mTOR INHIBITORS ROLE IN ADVANCED RENAL CANCER DEBATED

Two newly published phase 3 trials seek to answer different questions in the multiple-choice test that is the treatment of metastatic renal cell carcinoma (mRCC).

There are now 7 US-approved treatment options that are inhibitors of vascular endothelial growth factor (VEGF) or its receptor (VEGFR), or are mammalian target of rapamycin (mTOR) agents.

Both trials explore the hypothesis that combining these 2 classes of drugs with different mechanisms of action, either simultaneously or sequentially, would improve outcomes.

Unfortunately, neither trial had a positive result for their primary outcome. Nevertheless, one trial, which looked at second-line therapy in patients who progressed on sunitinib, may point the way to improved overall survival (OS) in those patients.

Both studies featured temsirolimus (Torisel, Pfizer), were funded by the company, had highly similar acronyms, and appeared online in the Journal of Clinical Oncology in early December.

In the phase 3 trial, Investigating Torisel As Second-Line Therapy (INTORSECT), the study authors compared the efficacy of temsirolimus, an mTOR, and sorafenib (Nexavar, Onyx), a VEGFR, as second-line therapy in patients with mRCC after disease progression on sunitinib. The new study is important, in part, because it is the first time that an mTOR inhibitor has been directly compared with VEGFR inhibitors as second-line therapies.

There was no significant difference between treatment arms for overall response rate or progression free survival (PFS), the median of which was 4.3 months in the temsirolimus arm and 3.9 months in the sorafenib arm.

However, there was a significant difference in favor of sorafenib for OS, which was a secondary endpoint (hazard ratio, 1.31; 95% confidence interval, 1.05 to 1.63; P =.01). The median OS was 12.3 months in the temsirolimus arm and 16.6 months in the sorafenib arm.

The finding of a survival benefit is a shot in the arm for sequential use of VEGFR inhibitors, say the authors, led by Thomas E. Hutson, DO, PharmD, from the Charles A Simmons Cancer Center, at Baylor University Medical Center in Houston, Texas.

The findings add to the "growing body of evidence regarding sequential use of targeted therapies in mRCC," they write.

The authors believe clear-cell RCC is a VEGF-driven tumor, thus mTOR inhibition with temsirolimus in the trial did not offer help beyond slowing progression. On the other hand, sustained VEGFR inhibition by sequential tyrosine kinase inhibitors (in this case, sunitinib and then sorafenib) may explain the mechanism of action behind the improved survival in the trial.

So, should clinicians now treat mRCC patients who progress on a VEGF inhibitor with sequential tyrosine kinase inhibitors (and thereby provide sustained VEGFR inhibition)?

Dr. Hutson did not directly say yes.

"Right now, and rightfully so, most patients receive front line therapy with a VEGF inhibitor (sunitinib or pazopanib). In the second line setting there have been two options...continue with another type of VEGF inhibitor or change mechanism of action to a mTOR inhibitor," he told Medscape Medical News in an email.

The literature, including the current study, "supports sequential VEGF inhibitors moving mTOR inhibitors to third line or fourth line," Dr. Hutson said.

In the phase 3 trial, Investigation of Torisel and Avastin Combination Therapy trial (INTORACT), the researchers compared combination therapy with temsirolimus/bevacizumab against the standard combination at that time — interferon alfa (IFN)/ bevacizumab — in the first-line treatment of mRCC.

The trial was a wash.

Median PFS in patients treated with temsirolimus/bevacizumab vs IFN/bevacizumab was 9.1 and 9.3 months, respectively (P = .8).

There were no significant differences in overall survival (25.8 vs 25.5 months; P = .6) or objective response rate (27.0% vs 27.4%) with temsirolimus/bevacizumab vs IFN/bevacizumab, respectively.

Thus the trial further confirmed the lack of evidence that combination therapy with a VEGFR inhibitor and an mTOR agent has an advantage over other strategies in the first line, including using an approved single agent, write the authors, led by Brian I. Rini, MD, from the Cleveland Clinic Taussig Cancer Institute in Ohio.

Dr. Hutson and Dr. Rini report financial ties with Pfizer and other companies. Coauthors of both studies include company employees.

J Clin Oncol. 2013. Published online. INTORSECT, INTORACT