Abstract CT232: SU2C Phase Ib study of the PI3K-alpha inhibitor BYL719 (alpelisib) with letrozole in ER+/HER2-metastatic breast cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Mutations in PIK3CA, the gene encoding the p110α subunit of PI3K, have been associated with antiestrogen resistance in ER+ BC. In general, antiestrogen-resistant cancers retain ER and responsiveness to estradiol. This suggests that treatment of ER+ BC with PI3K inhibitors should also include antiestrogens. Methods: We conducted a phase Ib 3+3 dose escalation trial of letrozole (2.5 mg/day) with the PI3Kα inhibitor BYL719 in post-menopausal patients (pts) with ER+/HER2- metastatic breast cancer (MBC) refractory to previous endocrine therapy. BYL719 doses ranged from 300-400 mg/daily. Treatment continued until unacceptable toxicity or disease progression. Disease was assessed every 2 months. PIK3CA mutation status was determined by SNaPshot or targeted next generation sequencing (NGS) in all patients’ tumors. Results: Twenty-six pts were accrued; all patients were refractory to endocrine therapies in the metastatic setting, 18 had prior aromatase inhibitor (AI) therapy in their first or second-line MBC treatment. Median age was 53 years (31-72); 76% of pts had bone and 61% had visceral metastases; 50% of pts had a somatic PIK3CA hotspot mutation. Toxicities are summarized in Table 1. Rash was the dose limiting toxicity* at 350 mg/day. Of the 5 pts with a partial response, 3 (60%) had a PI3KCA mutation, 6/9 pts (67%) that were on treatment for ≥6 months; 3/6 pts (50%) that were on treatment for ≥12 months and 4/6 pts (67%) that are still on study (range 11 - 19 months) had a PI3KCA mutation. Discussion: The combination of letrozole/ BYL719 is safe and tolerable in pts with AI-refractory ER+/HER2-negative MBC. The MTD and recommended dose for phase II trials of BYL719 in combination with letrozole was 300 mg/day. Rash and hyperglycemia were observed at this dose, suggesting drug-induced inhibition of PI3K. Pts with PIK3CA-mutant tumors appeared to derive better clinical benefit, although activity of the combination was also seen in patients with PIK3CA-wild type cancers. Additional NGS of >300 cancer genes and their correlation with clinical response will be updated at the meeting. Clinical trial information: [NCT01791478][1]. | Adverse Events (% by Grade) | |:---------------------------:| --------------- | | Toxicity | 300 mg (N = 20) | 300 mg (N = 20) | | 350 mg (N = 6) | 350 mg (N = 6) | | | | % by Grade | % by Grade | % Total | % by Grade | % by Grade | % Total | | | 2 | 3 | | 2 | 3 | | | Hyperglycemia | 18 | 12 | 56 | 20 | 20 | 70 | | Diarrhea | 12 | 12 | 81 | 10 | | 50 | | Fatigue | 25 | | 43 | 30 | | 80 | | Rash | 18 | | 43 | 10 | 20* | 40 | | Nausea | | | 62 | 10 | 10 | 60 | | Vomiting | | | 25 | | | 30 | | Anorexia | 6 | | 25 | 10 | | 40 | | Dysgeusia | | | 18 | | | 50 | Citation Format: Ingrid A. Mayer, Vandana Abramson, Justin Balko, Melinda Sanders, Dejan Juric, David Solit, Yisheng Li, Lewis Cantley, Eric Winer, Carlos Arteaga. SU2C Phase Ib study of the PI3K-alpha inhibitor BYL719 (alpelisib) with letrozole in ER+/HER2-metastatic breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT232. doi:10.1158/1538-7445.AM2015-CT232 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01791478&atom=%2Fcanres%2F75%2F15_Supplement%2FCT232.atom