June 2014, Vol 3, No 4
Highest Response Rate to Date With a Third-Line VEGF Inhibitor, Pazopanib, in Metastatic Renal Cell Carcinoma
Almost 50% of patients with metastatic renal cell carcinoma (mRCC) had objective responses to third-line treatment with the angiogenesis inhibitor pazopanib, according to the results from a small clinical trial reported at the 2014 American Association for Cancer Research annual meeting.
Overall, 12 of 28 patients achieved objective responses (including 1 complete response), and another patient had an unconfirmed partial response. In the subgroup of responding patients, the duration of response to pazopanib exceeded the duration of previous responses in a majority of cases.
The cohort had a median progression-free survival of 16.5 months, a “remarkable” clinical outcome for such a heavily pretreated group of patients, said principal investigator Sumanta K. Pal, MD, assistant professor of medical oncology and therapeutics research, City of Hope, Duarte, CA.
“This is the highest objective response rate observed to date in a trial of third-line therapy for metastatic renal cell carcinoma,” said Pal. “Equally unprecedented is the median progression-free survival, which is remarkable for this group of patients.”
Pazopanib, a multitargeted tyrosine kinase inhibitor, is approved for the treatment of advanced RRC. Previous studies of the agent included a phase 3 trial in patients who were refractory to cytokine therapy or were treatment naive. No previous trial had determined pazopanib’s activity in the third-line setting or examined temporal changes in molecular profile during therapy.
Pal and colleagues evaluated pazopanib’s third-line potential for mRCC in a well-defined group of previously treated patients. They performed a phase 3, single-arm trial involving patients whose disease had progressed after 2 previous systemic regimens, 1 of which had to be an inhibitor of vascular endothelial growth factor (VEGF). Other eligibility criteria included ECOG performance status of 0 to 2, and clear cell histology.
The primary outcome was response rate, and the trial was statistically powered to detect a 23% overall response rate, defined as “clinically encouraging.” Investigators also examined immunologic markers associated with treatment failure or success.
Patients received pazopanib 800 mg daily on 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or death.
None of the patients enrolled in the study had good-risk characteristics. Approximately 60% had intermediate-risk features, and about 40% had poor-risk features.
Overall, 23 of the 28 patients received anti-VEGF therapy as first-line treatment, and the most frequently used second-line therapy was the mTOR inhibitor class. Some of the patients received anti-VEGF therapy as first- and second-line therapy. The median duration of previous anti-VEGF therapy was 4 months.
In addition to the 13 patients who had responses (including the 1 unconfirmed response), 9 had stable disease, resulting in a clinical benefit rate of 78%. After a median follow-up of 17.1 months, the median overall survival had yet to be reached.
Biomarker analysis showed that response was associated with lower levels of hepatocyte growth factor, VEGF, interleukin (IL)-8, IL-6, and soluble IL-2 receptor (P<.05 for each analysis).
The most frequently reported adverse event was hypertension (93%, all grades), which was grade 3/4 in 50% of the cases. Blood pressure was manageable with antihypertensive medications, and no patient stopped treatment because of uncontrolled blood pressure. In addition, 14% of patients had grade 3 proteinuria. The most frequently reported laboratory abnormalities were hyponatremia and elevated creatinine.
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