Pazopanib Plus Paclitaxel Active in Refractory Bladder Cancer

Roxanne Nelson, RN

March 06, 2015

ORLANDO, Florida — In patients with relapsed or refractory urothelial carcinoma, the antitumor activity of paclitaxel chemotherapy plus the targeted agent pazopanib (Votrient, GlaxoSmithKline) is significant, according to data presented here at the Genitourinary Cancers Symposium 2015.

In a small single-group phase 2 trial, the overall response rate was 50%, and 11% of the patients achieved a complete response.

However, these results were tempered by a significant rate of myelosuppression, which necessitated a reduction in the dose of pazopanib in 75% of patients and the addition of growth factors in 44% of patients.

Metastatic urothelial carcinoma is an incurable disease typically treated with a platinum-based chemotherapy combination such as methotrexate, vinblastine, doxorubicin, and cisplatin or cisplatin plus gemcitabine, said lead investigator Sandy Srinivas, MD, associate professor of medicine at Stanford University in California.

Responses of 45% to 55% are typically observed, and median overall survival is 13 months.

"Despite these high response rates, cures are infrequent and relapse is inevitable," Dr Srinivas explained. And there are no standard treatments for relapsed or refractory urothelial carcinoma.

Trials evaluating established chemotherapeutics as single agents or in combination with other agents have yielded discouraging results, she reported. No major successes have been seen with combination chemotherapies, which have been limited because of toxic effects.

Previous attempts to add targeted therapy with drugs that act on various pathways, including sorafenib (Nexavar) and sunitinib (Sutent, Pfizer), have shown limited to no activity, she added.

"There are no approved drugs for second-line therapy; it is an unmet need," Dr Srinivas emphasized.

Building on Phase 1 Results

Paclitaxel has exhibited moderate activity when used alone or in combination in this setting, and pazopanib, a selective multitargeted receptor tyrosine kinase inhibitor, has shown activity in other solid tumors secondary to its potent antiangiogenic effects.

A previous phase 1 trial evaluated the combination of daily pazopanib at doses of 400 to 800 mg and weekly paclitaxel at doses of 15 to 80 mg/m². "At the maximum tolerated regimen, coadministration of 800 mg of pazopanib and 80 mg/m² of paclitaxel resulted in a higher geometric mean paclitaxel area under the curve," Dr Srinivas reported.

In the phase 2 study, she and her colleagues evaluated the combination of paclitaxel and pazopanib in refractory disease. The primary end point was objective response rate, and secondary end points included safety and progression free-survival.

Median age of the patients was 67 years, median ECOG performance status was 1, 17 patients (54%) had urothelial carcinoma of the upper urinary tract disease, and 15 patients (47%) had primary bladder tumors.

All patients had multiple metastatic sites, including nine (28%) with liver metastases. The median number of previous cytotoxic regimens was 2, and 50% of the group was considered to be responsive to cisplatin.

For 3 weeks in a 28-day cycle, pazopanib 800 mg was administered daily and paclitaxel 80 mg/m² was administered weekly. Patients remained on treatment until disease progression or unacceptable toxic effects.

Encouraging Results

A total of 28 patients were evaluable. According to RECIST 1.1 criteria, the response rate was 50%.

Table. Outcomes for 28 Evaluable Patients

Response n %
Complete 3 11
Partial 12 43
   Unconfirmed 1 4
   Confirmed 11 39
Stable disease 11 39
Progressive disease 2 7

 

An independent radiology assessment of 22 patients was similar to the investigators' assessment, Dr Srinivas said. "We did have three patients who achieved partial response go on to have consolidative radiation. One patient is alive more than 55 months out now."

Median progression-free survival was 6 months, and overall survival 8 months.

Grade 3/4 toxicities were relatively infrequent, although the majority of patients experienced hematologic adverse events, including anemia (69%), thrombocytopenia (47%), neutropenia (38%), and febrile neutropenia (6%).

Nonhematologic toxicities included fatigue (63%), diarrhea (44%), nausea/vomiting (41%), and neuropathy (34%).

Phase 3 Trial Scrapped

On the basis of these results, Dr Srinivas noted that this combination is worthy of further study. To that end, a phase 3 trial was designed to evaluate pazopanib combined with paclitaxel in patients with advanced urothelial cancer previously treated with systemic therapy for metastatic disease.

However, in August 2014, GlaxoSmithKline "decided to drop the phase 3 trial based on their corporate priorities," Dr Srinivas explained.

The 50% objective response rate with pazopanib plus paclitaxel is impressive, said study discussant Jonathan E. Rosenberg, MD, from the Memorial Sloan Kettering Cancer Center in New York City.

"Pazopanib with weekly paclitaxel had a high overall response rate in a single-arm study. The progression-free survival seems improved, but the overall survival was not substantially better than has been seen with chemotherapy alone," he said. In addition, the regimen "required significant dose reductions."

Although these are very encouraging early data, the "lack of corporate interest and sponsorship" will likely affect how this is developed, if it is developed at all, Dr Rosenberg noted.

"Perhaps the cooperative groups might think about whether this is worth the effort on their own," he added.

The study was funded by GlaxoSmithKline. Dr Srinivas reports serving is a consulting or advisory role for Genentech/Roche, Medivation, and Pfizer; and receiving research funding from GlaxoSmithKline. Coauthor Ulka N. Vaishampayan reports relationships with Astellas, Bayer, Janssen, Novartis, Pfizer, and Exelixis.

Genitourinary Cancers Symposium (GUCS) 2015: Abstract 294. Presented February 27, 2015.

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