Pazopanib/Paclitaxel Combination Demonstrates Activity in Relapsed/Refractory Urothelial Cancer

Sandy Srinivas, MD

The antiangiogenic agent pazopanib combined with paclitaxel showed significant antitumor activity in a phase II study of patients with relapsed/refractory urothelial cancer. In patients evaluable for treatment response, the overall response rate (ORR) with the combination was 50%, with 11% having a complete response (CR), said Sandy Srinivas, MD, at the 2015 Genitourinary Cancers Symposium.

The combination merits further evaluation, she said, but GlaxoSmithKline has decided to drop a phase III trial “based on corporate priorities.”

Metastatic bladder cancer is typically treated with platinum-based agents, with combination chemotherapy such as methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) or cisplatin and gemcitabine, with responses of 45% to 55% and median overall survival (OS) of 13 months.

Despite these high response rates, cures are infrequent and relapse is inevitable, said Srinivas, associate professor of Medicine (Oncology), Stanford University, Stanford, CA. “There is no approved drug for patients who have relapsed second line, and it represents an unmet need,” she said.

Many agents have been tested in the second-line setting of urothelial cancer, but none have been approved in the US. Vinflumine was tested in a phase III trial against best supportive care, and on the basis of an OS of 6.9 months in an adjusted analysis, it was approved in Europe.

“Paclitaxel is commonly used in the US, with responses of 10% and a progression-free survival (PFS) of 2.2 months and OS of 7 months,” she said. The response rate with either nab-paclitaxel or pemetrexed is 27%. No major success has been realized with combination chemotherapy, and these combinations have been limited by toxicities. Several drugs targeting various pathways have also been tested but with limited to no activity.

Pazopanib as a single agent has a 17% response rate in this setting. In a phase I trial, pazopanib at doses of 400 mg to 800 mg was given daily with weekly paclitaxel (15 to 80 mg/m²) on days 1, 8, and 15 every 28 days. At the maximum tolerated regimen, coadministration of 800 mg of pazopanib and 80 mg/ m² of paclitaxel resulted in a 26% higher geometric mean paclitaxel area under the curve.

This phase I study formed the basis of the phase II study that Srinivas presented here, the primary endpoint of which was objective tumor response rate. The study included 32 patients with urothelial cancer recurring after treatment with a maximum of two chemotherapeutic regimens. To be included, patients had to have an Eastern Cooperative Oncology Group performance status of 0 to 1 and measurable disease. The regimen under study was paclitaxel administered at 80 mg/ m² given on days 1, 8, and 15 of a 28-day cycle, with daily pazopanib given at 800 mg/day.

Patient characteristics included a median age of 67 years, renal pelvis tumors in 34%, failure of two prior chemotherapy regimens in 59%, and liver metastases in 28%. Time from last chemotherapy was <3 months in 47% and >3 months in 53%.

The response rate in 28 evaluable patients according to RECIST 1.1 criteria was 50%, with 11% complete response and 39% confirmed partial response. Another 39% had stable disease, said Srinivas. Three patients with partial response had consolidative radiation therapy. One patient is alive and free of disease at more than 55 months out.

Independent radiology assessment of 22 patients showed a response rate (50%) that was identical to the investigator assessment.

Median PFS was 6 months and median OS was 8 months. Median OS by Bellmunt risk groups was 14.2 months in patients with a Bellmunt risk score of 0, 7.3 months in those with a risk score of 1, and 3.8 months in those with a risk score of 2. “For patients in the higher risk group, our trial outperformed the expected OS,” Srinivas said.

The most common side effects of any grade were fatigue (63%), diarrhea (44%), nausea/vomiting (41%), and neuropathy (34%). Grade 3 or 4 toxicities were minimal. Two patients with wound dehiscence had to withdraw from the trial.

Laboratory abnormalities included mostly hematologic toxicities, such as anemia in 69%, neutropenia in 38%, and febrile neutropenia in 6%. Growth factor support was required to maintain blood counts in 44%.

Paclitaxel dose reduction was necessary in about 45% of patients and pazopanib dose reduction in 75%.

Srinivas S, Narayanan S, Harshman LC, et al. Phase II study of pazopanib with weekly paclitaxel in refractory urothelial cancer. Presented at: 2015 Genitourinary Cancers Symposium; February 26-28, 2015; Orlando, FL. Abstract 294.

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