Custom Search

Evolving Role of mTOR Inhibition in the Treatment of Renal Cell Carcinoma: An Expert Interview With Dr. Robert Motzer

Editor's Note:

The last decade has witnessed remarkable improvements in understanding the biology of renal cell carcinoma (RCC). On the basis of this new knowledge, the hypoxia-inducible factor-alfa/vascular endothelial growth factor (VEGF) pathway and the mammalian target of rapamycin (mTOR) signal transduction pathway have come to the fore as therapeutic targets in patients with RCC,[1] and novel agents have been developed and have rapidly undergone clinical testing.

At the American Society of Clinical Oncology (ASCO) 44th Annual Meeting, Medscape Hematology-Oncology Editorial Director Jill W. Chamberlain had the opportunity to discuss the evolving role of mTOR inhibition in RCC with Robert Motzer, MD, Attending Physician at Memorial Sloan-Kettering Cancer Center (MSKCC), in New York City. Dr. Motzer was a key investigator in a recent trial of the newer mTOR inhibitor everolimus in patients with RCC.

Medscape: What is the rationale for mTOR inhibition in patients with RCC?

Dr. Motzer: The mTOR pathway is a critical one for cell growth and angiogenesis. It is considered to be a major regulator of cell growth, whereby nutrients and growth factors turn on signals to promote subgrowth in angiogenesis. It has been shown to be abnormal in renal cancer; indeed, renal cancer growth and progression are dependent on the mTOR pathway. Multiple preclinical studies have shown that mTOR inhibitors, particularly temsirolimus, block renal cell cancer growth, and the clinical trials to date with both temsirolimus and the second-generation mTOR inhibitor everolimus (RAD001) have confirmed that inhibition of the mTOR pathway is a valid treatment strategy for RCC.[2]

Medscape: How does everolimus differ from temsirolimus, which has been available for use in patients with advanced RCC for about a year?

Dr. Motzer: Both temsirolimus and everolimus belong to the same family of drugs. Everolimus is a rapamycin analogue -- a novel, orally administered inhibitor of mTOR. Multiple phase 2 trials have confirmed the activity of everolimus in multiple tumor types. A phase 2 trial[3] of everolimus was conducted in patients with previously treated RCC, and it appeared that there was prolongation of progression-free survival (PFS). Everolimus has a favorable safety profile, with the most common adverse events being stomatitis, fatigue, some diarrhea, and laboratory abnormalities, including thrombocytopenia.

Medscape: What are the key findings from the REnal Cell cancer treatment with Oral RAD001 given Daily (RECORD)-1 trial,[4] in which everolimus was compared with placebo in patients with metastatic RCC who had failed prior therapy?

Dr. Motzer: RECORD-1 was a phase 3, randomized, multicenter trial that compared everolimus (10 mg orally daily) and placebo 2:1 in a double-blind fashion. Patients were assigned to everolimus plus best supportive care or to placebo plus best supportive care. The primary endpoint of the trial was PFS as assessed by independent central review. The trial was initially designed to assess for a 33% risk reduction requiring 290 events to achieve 90% power. Secondary endpoints included safety, response, patient-reported outcomes, and overall survival.

The key eligibility criteria were metastatic RCC with a clear-cell component and measurable disease by response evaluation criteria in solid tumors (RECIST). The distinguishing feature of the trial was that patients had to have had progressive disease on or within 6 months of treatment with the VEGF receptor tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, or both. In addition, other prior treatments were allowed, including bevacizumab, cytokines, or chemotherapy. Other eligibility criteria included adequate performance status, blood counts, and serum chemistry.

Two interim analyses were built into the design of the study as well as a final analysis. The first interim analysis was largely for safety, and the second was designed to take place when approximately 60% of events, or 191, had occurred.

Medscape: What are some of the specifics about the patients enrolled in the RECORD-1 study?

Dr. Motzer: Overall, 410 patients were randomized between September 2006 and October 2007. Stratification included number of prior VEGF receptor TKI agents (1 or 2) and MSKCC risk group[5] (favorable, intermediate, or poor), as established in previously treated patients. A total of 272 patients were randomized to everolimus plus best supportive care and 138 to placebo plus best supportive care. The 2 study arms were well balanced with regard to baseline characteristics. The median patient age was about 60 years, and about two thirds had Karnofsky performance status ≥ 90. About 90% of patients had metastatic disease at 2 or more sites, predominantly in the lungs.

One of the important aspects of this trial is the prior treatment of the study participants: 95% had undergone nephrectomy, and about 30% had prior radiation therapy. Overall, 46% of patients on the everolimus arm had prior sunitinib therapy compared with 44% on the placebo arm. Sorafenib treatment had been administered to 28% of patients on the everolimus arm compared with 30% in the placebo group. Slightly more than 25% of patients on each arm had received both sunitinib and sorafenib. Many of the patients had received other systemic therapies as well, with 50% having had prior interferon, 20% to 25% having received interleukin-2, and 10% prior bevacizumab.

Medscape: What were the results of the study?

Dr. Motzer: At the time of the second interim analysis, which had a cutoff date of October 15, 2007, 51% of patients on the everolimus arm had treatment ongoing compared with only 22% of patients on the placebo arm. One of the important factors that contributed to this difference is the proportion of discontinuations for progressive disease: 31% of patients had progressive disease on everolimus compared with 73% of patients on the placebo arm. The median duration of everolimus treatment was 95 days compared with only 57 days for placebo.

An independent data monitoring committee found that the interim results of the study showed significantly better PFS in patients with advanced RCC who received everolimus compared with placebo and recommended termination of the study in February 2008. Thus, the second interim analysis became the final analysis, and the study was discontinued. Patients who were on the placebo arm were followed closely; when investigators determined disease progression, an individual patient could be unblinded and crossed over to receive open-label everolimus.

Medscape: Is any information available about overall survival?

Dr. Motzer: We presented overall survival by treatment at the recent ASCO meeting.[4] The median survival for everolimus-treated patients has not yet been reached, but the median survival for patients on the placebo arm was 8.8 months. The hazard ratio was 0.83, and the P value was not statistically significant. We are quite certain that the patients who had been on placebo and crossed over to everolimus confound the survival endpoint: 81% of those with progression of disease on placebo successfully crossed over to everolimus. Thus, the indicator for clinical benefit and activity of everolimus will be PFS. The trial was, in fact, designed to ensure that all patients had access to everolimus.

Medscape: What were the safety results with everolimus in this study?

Dr. Motzer: In terms of laboratory abnormalities, myelosuppression was noted in patients who received everolimus, particularly thrombocytopenia and neutropenia, but the proportion of patients with grade 3 or higher laboratory abnormalities was absent or low. Other, somewhat unique, laboratory abnormalities noted in patients who received everolimus were hypercholesterolemia, hypertriglyceridemia, and hyperglycemia, which can be attributed to the fact that the mTOR pathway is important in the regulation of these factors.

With regard to treatment-related adverse events, as expected a higher proportion of patients who received everolimus had adverse events compared with placebo. Stomatitis occurred in about 40% of patients in the everolimus group compared with 8% of those who received placebo. Severe treatment-related adverse events included infections as well as pneumonitis, which is a known adverse event associated with rapamycin and its analogues, including temsirolimus. Efforts will be needed to define, better characterize, and manage pneumonitis in patients who receive mTOR inhibitors.

Medscape: What are some of the practical issues associated with everolimus, such as drug administration?

Dr. Motzer: Unlike temsirolimus, which is administered parenterally every week on an ongoing basis, everolimus is an orally administered compound. Patients take 10 mg orally daily with a light-fat meal, and the treatment is continued chronically unless there is progression or intolerance.

Medscape: Are additional trials of everolimus planned in patients with advanced RCC?

Dr. Motzer: Yes, additional trials are planned with everolimus in this patient population. In development is a study of the combination of everolimus and bevacizumab, inasmuch as results of a phase 2 study[6] of this combination showed that full doses of both agents could be given and that the combination was relatively well tolerated and promising. A variety of treatment strategies with everolimus, including its use in the first-line setting in patients with advanced RCC, are being considered.

Medscape: Finally, would you clarify what is known about the use of mTOR inhibitors in renal cancer patients with clear-cell vs non-clear-cell histology?

Dr. Motzer: In the phase 3 trial[2] of first-line treatment of temsirolimus in patients with poor-risk renal cell cancer, in which temsirolimus was compared with interferon alone as well as with the combination of interferon and temsirolimus, the eligibility criteria did not specify clear-cell histology. Thus, patients who were included in that trial were classified as "clear cell" or "other." In subgroup analysis, patients classified as "other" seemed to benefit at least as much as those with clear-cell histology, if not more. That raised a question about the efficacy of mTOR inhibitors in patients who have other, less common renal cancer histologies, including papillary chromophobe or some sort of sarcomatoid variant.

There has not yet been a study in which the pathology has been reviewed prospectively and in which there has been central review of pathology to clearly assess the efficacy of the mTOR inhibitors in RCC for these unusual cell types. Ongoing trials with temsirolimus and everolimus are addressing this issue.

This activity is supported by an independent educational grant from Novartis.