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Metastatic Urothelial Cancer: Nab-Paclitaxel Effective, Vandetanib Fails

Laino, Charlene

doi: 10.1097/01.COT.0000396393.67520.fa
GU Cancers Symposium

GU Cancers Symposium

ORLANDO—Nanoparticle albumin-bound (nab)-paclitaxel was associated with an unprecedented objective response rate of 32% when used as single-agent second-line treatment for patients with metastatic urothelial cancer, according to preliminary results from a Phase II trial.

But second-line therapy with a combination of the multikinase inhibitor vandetanib and docetaxel did not benefit these patients, suggests a multicenter placebo-controlled, randomized study.

Both studies were presented here at the Genitourinary Cancers Symposium, which is cosponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Patients with metastatic urothelial cancer are generally treated with cisplatin-based chemotherapy, explained Maha Hussain, MD, Professor of Medicine and Urology at the University of Michigan and Associate Director for Clinical Research at the UM Comprehensive Cancer Center, who was not involved with either study. However, 50% of patients don't respond, and 50% of the other patients relapse.



Currently, there are no approved second-line therapies for metastatic urothelial cancer—“It's almost always fatal,” she said. As a result, the race is on to find new drugs and combinations of drugs.

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Previous Trials

The largest single-agent trial of second-line treatment to date involved 370 patients randomized to receive the microtubule inhibitor vinflunine plus best supportive care or best supportive care alone. The combination was associated with a 9% response rate and median survival time of 6.9 months (Bellmunt J et al: JCO 2009;27:4554-4561).

Of eight other single-agent second-line trials, pemetrexed produced the highest response rate, 28%, with a median time to progression of 2.9 months and a median survival time of 9.6 months, noted Srikala S. Sridhar, MD, Assistant Professor of Medicine at the University of Toronto.

Trials of combinations of drugs have generally been small, with no more than 50 patients, she said. A combination of gemcitabine and paclitaxel achieved the best response rate—60%—and a median survival time of 14.4 months.



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Nab-Paclitaxel Trial

Dr. Sridhar reported preliminary analyses of data on 48 patients in a Phase II, single-arm study of second-line treatment with nab-paclitaxel for metastatic urothelial cancer.

Patients had measurable distant or unresectable local urothelial cancer of mixed histology that had progressed on platinum-based therapy or within a year of stopping treatment.

The mean age of the patients, 40 of whom were men, was 66. Three-fourths had visceral/bone metastases.

Patients received 260 mg/m2 of nab-paclitaxel every three weeks until disease progression, intolerable toxicity, or withdrawal.

The primary endpoint was tumor response, and secondary endpoints were the disease-control rate, the progression-free survival rate, and overall survival time.

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Disease Control Tops 50%

Of the 47 patients evaluable for response, 15 (32%) had partial responses, and 10 (21%) had stable disease, for a disease control rate of 53%.

The median progression-free survival time was 6.0 months. A total of 72% of patients were alive, with no signs of disease progression, at three months, 49% at six months, and 43% at 8.4 months.

The median overall survival time was 10.8 months, with 65% of patients alive at six months, 48% at 12 months, and 25% at 18 months.

“This is so far the highest reported single-agent response rate in second-line urothelial cancer,” Dr. Sridhar said. “Time to progression and progression-free survival are higher, as is median survival.”

MAHA HUSSAIN, MD, explained that although patients with metastatic urothelial cancer are generally treated with cisplatin-based chemotherapy, patients typically either don't respond or have disease relapse

MAHA HUSSAIN, MD, explained that although patients with metastatic urothelial cancer are generally treated with cisplatin-based chemotherapy, patients typically either don't respond or have disease relapse

The most common adverse events were alopecia, seen in 13% of patients, fatigue (12%), pain (12%), and neuropathy (10%). The most common Grade 3 toxicity was pain, which affected 23% of patients, but was not always drug related.

Study of nab-paclitaxel, alone or in combination, may be warranted in the first-line metastatic setting, Dr. Sridhar added.

Dr. Hussain said she is “cautiously optimistic—“There appears to be better response rates and better progression-free survival than what we see historically. But the study was not very large and the data are not yet mature.”

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No Benefit with Vandetanib

In contrast, the targeted agent vandetanib showed “no hint of benefit” when added to docetaxel, Dr. Hussain said.

Vandetanib is a dual inhibitor of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), both of which contribute to the pathogenesis and progression of urothelial cancer, explained Toni K. Choueiri, MD, Assistant Professor of Medicine at Harvard Medical School and a genitourinary medical oncologist at Dana-Farber Cancer Institute.

Dr. Choueiri and colleagues studied 142 patients with metastatic urothelial cancer that had progressed on first-line platinum-based chemotherapy.

Patients had received up to three prior chemotherapy regimens, but could not have taken docetaxel or anti-VEGF agents.

The patients were randomized to receive 75 mg/m2 of docetaxel every three weeks, in combination with daily vandetanib (100 mg) or placebo. Treatment continued until disease progression, at which time patients on the placebo could be switched to receive single-agent vandetanib.

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Toxicities Increased

The median progression-free survival time was 1.58 months in the placebo group, compared with 2.56 months in the vandetanib group, a nonsignificant difference.

The median overall survival time was 30.6 weeks in the placebo group versus 25.4 weeks in the vandetanib arm, also a nonsignificant difference.

Exploratory analyses did not identify any subgroups of patients who would benefit from the targeted agent.

Toxicities were significantly higher with the combination treatment, including Grade 3-4 diarrhea (7% vs 0%) and rash/photosensitivity (11% vs 0%).

“There does not appear to be a role for vandetanib in this setting,” Dr. Choueiri said.

Funding for the vandetanib study was provided by Astra Zeneca.

© 2011 Lippincott Williams & Wilkins, Inc.
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