Second-Line Ramucirumab Plus Docetaxel in Urothelial Cancer Improves Progression-Free Survival

Daniel P. Petrylak, MD

Ramucirumab added to docetaxel significantly improved progression-free survival (PFS) compared with docetaxel monotherapy as second-line treatment in a phase II study of patients with metastatic transitional cell carcinoma. A second human monoclonal antibody—icrucumab—had no effect when combined with docetaxel in this setting. The data were reported by Daniel P. Petrylak, MD, professor of medicine (medical oncology), Yale University Cancer Center, New Haven, Connecticut, at the 2015 Genitourinary Cancers Symposium.

“Ramucirumab plus docetaxel conferred a statistically significant PFS improvement of >11.5 weeks at the median, reducing the risk of disease progression by 61%,” said Petrylak, adding that the agent showed an acceptable safety profile.

The results support the initiation of a phase III study, known as RANGE, of docetaxel in combination with ramucirumab compared with docetaxel alone in patients with urothelial carcinoma, according to Petrylak.

Treatment options for patients with metastatic urothelial cancer who progress after first-line chemotherapy are limited.

Vascular endothelial growth factor receptor (VEGFR) 1 and 2 and their ligands are important mediators of tumor angiogenesis and likely contribute to the pathogenesis and progression of urothelial carcinoma, according to Petrylak. Ramucirumab is a human IgG1 monoclonal antibody that antagonizes VEGFR2. As monotherapy or in combination with chemotherapy, ramucirumab prolonged overall survival (OS) in the second-line setting in patients with gastric cancer, colorectal cancer, and lung cancer. Icrucumab is a human IgG1 monoclonal antibody that is a VEGFR1 antagonist.

Both agents were studied with docetaxel in an open-label, multicenter, randomized phase II study that assessed PFS in patients with metastatic or locally advanced, unresectable, transitional renal cell carcinoma of the bladder, urethra, ureter, or renal pelvis, who relapsed ≤1 year from a platinum-based regimen. The 139 patients in the study were randomized in a 1:1:1 fashion to either 1) docetaxel, 75 mg/m² on day 1 of a 21-day cycle; 2) docetaxel plus ramucirumab, 10 mg/kg/day on day 1 of a 21-day cycle; or 3) docetaxel plus icrucumab, 12 mg/kg/day on days 1 and 8 of a 21-day cycle. Patients were treated until disease progression or intolerable toxicity. The analysis included patients who were randomized and treated between April 2011 and February 2014. A planned interim analysis was performed after 75% of the expected PFS events.

The median age ranged from 66.0 to 69.0 years in the three groups, which were evenly distributed for Eastern Cooperative Oncology Group performance status, presence of visceral metastases (52%- 61%), and absence of prior antiangiogeneic therapy (94%-98%).

At the interim analysis, PFS was a median of 10.4 weeks in the docetaxel monotherapy arm and 22.0 weeks in the docetaxel-plus-ramucirumab arm (stratified hazard ratio [HR], 0.388; P <.001). Median PFS in the docetaxel-plus-icrucumab arm was 7.0 weeks. PFS favored the docetaxel-plus-ramucirumab arm compared with docetaxel monotherapy in all prespecified subgroups examined.

“Overall survival[OS] data are not mature at this point,” said Petrylak. At the interim analysis, median OS in the docetaxel monotherapy arm was 33.4 weeks compared with 48.9 weeks in the docetaxel-plus-ramucirumab arm (stratified HR, 0.775; P = .387). Median OS was 27.7 weeks in the docetaxel-plus-icrucumab arm.

“The 11-month median OS [in the docetaxel/ramucirumab arm] is actually quite robust in this patient population compared with other studies. There was an OS trend that was not yet statistically significant, and there was no placebo, and so whether this influenced the patients coming off study is not clear,” commented Jonathan Rosenberg, MD, section head, nonprostate genitourinary malignancies, Memorial Sloan Kettering Cancer Center, who was not involved in the study.

The objective response rate (complete response plus partial response) was 5% in the docetaxel monotherapy arm, 20% in the docetaxel-plus-ramucirumab arm (P = .05 vs docetaxel monotherapy), and 10% in the docetaxel-plus-icrucumab arm. Disease control rates (complete response plus partial response plus stable disease) were 43% with docetaxel monotherapy, 67% with docetaxel plus ramucirumab (P = .033 vs docetaxel monotherapy), and 31% with docetaxel plus icrucumab.

Treatment-emergent adverse events (AEs) that occurred more often with docetaxel plus ramucirumab compared with docetaxel alone included fatigue (reported by 80% vs 75%, respectively), febrile neutropenia (22% vs 11%), pneumonia (15% vs 9%), diarrhea (48% vs 23%), stomatitis (30% vs 16%), and thrombocytopenia (20% vs 7%). Grade ≥3 AEs that occurred with greater frequency in the docetaxel-plus-ramucirumab arm compared with the docetaxel-alone arm were fatigue (33% vs 11%), febrile neutropenia (20% vs 11%), diarrhea (7% vs 2%), stomatitis (7% vs 0%), and thrombocytopenia (7% vs 0%).

Petrylak DP, Tagawa ST, Kohli M, et al. Interim results of a randomized phase 2 study of docetaxel with ramucirumab versus docetaxel in second-line advanced or metastatic urothelial carcinoma. Presented at: 2015 Genitourinary Cancers Symposium; February 26-28, 2015; Orlando, FL. Abstract 295.

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