Two studies presented at this year’s Genitourinary Cancers Symposium shed light on treatment of metastatic renal cell carcinoma. The first study confirmed that the approved dosing schedule for sunitinib (Sutent) should be the schedule of choice in metastatic renal cell carcinoma. The second study showed that adding a monoclonal antibody targeted to angiogenesis did not provide additional efficacy when combined with the VEGF inhibitor sorafenib (Nexavar).

Dosing of Sunitinib

The approved dosing schedule for sunitinib in metastatic renal cell carcinoma—4 weeks on treatment and 2 weeks off—should be followed to achieve optimal results, according to results of a randomized, phase II study.¹ Time to progression was superior on the approved schedule vs a continuous schedule on lower-dose sunitinib (see Fig. 1). The study was supported by Pfizer.

According to lead investigator Robert Motzer, MD, Attending Physician at Memorial Sloan-Kettering Cancer Center, New York, “The message of this study is straightforward and simple, but the data impact the real-world use of sunitinib. Physicians should have patients adhere to the standard dosing schedule. Some [community] physicians are inventing their own schedules, but they should be using the approved schedule.”

The standard schedule of sunitinib (50 mg once daily, 4 weeks on/2 weeks off) was approved because studies suggested that this was the most effective way to give the drug. “The 2 weeks off gave patients a break from the associated toxicities of fatigue, hand-foot syndrome, hypertension, and diarrhea,” Dr. Motzer explained.

“There has been interest in an alternative dosing schedule to reduce side effects further,” he noted. “We chose to evaluate low-dose continuous sunitinib 37.5 mg orally once a day.” The continuous schedule is potentially attractive because of concerns that the 2‑week break could allow the cancer to return and/or compromise compliance, he explained.

Study Data

The phase II study randomly assigned 292 patients to the approved schedule (arm A) vs continuous sunitinib (arm B). Median age was 62 years, and 65% were male. Patients were treated with a median of four cycles in arm A and five cycles in arm B.

Median time to progression favored the approved schedule: 9.9 vs 7.1 months for arm A and B, respectively; this difference was not statistically significant but indicated a strong trend favoring the 4/2 schedule, Dr. Motzer commented. Objective response rates were 32.2% vs 28.1%—a difference that was not statistically significant. Median overall survival was similar between groups: 23.1 vs 23.5 months, respectively.

Interestingly, there was no difference in the side-effect profiles of the two arms. “We saw no benefit for continuous dosing related to side effects,” Dr. Motzer stated. The most common treatment-related adverse events were fatigue (62% in both arms), nausea (56% in arm A, 49% in arm B), and diarrhea (56% in arm A, 64% in arm B).

In general, quality of life was not significantly different in the two study arms. It improved and then plateaued on continuous dosing, and as might be expected, there was an “on/off” phenomenon with the 4/2 schedule. “We saw no benefit on quality of life with the continuous schedule,” Dr. Motzer noted.

“Sunitinib is the most common first-line therapy for metastatic renal cell carcinoma. This study confirms the need to give the standard dosing schedule. There is no benefit for continuous dosing,” he emphasized.

“We’ve been waiting for this information [on sunitinib] for a long time. The study shows that how you give a drug—the dose and schedule—does matter. It is important to do a study like this, because different patients have different needs,” said Brian Rini, MD, Associate Professor of Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland.

Pazopanib vs Sunitinib

Dr. Motzer mentioned that he is lead investigator of an ongoing, 900-patient, phase III trial to compare pazopanib (Votrient) vs sunitinib as first-line therapy for metastatic renal cell carcinoma. That study, sponsored by GlaxoSmithKline, has just completed accrual, and Dr. Motzer hopes to present results in 2012.

“Both drugs target angiogenesis, but they have different toxicity profiles,” he said. “Pazopanib may have less toxicity than sunitinib. If this study shows equal efficacy for pazopanib, then we may have another treatment option. One drug may be better than another for certain patients. . . . The main point is to use whatever drug is best for the patient.”

Related Study

Dr. Rini was lead author of a related phase II study designed to evaluate the combination of sorafenib—another standard therapy for metastatic renal cell carcinoma—with AMG 386.² The goal of that study, which was supported by Amgen, was to determine whether the addition of the first-in-class peptibody targeted to angiopoietin-1 and -2 would augment VEGF inhibition achieved with sorafenib.

“The rationale for the combination is that these two drugs attack angiogenesis by two different means,” he said.

The study randomly assigned 152 patients with metastatic renal cell carcinoma to one of three treatment arms: sorafenib plus placebo; sorafenib plus AMG 386, 10 mg/kg; or sorafenib plus AMG 386, 3 mg/kg. AMG 386 provided no additional benefit over sorafenib alone. For the primary endpoint of progression-free survival, all three arms of the study had a median progression-free survival of 9 months. The data showed a hint of a benefit for overall response rate when AMG 386 was added, but this was not the primary endpoint of the trial, Dr. Rini said.

At the time the study was initiated, it was not clear that sunitinib would become the preferred first-line therapy for metastatic renal cell carcinoma. “Over the course of the study, sunitinib emerged as the preferred first-line therapy, and ovarian cancer studies suggested that higher doses of AMG 386 would be more effective. In the future, AMG 386 will be studied in higher doses in combination with sunitinib in metastatic renal cell carcinoma,” Dr. Rini said. ■

Financial Disclosure: Dr. Motzer has received research funding from Pfizer and Wyeth. Dr. Rini disclosed financial ties with Amgen, AVEO, Bayer, GlaxoSmithKline, Novartis, Pfizer, Roche, Celgene, Sanofi-aventis, and Novartis.

References

1. Motzer RJ, Hutson TH, Olsen MR, et al: Randomized phase II multicenter study of the efficacy and safety of sunitinib on the 4/2 versus continuous dosing schedule as first-line therapy of metastatic renal cell carcinoma: Renal EFFECT Trial. Genitourinary Cancers Symposium. Abstract LBA308. Presented February 19, 2011.

2. Rini BI, Szczylik C, Tannir NM, et al: AMG 386 in combination with sorafenib in patients with metastatic renal cell cancer: A randomized, double-blind, placebo-controlled, phase II study. Genitourinary Cancers Symposium. Abstract 309. February 19, 2011.