Two New Drug Pairings are Active in Advanced and Refractory Urothelial Cancer, Studies Show

Sandy Srinivas, MD

Investigators reported at the 2014 Genitourinary Cancers Symposium that two new combinations demonstrated activity in refractory or advanced, previously untreated urothelial carcinoma in phase II evaluations.

The combination of daily pazopanib and weekly paclitaxel demonstrated significant anti-tumor activity in an ongoing multicenter phase II trial of 26 patients with recurrent urothelial cancer, said Sandy Srinivas, MD. Paclitaxel has already demonstrated activity when used alone and in combination in urothelial cancer, and pazopanib, a vascular endothelial growth factor (VEGF) inhibitor, is active in solid tumors. The two together were studied in a phase I trial that established the maximum tolerated dose for each when used in combination. On this basis, the phase II trial was undertaken.

“At the time the trial was planned, there wasn’t much experience using VEGF inhibitors,” said Srinivas, associate professor of Oncology at Stanford University, in Stanford, California. “Subsequently, there have been trials looking at bevacizumab, and there have been single-agent regimens such as sunitinib that have been used. We believed there was a rationale to combine paclitaxel as a backbone with pazopanib, based on the phase I study.”

Patients in the study have urothelial cancer that has relapsed after treatment with a maximum of two chemotherapeutic regimens. “It was a pretty heavily pretreated population,” she said. “Half of our patients received one, and half received two prior chemotherapy regimens before coming into our trial.”

They received pazopanib at 800 mg/day orally, and paclitaxel at 80 mg/m²for 3 weeks in a 28-day cycle. Treatment is being continued until disease progression or unacceptable toxicity. Site of the primary tumor is bladder in 10 patients, renal/pelvis in 11, and ureter in five. The median patient age is 67 years and their median ECOG performance status is 1. All patients had multiple metastatic sites, including nine with liver metastases. The time from their last chemotherapy cycle was a median 55 days.

“We had a difficult-to-treat population. Liver metastasis is considered to be a bad player,” Srinivas said. “Seven patients ended up having bone disease.”

The objective response rate based on RECIST criteria was 60%, with a complete response in two patients (8%) and a partial response in 12 (52%). Six of 23 evaluable patients (26%) experienced stable disease.

The most common laboratory adverse events are hematologic, with neutropenia requiring growth factor support in 54%, anemia in 84%, and thrombocytopenia in 56%. Fifty-two percent of patients had elevations in levels of serum creatinine and 19% experienced proteinuria.

“The overall survival is about 10 months, but there are many patients who are still alive, and some are still on study and on active treatment,” said Srinivas. “I think 10 months for median survival is a good number for second-line and third-line patients. It’s a reasonable combination to study, given that we don’t have any standard for second-line bladder cancer. It’s an unmet need; we haven’t found a good treatment program for patients in whom front-line cisplatin therapy has failed.”

In previously untreated patients with advanced urothelial carcinoma, investigators at Asan Medical Center, in Seoul, South Korea, led by Jae-Lyun Lee, MD, found significant clinical activity with the combination of pemetrexed and cisplatin. As a single agent in a first-line and second-line setting, pemetrexed has produced response rates of up to 32% with minimal toxicity, they note.

Their study included 42 patients with chemotherapy-naïve advanced urothelial cancer, measurable disease, and an ECOG performance status of 0 to 2. The primary cancer site was bladder in 23 patients, renal/pelvis in 11, ureter in nine, and others in two. Pemetrexed was given as 500 mg/m²on day 1 with cisplatin 70 mg/m²on day 1 every 3 weeks until disease progression or a maximum of 8 cycles.

Of 40 evaluable patients, the overall response rate was 68% (27 patients), with all responders having a partial response. Six patients (15%) had stable disease. The disease control rate was 83%. Median progression-free survival was 6.9 months and median overall survival was 14 .4 months.

The most common hematologic toxicities were neutropenia (61.9%) and anemia (54.8%). There were few grade 3 or 4 toxicities.

References

1. Srinivas S, Narayanan S, Harshman LC, et al. Phase II trial of pazopanib and weekly paclitaxel in metastatic urothelial cancer. Presented at: the 10th Annual Genitourinary Cancers Symposium; January 30-February 1, 2014; San Francisco, California. Abstract 299.
2. Lee J-L, Lee S-H, Choi YJ, et al. PECULIAR study: phase II study of pemetrexed in combination with cisplatin in patients with advanced urothelial cancer. Presented at: the 10th Annual Genitourinary Cancers Symposium; January 30-February 1, 2014; San Francisco, California. Abstract 301.

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