the objective response rate was only 8% in each arm.
Overall survival, a secondary endpoint, favored sorafenib (median, 16.6 months) over temsirolimus (median, 12.3 months; P=0.01). This difference was apparent only for patients receiving more than 180 days of sunitinib.
Adverse events occurred at a similar rate in the two treatment groups.
“The longer overall survival with sorafenib is consistent with the hypothesis that sequenced VEGFR inhibition results in improvement in overall survival in patients with metastatic RCC,” the researchers conclude.
Wyeth Research (acquired by Pfizer) funded both studies.
Dr. Hutson did not respond to a request for comments on this report.
SOURCES: Randomized Phase III Trial of Temsirolimus and Bevacizumab Versus Interferon Alfa and Bevacizumab in Metastatic Renal Cell Carcinoma: INTORACT Trial and Randomized Phase III Trial of Temsirolimus Versus Sorafenib As Second-Line Therapy After Sunitinib in Patients With Metastatic Renal Cell Carcinoma
J Clin Oncol 2013.