Buparlisib at a dose of 80 mg/day in combination with bevacizumab was a tolerable and demonstrated preliminary activity in patients with vascular growth factor (VEGF)-refractory metastatic renal cell carcinoma (mRCC), a study published in Cancer has shown.1
Because the phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is dysregulated in patients with mRCC, researchers sought to evaluate the tolerability and activity of buparlisib, a pan-PI3K inhibitor, with bevacizumab in mRCC. Their objective was also to determine the maximum tolerated dose and dose-limiting toxicities of the combination.
For the phase 1 trial, researchers enrolled 32 patients with mRCC who were refractory to prior anti-VEGF therapy. A total of 87% had clear cell histology and half received 2 or more prior lines of therapy. Participants received buparlisib at a dose of 60, 80, or 100 mg orally per day plus bevacizumab 10 mg/kg intravenously every 2 weeks.
Investigators determined the maximum tolerated dose of buparlisib to be 80 mg/day with bevacizumab.
Researchers found that 28 patients discontinued therapy: 17 due to disease progression, 7 because of toxicity, and 4 for other reasons. Dose-limiting toxicities included rash, pruritis, elevated lipase, elevated amylase, anorexia, and psychiatric disorders.
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In regard to efficacy, of the 30 evaluable patients, 13% (95% CI, 4-31) achieved a partial response. Of note, 2 patients who harbored activating PI3KA mutations experienced 42% and 16% maximal tumor shrinkage, respectively.
The findings ultimately suggest that further trials evaluating this combination are warranted for patients with mRCC, particularly those with activating PI3KA mutations.
- McKay RR, De Velasco G, Werner L, et al. A phase 1 study of buparlisib and bevacizumab in patients with metastatic renal cell carcinoma progressing on vascular endothelial growth factor-targeted therapies [published online ahead of print May 19, 2016]. Cancer. doi: 10.1002/cncr.30056.