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A Phase Ib Study of Alpelisib Or Buparlisib Combined with Tamoxifen Plus Goserelin in Premenopausal Women with HR-Positive HER2-Negative Advanced Breast Cancer

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A Phase Ib Study of Alpelisib Or Buparlisib Combined with Tamoxifen Plus Goserelin in Premenopausal Women with HR-Positive HER2-Negative Advanced Breast Cancer Author Manuscript Published OnlineFirst on July 27, 2020; DOI: 10.1158/1078-0432.CCR-20-1008 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. A Phase Ib study of alpelisib or buparlisib combined with tamoxifen plus goserelin in premenopausal women with HR-positive HER2-negative advanced breast cancer Yen-Shen Lu,1 Keun Seok Lee,2 Tsu-Yi Chao,3 Ling-Ming Tseng,4 Imjai Chitapanarux,5 Shin-Cheh Chen,6 Chien-Ting Liu,7 Joohyuk Sohn,8 Jee Hyun Kim,9 Yuan-Ching Chang,10 Youngsen Yang,11 Kanjana Shotelersuk,12 Kyung Hae Jung,13 Roberta Valenti,14 Cassandra Slader,14 Melissa Gao,14 Yeon Hee Park15 1Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. 2Center for Breast Cancer, National Cancer Center, Goyang, Republic of Korea. 3Division of Hematology/Oncology, Shuang Ho Hospital and Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan. 4Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University in Taipei. 5Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. 6Breast Surgery Division, Chang Gung Memorial Hospital, Linkou, Taoyouan City, Taiwan. 7Division of Hematology and Oncology, Chang Gung Memorial Hospital-Kaohsiung, Kaohsiung City, Taiwan. 8Division of Medical Oncology, Yonsei Cancer Center, Seoul, South Korea. 9Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea. 10Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan. 11Taichung Veterans General Hospital, Taichung, Taiwan. 12Division of Therapeutic Radiology and Oncology, Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. 13Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 14Novartis Pharma AG, Basel, Switzerland. 15Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Seoul, South Korea. Running Title: PI3K inhibitors in premenopausal advanced breast cancer This trial is registered at www.clinicaltrials.gov (NCT02058381). Financial Support: This study was funded by Novartis Pharmaceuticals. Address correspondence and reprint requests to Yeon Hee Park, MD, PhD Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine 81 Irwon-ro Gangam-gu, Seoul, 06351, Korea Phone: 82234101780 E-mail: [email protected] 1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 27, 2020; DOI: 10.1158/1078-0432.CCR-20-1008 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Disclosure of Potential Conflicts of Interest Yen-Shen Lu: Grants and personal fees from Novartis during the conduct of the study and outside of the submitted work; speaker and consulting fees from Pfizer, Boehringer Ingelheim, and Roche; grant from Merck; contracted research from Roche, Merck Sharp & Dohme, Pfizer, and GlaxoSmithKline. Keun Seok Lee: Personal fees from Novartis, Roche, Pfizer, and Lilly; nonfinancial support from Dong-A Pharm outside the submitted work. Tsu-Yi Chao: None. Ling-Ming Tseng: None. Imjai Chitapanarux: None. Shih-Cheh Chen: None. Chien-Ting Liu: None. Joohyuk Sohn: None. Jee Hyun Kim: None. Yuan-Ching Chang: None. Youngsen Yang: None. Kanjana Shotelersuk: Grants from Novartis Oncology during the conduct of the study. Kyung Hae Jung: Consultancy for Eisai, Novartis, AstraZeneca, Celgene, and Roche. Roberta Valenti: Support from Novartis FARMA SPA during the conduct of the study and outside the submitted work; employee of Novartis. Cassandra Slader: Employee and stockholder of Novartis Pharma AG. Melissa Gao: Employee of Novartis. Yeon Hee Park: Consultancy for Pfizer, Eisai, Roche, Lilly, and Novartis; research funding from AstraZeneca, Pfizer, Roche, and Novartis. Preliminary data from this study were previously presented: Lu Y-S, Ro J, Tseng L-M, et al. A Phase Ib Dose De-escalation Study of Combined Tamoxifen and Goserelin Acetate With Alpelisib (BYL719) or Buparlisib (BKM120) in Premenopausal Patients With HR+/HER2– Locally Advanced or Metastatic Breast Cancer. Presented at the San Antonio Breast Cancer Symposium, December 8–12, 2015, San Antonio, TX. Poster P4-13-27. 2 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 27, 2020; DOI: 10.1158/1078-0432.CCR-20-1008 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Statement of translational relevance Phosphatidylinositol 3-kinase (PI3K) signaling is frequently upregulated in breast cancer and is linked to increased resistance to endocrine therapy. Inhibition of PI3K has been shown to prevent proliferation of long-term estrogen-deprived cell lines. Alpelisib and buparlisib are novel PI3K inhibitors that have demonstrated antitumor activity in preclinical studies. Results from phase 3 studies (SOLAR-1 and BELLE-2) showed that alpelisib or buparlisib in combination with fulvestrant was associated with clinically significant improvement in progression-free survival compared with placebo in postmenopausal patients with PIK3CA mutation. Inhibition of the PI3K pathway is a potential therapeutic target for treating premenopausal patients whose treatment options are largely extrapolated from guidelines for postmenopausal patients. Here, we report the results of B-YOND, a phase 1b and the first study of the combination of tamoxifen plus goserelin acetate with alpelisib or buparlisib in premenopausal women with hormone receptor- positive, human epidermal growth factor receptor-2–negative advanced breast cancer. 3 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 27, 2020; DOI: 10.1158/1078-0432.CCR-20-1008 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Purpose: This study reports the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and preliminary efficacy of alpelisib or buparlisib used in combination with tamoxifen plus goserelin in premenopausal patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC). Patients and Methods: This study enrolled premenopausal women with HR+, HER2– ABC. Patients received tamoxifen (20 mg once daily) and goserelin acetate (3.6 mg every 28 days) with either alpelisib (350 mg once daily; n=16) or buparlisib (100 mg once daily; n=13) in 28-day cycles until MTD was observed. Results: The criteria for MTD were not met for both alpelisib and buparlisib. The RP2D of alpelisib and buparlisib in combination with tamoxifen and goserelin were 350 mg and 100 mg, respectively. Both combinations met protocol-specified criteria for tolerability. The most common grade 3/4 treatment-emergent adverse events (TEAEs) were hypokalemia (12.5%), hyperglycemia (6.3%), and rash (6.3%) for alpelisib and ALT increase (30.8%), AST increase (23.1%), and anxiety (15.4%) for buparlisib. TEAEs led to treatment discontinuation in 18.8% and 53.8% of alpelisib- and buparlisib-treated patients, respectively. Progression-free survival was 25.2 months in the alpelisib group and 20.6 months in the buparlisib group. Conclusions: The RP2Ds of alpelisib and buparlisib were 350 mg and 100 mg, respectively. No unexpected safety findings were reported. Although an early-phase study, data suggest that alpelisib plus endocrine therapy may be a potentially efficacious treatment that warrants further evaluation for premenopausal patients with HR+, HER2– ABC. 4 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 27, 2020; DOI: 10.1158/1078-0432.CCR-20-1008 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION Breast cancer is the leading cancer diagnosed in women (24%) and is the most common cause of cancer-related deaths (15%) worldwide. The worldwide estimate in 2018 for newly diagnosed female breast cancer was 2.1 million, or 1 in 4 cases of cancer among women. Australia, New Zealand, Europe, and North America have the highest incidence rates of breast cancer (1). In the United States, breast cancer predominantly affects women aged 60 years and above, whereas in East Asia, incidence peaks in women aged 40-75 years (2). Approximately 42% of women in the Asia-Pacific region and 47% in Southeastern Asia were younger than 50 years at the time of diagnosis, in contrast to 20% of women in Western countries (3,4). The most common molecular subtype of breast cancer is luminal disease, characterized as hormone receptor-positive (HR+) and human epidermal growth factor receptor-2–negative (HER2–), occurring in around 70% of cases (5,6). In East Asia, the prevalence rate of luminal disease is even higher in premenopausal breast cancer patients than in postmenopausal patients (2). Treatment options for premenopausal patients with HR+, HER2–, advanced breast cancer (ABC [includes locally advanced and metastatic
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