Failed Studies Provide Clues in Renal Cell Carcinoma

Silas Inman
Published Online: Monday, December 23, 2013
Dr. Brian Rini

Brian Rini, MD

The mTOR inhibitor temsirolimus has limited utility in combination with frontline bevacizumab and as a second-line single agent for patients with metastatic renal cell carcinoma (mRCC), according to two recently published articles in the Journal of Clinical Oncology.1,2

The first of the studies, labeled INTORACT, compared first-line temsirolimus plus the VEGF inhibitor bevacizumab to the combination of interferon alfa (IFN) plus bevacizumab for patients with mRCC. In this analysis, both progression-free survival (PFS) and overall survival (OS) were similar between the two arms, with more severe adverse events seen with the temsirolimus combination.

“I think what we learned in this trial is that—at least with our present agents—combinations aren’t really a path forward; they may be with novel agents—and it needs to be explored—but of our current agents, their FDA approved use—and how they should be used—is as monotherapy,” the study’s lead investigator, Brian I. Rini, MD, a professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve in Ohio, said in discussing the trial’s results during a recent OncLive Peer Exchange roundtable entitled “Clinical Developments in Renal Cell Carcinoma.”

In the open-label phase III study, 791 patients with previously untreated, predominantly clear-cell mRCC were evenly randomized to receive bevacizumab at 10 mg/kg IV every 2 weeks plus either temsirolimus (25 mg IV, weekly) or IFN (9 MIU subcutaneously, 3 times weekly). Patients in the trial were stratified prior to receiving nephrectomy. Altogether, 400 patients were treated with temsirolimus plus bevacizumab compared with 391 for IFN plus bevacizumab. The primary endpoint was independently assessed PFS.

The median PFS for patients receiving the temsirolimus combination was 9.1 months compared with 9.3 months with the IFN combination (hazard ratio [HR] = 1.1; 95% CI, 0.9-1.3; P = .8). Moreover, OS was 25.8 months versus 25.5 months (HR = 1.0; P = .6) and objective response rate was 27.0% compared with 27.4%, for temsirolimus plus bevacizumab and IFN plus bevacizumab, respectively.

The most common grade ≥3 adverse events associated with the VEGF plus mTOR combination were mucosal inflammation, stomatitis, hypophosphatemia, hyperglycemia, and hypercholesterolemia. In general, higher-grade adverse events were more common in the temsirolimus arm of the trial (P <.001).

Bevacizumab plus IFN is a currently approved option for the frontline treatment of patients with mRCC. Despite this, the combination is used less commonly in the frontline setting than other VEGF agents, such as sunitinib. The underuse for the combination is generally attributed to IFN and the inconvenience of the administration route.

“The role of interferons is a whole other question,” Rini noted during the Peer Exchange. “I think it probably adds something in terms of benefit but it also adds a lot of toxicity. I tend—if I’m going to use interferon—to start at lower doses and get rid of it pretty quickly, and I think that’s been the compromise for many of the investigators and many of the doctors using it.”

Second-Line Temsirolimus Fails to Impress

In addition to the study examining the combination, temsirolimus was compared with the VEGF inhibitor sorafenib as a second-line therapy in mRCC. Overall, this analysis did not reveal a significant advantage in the primary endpoint of PFS for temsirolimus; moreover, the secondary endpoint of OS favored the comparator, sorafenib.

The data for the secondary endpoint of OS were surprising, said the lead author, Thomas E. Hutson, DO, PharmD, a professor of Medicine at Texas A&M Health Science Center in Dallas, during the Peer Exchange. “We saw a statistically significant advantage in favor of the VEGF inhibitor, sorafenib,” said Hutson. “[This advantage was] highly statistically significant, fraught with a lot of interpretation, potential biases but, nonetheless, a 4.5 month difference in overall survival. That’s hard to just completely discount.”

In the phase III trial, labeled INTORSECT, 512 patients with mRCC were randomized in a 1:1 ratio to receive either temsirolimus (n = 259) or sorafenib (n = 253) following prior treatment with sunitinib. Treatment with temsirolimus was delivered intravenously at 25 mg once weekly and sorafenib was dosed orally at 400 mg twice daily. In general, approximately 98% of patients were ECOG performance status 0 to 1, 80% of patients had clear-cell histology, and 86% to 87% of patients in each arm had undergone nephrectomy.

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