PI3K Inhibitor Combinations in Breast Cancer

The combination of letrozole with either the CDK4/6 inhibitor LEE011 or the PI3 kinase Inhibitor BYL719 demonstrated clinical activity for women with ER-positive, HER2-negative breast cancer, according phase Ib data presentation by Pamela N. Munster, MD, at the 2014 Breast Cancer Symposium.

In the phase Ib portion of the study, patients received treatment with LEE011 and BYL719 at various doses in a 28-day cycle. Letrozole was administered at 2.5 mg per day. LEE011 was administered for 21 days followed by a 7-day break, and BYL719 was administered daily. The goal of the analysis was to find a maximum tolerated dose, at which point the study would enroll patients with metastatic disease who had not received a prior systemic therapy other than letrozole into a dose expansion cohort. This randomized phase II portion of the study will compare letrozole, LEE011, and BYL719 to letrozole plus either LEE011 or BYL719.

PI3 kinase is activated in many cancers. The CDK4/6 -Rb pathway is crucial to many cancers. In estrogen receptor-positive tumors, that pathway is particularly vulnerable to inhibition. In the dose escalation portion of the study, patients received several prior lines of endocrine therapy and up to one prior cytotoxic regimen in the metastatic or locally advanced setting. All patients had ER-positive, HER2-negative breast cancer. Results were available for 13 patients treated with LEE011 and letrozoleand 12 treated with BYL719 and letrozole.

In the LEE011 plus letrozole arm, there was 1 confirmed partial response in a patient who received prior treatment with letrozole, fulvestrant, and a PI3K inhibitor for advanced/metastatic disease. Additionally, 3 patients had stable disease and 5 had neither complete response nor progressive disease (NCRNPD). In patients treated with BYL719 plus letrozole, 3 had stable disease and 3 had NCRNPD.

The phase II dose of LEE011 was declared to be 600 mg/day. In arm 2, only 9 of the 12 patients were evaluable for dose-determining decisions, and no dose-limiting toxicities occurred. The phase II dose of BYL719 was determined to be 300 mg/day.The most common adverse events (all grade) in LEE011 recipients were neutropenia (85%), leucopenia (39%), nausea (39%), anemia (23%), fatigue (23%), and lymphopenia (23%). Grade 3/4 adverse events suspected to be drug-related were neutropenia (46%), leucopenia (15%), and lymphopenia (23%).

In BYL719 recipients, diarrhea (50%), nausea (42%), and hyperglycemia (42%) were the most common adverse events, and the grade 3/4 adverse events suspected to be drug-related were hyperglycemia (17%), fatigue (8%), hyponatremia (8%), lymphopenia (8%), rash (8%), and morbilliform (8%). BYL719 had demonstrated activity in HR-positive breast cancer as a single agent and in combination with letrozole in preclinical mouse models. Additionally, LEE011 demonstrated early signs of single-agent clinical activity in advanced solid tumors. The phase Ib/II study sought to explore LEE011, BYL719, and letrozole. The maximum tolerated dose discovered in the dose-escalation portion of the study will be utilized in the phase II expansion study.

The evidence of feasibility of combining LEE011 and letrozole has led to the design of a phase III study for postmenopausal women with HR-positive, HER2-negative disease who have not received prior therapy. In this study, patients will be randomized to LEE011 and letrozole or placebo plus letrozole, with progression-free survival as the primary endpoint. This study, labeled MONALEESA-2, is currently recruiting patients (NCT01958021).

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