The combination of an antiestrogen and a PI3K inhibitor is safe, well tolerated, and active.
Major finding: The combination of an antiestrogen and a PI3K inhibitor is safe, well tolerated, and active.
Concept: The combination of buparlisib and letrozole had activity regardless of PIK3CA hotspot mutation status.
Impact: Combination PI3K and aromatase inhibitor therapy may have clinical benefit in ER-positive breast cancer.
Preclinical studies have indicated that phosphoinositide-3-kinase (PI3K) signaling contributes to endocrine therapy resistance and estrogen-independent growth of estrogen receptor (ER)–positive breast cancer cells, suggesting that the combined use of PI3K inhibitors and antiestrogens would be beneficial. Mayer and colleagues performed a multicenter, open-label phase Ib trial of buparlisib, an oral pan-PI3K inhibitor, in combination with the oral aromatase inhibitor letrozole in patients with metastatic ER-positive breast cancer. The study had two arms, with 20 patients receiving continuous buparlisib treatment and 31 patients receiving buparlisib intermittently, and almost every patient had previously received endocrine therapy. The primary objective was to assess the safety and tolerability of buparlisib plus letrozole and the secondary objectives were to evaluate antitumor activity and tumor metabolic responses. Buparlisib and letrozole combination therapy was well tolerated, with few serious adverse events; the most commonly observed adverse events were gastrointestinal disorders, transaminitis, hyperglycemia, and mood disorders. In the continuous arm, 1 (5%) patient had a complete response and 1 (5%) patient had a partial response, and 11 (55%) had stable disease. In the intermittent arm, 14 (45%) patients had stable disease. Of 7 patients with stable disease lasting a year or longer, 3 (43%) had tumors with hotspot mutations in the PI3Kα catalytic subunit gene PIK3CA. Additionally, 3 of 9 (33%) patients who had a metabolic partial response as measured by [18F]fluorodeoxyglucose uptake had PIK3CA mutations. Although the clinical activity of buparlisib and letrozole was not limited to breast cancers with PIK3CA mutations, it remains possible that other alterations in the PI3K pathway in these tumors conferred buparlisib sensitivity. Collectively, these findings indicate that combined use of a PI3K inhibitor and an antiestrogen is safe and effective in patients with endocrine therapy–refractory metastatic ER-positive breast cancer and support further evaluation of buparlisib and letrozole combination therapy in larger clinical trials.
Mayer IA, Abramson VG, Isakoff SJ, Forero A, Balko JM, Kuba MG, et al. Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2014 Mar 24 [Epub ahead of print].
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