A Randomized Phase II Study to Determine the Effect of 2 Different Doses of Aflibercept in Patients With Metastatic Renal Cell Carcinoma (ECOG-ACRIN [E4805]).
BACKGROUND
Aflibercept is a recombinantly produced fusion protein that has potent anti-vascular endothelial growth factor (VEGF) activity. We tested whether aflibercept has clinical activity in clear-cell renal cell carcinoma (ccRCC). The recommended phase II dose was 4 mg/kg but several patients (pts) treated at 1 mg/kg showed prolonged progression-free survival. We therefore tested both doses in a parallel group randomized trial.


PATIENTS AND METHODS
Eligible pts had histologically confirmed advanced or metastatic ccRCC and previous treatments included exposure to a VEGF receptor tyrosine kinase inhibitor. Pts received aflibercept (either 1 mg/kg or 4 mg/kg) on day 1 of a 14-day cycle until disease progression. Pts randomized to 1 mg/kg could crossover to 4 mg/kg at the time of disease progression. The primary end point was proportion alive and progression-free at 8 weeks. A Simon 2-stage design was used for each arm with 33 and 24 eligible pts per arm enrolled in stages 1 and 2.


RESULTS
Ninety-four pts were enrolled, 59 and 35 to 4 mg and 1 mg doses, respectively. Seventy-two percent had 1 previous treatment most commonly sunitinib. Sixteen eligible pts crossed over at the time of disease progression to the 4-mg dose. Most common adverse events were hypertension, proteinuria, and fatigue. Only 4 pts reported Grade 4 or higher toxicity. With 36 of 59 pts (61%) progression-free at 8 weeks, the 4-mg/kg dose met protocol-specified efficacy criteria.


CONCLUSION
Aflibercept is active in previously treated ccRCC and might be worthy of further study.
['Pili|Roberto|R|', 'Jegede|Opeyemi|O|', 'Carducci|Michael A|MA|', 'Manola|Judith|J|', 'Groteluschen|David L|DL|', 'Appleman|Leonard L|LL|', 'Liu|Glenn|G|', 'Shanks|James C|JC|', 'Dakhil|Shaker R|SR|', 'Dutcher|Janice|J|', 'DiPaola|Robert S|RS|']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D020533:Angiogenesis Inhibitors D002292:Carcinoma, Renal Cell D018572:Disease-Free Survival D004305:Dose-Response Relationship, Drug D005260:Female D006801:Humans D007680:Kidney Neoplasms D008297:Male D008875:Middle Aged D009362:Neoplasm Metastasis D011897:Random Allocation D040262:Receptors, Vascular Endothelial Growth Factor D011993:Recombinant Fusion Proteins D016896:Treatment Outcome
Angiogenesis inhibitor Antiangiogenesis Drug resistance VEGF blocker