Failed Studies Provide Clues in Renal Cell Carcinoma

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.

Second-Line Temsirolimus Fails to Impress

“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.”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.

The median PFS in the temsirolimus arm was 4.3 months compared with 3.9 months with sorafenib (HR = 0.87; 95% CI, 0.71-1.07; P = .19). The median OS for temsirolimus was 12.3 months versus 16.6 months with sorafenib (HR = 1.31; 95% CI, 1.05-1.63; P = .01).

Data on additional treatments received after the cessation of the trial were only available for 10% of patients, due to the trial’s design. In this population, the follow-up care was consistent with standards of care.

“Patients who were on the mTOR inhibitor, temsirolimus, they went on to receive VEGF inhibitors and once in a while they got everolimus, too,” Hutson noted during the discussion. “And those people that were on the VEGF got the mTOR inhibitor.”

The discordance between PFS and OS in this trial has broader implications for clinical research, panelists believed. When these endpoints do not align, it raises questions regarding the effectiveness of the drugs and whether everything is being adequately measured.

Sequencing Implications

“When we’re getting into some of these second- or third-line settings, that’s where PFS may not be as necessarily robust. Even response rates may not be what we’d expect to see in the front-line setting,” Daniel J. George, MD, director of Genitourinary Oncology at the Duke Cancer Institute in North Carolina, noted during the discussion. “I think it’s a really important point that each of these settings, those secondary endpoints of OS, need to line up with what we’d expect to see for a PFS result.”The overall findings from these trials, despite being negative by the primary endpoint, still may have an effect on practice patterns. For some, it confirmed that a VEGF-VEGF sequence is ideal for patients with mRCC, whereas others remain unconvinced.

“We have one trial that’s suggesting perhaps superior overall survival in a VEGF-VEGF sequence. We have a number of other studies that sort of demonstrate that people do okay if they receive an mTOR inhibitor,” said Eric Jonasch, MD, associate professor of Medicine at The University of Texas MD Anderson Cancer Center in Houston, during the panel discussion. “So the question of whether or not there’s something clearly happening here with regard to VEGF-mTOR versus VEGF-VEGF, I think needs to be proven and we don’t have that proof.”

Other clinical trials, such as the RECORD-3 study, have compared treatment with VEGF and mTOR inhibitors in the frontline setting. In this phase III study, the standard approach of sunitinib followed by everolimus was compared with sequential everolimus and sunitinib. In the trial, 471 patients with both clear and non-clear cell mRCC were evenly randomized between the two treatment arms. A majority of patients (86%) presented with favorable or intermediate prognoses.

Overall, this trial did not demonstrate that first-line everolimus was noninferior to first-line sunitinib. However, since only a small subpopulation of high-risk patients were enrolled, it may still be appropriate to utilize the mTOR inhibitor temsirolimus in this setting.

“When you have multiple agents across a space with efficacy, you spend a lot of time trying to tailor the agent to the patient as opposed to just saying I’m going to use one agent in all patients,” Robert A. Figlin, MD, professor of Medicine and Biomedical Sciences and chief of the Division of Oncology at Cedars-Sinai Comprehensive Cancer Center in Los Angeles, said during the discussion. “It means that your understanding of the toxicity profile and the quality of life issues then become predominant in thinking about how to choose an agent for a given person.”

References

1. Rini BI, Bellmunt J, Clancy J, et al. Randomized phase iii trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT Trial [published online December 2, 2013]. J Clin Oncol. doi: 10.1200/JCO.2013.50.5305.
2. Hutson TE, Escudier B, Esteban E, et al. Randomized phase iii trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma [published online December 2, 2013]. J Clin Oncol. doi: 10.1200/JCO.2013.50.5305.