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Clinical Trial Rejects Combination of Sunitinib & Gemcitabine for sRCC Treatment

Hocevar, Robin

doi: 10.1097/01.COT.0000489532.93891.05
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sarcomatoid RCC

sarcomatoid RCC

CHICAGO—A clinical trial evaluating the effectiveness of sunitinib alone or sunitinib combined with gemcitabine in advanced renal cell carcinoma with sarcomatoid features was presented during a poster session at the 2016 American Society of Clinical Oncology Annual Meeting in Chicago. Sarcomatoid RCC is an especially aggressive form of kidney cancer and outcomes are often poor.

Specifically, patients with ≤20 percent sarcomatoid features often have a lower response rate to VEGF tyrosine kinase inhibitors. To date, this has been the largest and the first randomized trial studying patients with sarcomatoid RCC.

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Selecting Viable Drug Combinations

Applying a principle upheld first in bladder cancer trials and later in RCC with sarcomatoid features, a team of researchers led by chair Naomi Haas, MD, University of Pennsylvania, Philadelphia, speculated about the role of combination drug therapy for advanced renal cell carcinomas with sarcomatoid features.

“We'd completed ECOG trials testing doxorubicin in combination with gemcitabine,” she recalled. “We'd observed responses from this therapy in kidney cancer with sarcomatoid features. The perception, however, was that this combination was quite toxic. We felt the only feasible combination using a more contemporary kidney cancer drug was to combine gemcitabine with the (vascular endothelial growth factor tyrosine kinase inhibitor) VEGF TKI, sunitinib. This was based on a phase I trial conducted at Massachusetts General Hospital, which tested this combination in patients with poor risk kidney cancer as well as in patients with kidney cancer containing sarcomatoid features (sometimes an overlapping group). We knew we had a tolerable dose and wanted to test it against the new standard in kidney cancer, sunitinib.”

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Study Methodology

Haas and the team randomized patients 1:1 to Arm A (sunitinib only) and Arm B (gemcitabine and sunitinib) using a two-stage design. Those with sarcomatoid change and ≤1 prior (VEGF-TKI) were grouped in three categories, according to individual prognosis.

In both treatment arms, patients were predominantly male (approximately 65%) and white. The median age range was 59.4 and 60.9, respectively.

RR was the primary endpoint and secondary endpoints were progression-free survival (PFS), overall survival (OS) and patient safety.

For the combination arm, the null RR was 15 percent and a RR of 30 percent was of interest. By comparison, in the sunitinib alone arm, a 20% RR was of interest vs. a 5% null rate.

“We originally thought the combination would have a better response rate in patients with sarcomatoid features than those on sunitinib alone,” Haas explained. The team defined success as 10/43 patients taking sunitinib and gemcitabine or 4/37 patients prescribed sunitinib alone showing a partial response. Accrual goals were 40 patients in Arm A and 45 patients in Arm B.

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Toxicity Reports

Admittedly, Haas noted a high rate of toxicity. “This population is very ill to begin with,” she qualified.

In Arm A, most toxicities were grade 3, but several were categorized at grade 4, including anemia, decreases in lymphocyte and neutrophil counts, and platelets and white blood cells, anorexia, and hypertension. In Arm B, all toxicities were grade 3, including pericardial effusion, fatigue, decreases in lympocyte, neutrophil and platelet counts, anorexia, dehydration and hypoalbuminemia and hypertension.

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Study Results

Both arms met the established protocol for continuing to stage 2 of accrual. In the combination arm (Arm A), 8/43 patients experienced a partial response, compared with 4/37 in the sunitinib alone (Arm B). Median progression-free survival was 23.4 and 17 weeks, respectively. Overall survival was calculated at 40.9 weeks in Arm A and 50 weeks in Arm B. Patients in Arm A received three cycles and those in Arm B submitted to two cycles. Perhaps most telling, 27.9 percent of patients in Arm A and 21.6 percent of patients in Arm B were classified with Stable Disease.

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Implications for Oncologists

While the response rate for patients on sunitinib alone met the criteria for success, those on the combination arm did not. The authors did note that patients on sunitinib and gemcitabine stayed on therapy longer than those on the sunitinib arm alone. Tumor shrinkage was more common to patients on the combination arm as well.

“This is still very early in analysis,” noted Haas. “However, the spider plot illustrated patients on the combination arm staying on therapy longer.” She also pointed out that some patients just started the study in November, meaning the progression-free survival information is not mature. She expects the overall survival and progression-free survival curves to change a bit.

While the response rate of 18 percent didn't achieve an endpoint logical for pursuing further study, Haas remarked that there was a great deal of interest at ASCO. Many oncologists are using this regimen and will now be waiting for potential changes, especially with respect to progression-free survival, as the data matures.

“The implication for the oncological community is that we still believe combination therapy achieves better control for patients with advanced renal cell carcinoma with sarcomatoid features,” shared Haas. “We note that the dose of gemcitabine used was a lower dose than that used in the earlier combination doxorubicine/gemcitabine trials and that the dose of sunitinib in the combination arm is also lower than the dose in the sunitinib alone arm. We now need to identify potential combinations that might work better. There's immense interest right now in immune checkpoint inhibitors.”

Robin Hocevar is a contributing writer.

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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