ORLANDO, Florida ― Adding the new antiangiogenic agent ramucirumab (Cyramza, Eli Lilly and Company) to docetaxel (multiple brands) chemotherapy has shown promising results as a second-line therapy in advanced or metastatic urothelial carcinoma.
The interim analysis of a phase 2 randomized trial showed that the combination regimen significantly increased progression-free survival (22 weeks) as compared with docetaxel alone (10.4 weeks).
The results were presented here at Genitourinary Cancers Symposium (GUCS) 2015.
"At the planned interim analysis, the ramucirumab plus docetaxel combination conferred a statistically significant progression-free survival improvement of greater than 11.5 weeks and reduced the risk of disease progression by 61%," commented lead author Daniel P. Petrylak, MD, professor of medicine (medical oncology) and of urology at Yale School of Medicine, New Haven, Connecticut.
"Results were consistent across prespecified subgroups," he said, "and it showed an acceptable safety profile."
One arm of the study also paired the investigational antiangiogenic agent icrucumab (ImClone Systems Incorporated) with docetaxel, but that arm did not meet the primary endpoint. "That will not be pursued for further investigation," Dr Petrylak added.
Both drugs are monoclonal antibodies that act to inhibit vascular endothelial growth factor (VEGF), but ramucirumab acts on VEGF-2, whereas icrucumab acts on VEGF-1.
Ramucirumab was approved for use in gastric cancer and non–small cell lung cancer after it was shown to prolong overall survival in phase 3 second-line studies. The drug has also shown this activity in colorectal cancer, but it is not approved for that indication (as yet).
Limited Options for Metastatic Bladder Cancer
Cisplatin-based combination chemotherapy regimens are the standard of care for metastatic bladder cancer. Patients with metastatic urothelial carcinoma who progress after first-line chemotherapy have limited treatment options, Dr Petrylak pointed out during his presentation.
The study that he presented at the meeting was conducted in nearly 150 patients with advanced urothelial carcinoma and ECOG performance status 0-1 who had relapsed 1 year or less after treatment with a platinum-based regimen. They were randomly assigned to receive docetaxel 75 mg/m2intravenously alone (n = 44) or in combination with ramucirumab 10 mg/kg IV on day 1 of repeating 21-day cycles (n = 46), or in combination with icrucumab 12 mg/kg on days 1 and 8 of a 21-day cycle (n = 49). Treatment continued until disease progression or unacceptable toxicity.
The study's primary endpoint was progression-free survival; the planned interim analysis was performed after 75% of the progression-free events.
At this interim analysis, the progression-free survival for the docetaxel alone group was 10.4 weeks, compared with 22 weeks for the docetaxel plus ramucirumab group (hazard ratio [HR], 0.388; P < .001).
"This was statistically significant," said Dr Petrylak. "Even after taking into account various clinical factors such as age, sex, ECOG performance status, prior antiangiogenic therapy, visceral metastasis, liver metastasis, prior and/or type of platinum-based therapy, it still favored the ramucirumab and docetaxel arm."
For patients receiving docetaxel plus icrucumab, the progression-free survival was 7 weeks (HR, 0.988; P = .932).
For overall survival, Dr Petrylak cautioned that the data are not yet mature, but they did appear better for the combination of ramucirumab and docetaxel compared with docetaxel alone (48.9 week vs 33.4 weeks; HR, 0.775; P = .387). Overall survival for docetaxel plus icrucumab was 27.7 weeks (HR, 1.080; P = .754).
A total of 5% of patients in the docetaxel alone arm had a complete or partial response, compared with 20% in the ramucirumab plus docetaxel arm and 10% in the other combination group.
Table. Overall Response
| Docetaxel Alone | Doc + Ram | Doc + Icr | |
| Complete response rate | 0 | 1 | 1 |
| Partial response rate | 2 | 8 | 4 |
| Stable disease | 17 | 22 | 10 |
| Progressive disease | 17 | 7 | 26 |
| Not evaluable | 8 | 8 | 8 |
| Disease control rate: cr + pr + sd, n (%) | 19 (43) | 31(67) | 15(31) |
| P-value | 0.03 | 0.28 |
Adverse events were higher in patients taking the combination of docetaxel plus ramucirumab than in those taking docetaxel alone. The most common adverse events (all grades) were fatigue (80.4% with docetaxel plus ramucirumab vs 75.0% with docetaxel), decreased appetite (54.3% vs 43.2%), nausea (54.3% vs 25.0%), and neuropathy (50.0% vs 38.6%). Rates of grade ≥3 febrile neutropenia (19.6% vs 11.4%), pneumonia (13% vs 9.1%), hypertension (4.3% vs 0%) were also higher in that arm.
The combination showed an acceptable safety profile, and these results support the initiation of the RANGE trial, a phase 3 trial of docetaxel plus ramucirumab vs docetaxel alone.
Worthy of Further Study
Discussing the presentation, Jonathan E. Rosenberg, MD, from Memorial Sloan Kettering Cancer Center, in New York City, noted that the study had both strengths and weaknesses. "It had a randomized design, and all endpoints trend in the same direction, and 11 months' median overall survival is robust in this patient population," he said. "There was a provocative trend towards overall survival, and while it's not the primary endpoint of the study, it is certainly trending in the right direction," he said.
On the downside, the overall survival trend was not statistically significant, and the authors did not use known second-line stratification factors, he said.
Overall, this combination does appear worthy of further investigation, Dr Rosenberg continued. "The primary endpoint was reached and the toxicities seem manageable."
The study was sponsored by Eli Lilly. Dr Petrylak reports relationships with Eli Lilly, Genentech, and Sanofi. Several of the coauthors also report relationships with Eli Lilly.
Genitourinary Cancers Symposium (GUCS) 2015. Abstract 295. Presented February 27, 2015.
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