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A Multicentre Phase II Study of Cisplatin (C), Gemcitabine (G), and Bevacizumab (B) as First-Line Chemotherapy for Metastatic Urothelial Carcinoma

(UC): Hoosier Oncology Group GU-0475

Authors: Hahn NM et al, ASCO 2009.Reviewed by: Dr. Lori WoodAbstract: 5018Date posted: June 12, 2009

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RTreatment

Cisplatin 70 mg/m2

Gemcitabine 1250 mg/m2 d1 and d8*Bevacizumab 15 mg/kg d1 q21 days x 8

metastatic urothelial cancer

ECOG 0-1

first-line

1 endpoint = PFS (by RECIST)

n = 40 to PFS from 7.5m 11.25m

*After first 17 patients, venous thromboembolic events and Gemcitabine to 1000 mg/m2.

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STUDY RATIONALE

•Cisplatin/Gemcitabine would be considered standard first-line chemotherapy for metastatic urothelial cancer in North America.

• Adding more chemotherapy (i.e.: the triplet of Gemcitabine/Cisplatin/Taxol) did not improve outcome in a previous phase III study. Unlikely to be further advantages to adding more/other chemotherapy drugs.

• Therefore, reasonable to add targeted therapy to traditional chemotherapy

VEGF expression associated with poor prognosis in bladder cancer.

• So, combination of Gemcitabine/Cisplatin and Bevacizumab studied

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RESULTS

• n = 43

• Median 6 cycles; 30% received all 8 and received maintenance Bevacizumab

• Dose modifications 60%

• Discontinued secondary to toxicity 42% 21% secondary to DVT/PE

• Gemcitabine:

• 1250 mg/m2 = 39% grade 3-4 DVT/PE and 0% grade 3-4 hemorrhage

• 1000 mg/m2 = 8% grade 3-4 DVT/PE and 12% grade 3-5 hemorrhage

• Deaths = 3 (sudden cardiac, aortic dissection, CNS hemorrhage)

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RESULTS (CONTINUED)

• RECIST response rates:

• CR = 14%

• PR = 44%

• SD = 30%

• PD = 9%

• PFS = 8.2 months with median follow-up 14.6m

• PFS at 12m = 29%

• Overall survival = 19.1 months

• Overall survival at 12m = 65%

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STUDY COMMENTARY

• Significant toxicity with this combination, especially DVT/PE.

• CR + PR = 58% with PFS = 8.2m and OS = 19.1m.

• The PFS and OS is higher than with Gemcitabine/Cisplatin alone; however, these were highly selected patients.

• Currently an ongoing phase I study of Carboplatin/Gemcitabine/ Bevacizumab.

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BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS

• This triplet is far from prime time.

• It is very important in the metastatic palliative setting to “do no harm” and this combination looks like it does/could.

• Another example of how the tolerability of systemic therapy in patients with bladder cancer is different than other cancer populations

• i.e.: lung cancer: doses of Carboplatin/Gemcitabine are an AUC = 6 and full dose Gemcitabine

• i.e.: bladder cancer: just cannot get those doses in because of myelosuppression

• Tough combination to move into a phase III study.