Open label, phase II trial of neoadjuvant TAK-228 plus tamoxifen in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor type 2 (HER2)-negative breast cancer-ANETT.

person Emre Koca Houston Methodist Hospital, Houston, TX info_outline Emre Koca, Polly Ann Niravath, Joe Ensor, Tejal Amar Patel, Xiaoxian Li, Pej Hemati, Helen Wong, Wei Qian, Toniva Boone, Jing Zhao, Priya V. Ramshesh, Adam Louis Cohen, Asha Murthy, Sindhu Nair, Jorge German Darcourt, Anna Belcheva, Virginia G. Kaklamani, Jenny Chee Ning Chang

Authors person Emre Koca Houston Methodist Hospital, Houston, TX info_outline Emre Koca, Polly Ann Niravath, Joe Ensor, Tejal Amar Patel, Xiaoxian Li, Pej Hemati, Helen Wong, Wei Qian, Toniva Boone, Jing Zhao, Priya V. Ramshesh, Adam Louis Cohen, Asha Murthy, Sindhu Nair, Jorge German Darcourt, Anna Belcheva, Virginia G. Kaklamani, Jenny Chee Ning Chang Organizations Houston Methodist Hospital, Houston, TX, Baylor College of Medicine, Houston, TX, Methodist Cancer Center, Houston, TX, Emory University, Atlanta, GA, Houston Methodist Cancer Center, Houston, TX, Houston Methodist Research Institute, Houston, TX, Houston Methodist Woodlands, The Woodlands, TX, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, Univ of Texas Onc, Houston, TX, Northwestern University Division of Hematology/Oncology, Chicago, IL Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: Neoadjuvant endocrine therapy is standard care for women with hormone receptor-positive breast cancer. However, both primary and acquired endocrine resistance is not uncommon, thereby limiting efficacy. [1] The PI3K-Akt-mTOR pathway is a major mediator of endocrine resistance. [2,3] Therefore, we determined the efficacy and safety of the mTORC1/2 inhibitor TAK-228 in combination with tamoxifen in neoadjuvant setting. Methods: In this single-arm, open-label phase II trial, newly diagnosed patients with stage I−III ER-positive, HER2-negative breast cancer received TAK-228 (30 mg weekly) and tamoxifen (20 mg daily) for 16 weeks until 2-4 weeks prior to surgery. The primary endpoint was the change in Ki67 after 6 weeks. Secondary endpoints included pathological complete response rate (pCR), preoperative endocrine prognostic index (PEPI) score, and safety. Results: Of the 28 patients enrolled in the study, 3 were excluded due to non-compliance. Mean patient age was 51.7 years. Most patients had stage I or II disease (12 [43%] each); 4 (14%) had stage III disease. Mean Ki67 was significantly lowered from baseline to Week 6 (17.2% vs. 15.2%, p = 0.0023). Interestingly, mean Ki67 increased to 20.1% from baseline to the time of surgery. This may have been due to a rebound effect, as TAK-228 was discontinued 2-4 weeks prior to surgery. Tumor size also significantly decreased from baseline to surgery, with a median decrease of 0.75 centimeters (p < 0.0001). PEPI score was intermediate risk (score 1−3) in 6 patients and high risk group (score ≥4) in 15 patients. No patients achieved a PEPI score of 0 and no pCR was achieved. Overall, the combination was well tolerated, the most common side effects were nausea (72%), vomiting (72%), fatigue (72%), mucositis (45%), and headache (45%). The any Grade 3 AE rate was 7.7%. Conclusions: The TAK-228 and tamoxifen combination was found to be an effective neoadjuvant strategy with a favorable safety profile in newly diagnosed patients with hormone receptor-positive breast cancer. Further molecular analysis (PI3K-Akt-mTOR pathway) are pending and will be presented. Clinical trial information: NCT02988986