Inhibiting the PI3K Pathway: Buparlisib, BYL719, and Taselisib Emerge as Contenders
The fact that a tumor’s response to a PI3K inhibitor cannot be predicted has led to myriad clinical trials of agents targeting this signal transduction pathway.
Which breast tumors will respond to a phosphatidylinositol 3 (PI3K) pathway inhibitor?
To answer that question first requires an understanding of the PI3K pathway, which plays a critical role not only in cancer, by mediating cell transformation via oncogenes, but in stimulating insulin-dependent glucose uptake and metabolism.1,2
Discovered in 1985 by Lewis C. Cantley, PhD, and colleagues at Tufts University School of Medicine in Boston, MA, the PI3K pathway is one of the most mutated in human cancer. Mutations in PIK3CA, the gene that encodes the p110α subunit of PI3K, are associated with antiestrogen resistance in estrogen receptor-positive breast cancer.3
To date, however, tumor response to a PI3K inhibitor cannot be predicted, which has led to myriad clinical trials of agents targeting this signal transduction pathway.
The goal: to find an approach that “will accelerate personalized cancer care that can be incorporated into standard practice,” according to the Stand Up to Cancer (SU2C) PI3K Dream Team, “Targeting the PI3K Pathway in Women's Cancers,” which includes breast, ovarian, and endometrial cancers.
Dr. Cantley, Margaret and Herman Sokol Professor and Director, Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College/Ronald P. Stanton Clinical Cancer Program, New York Presbyterian Hospital in New York, NY, and Team Leader for the SU2C PI3K Dream Team, one of the original five Dream Teams created in 2009, told Cancer Therapy Advisor that work completed by the group, a global consortium of investigators, has led to four “discovery trials” of PI3K inhibitors for breast cancer, three of which are still accruing participants.
The team has modeled their approach on the development of trastuzumab. In 2001, the finding that trastuzumab significantly improved median survival from 20.3 to 25.1 months in HER2-positive metastatic breast cancer was groundbreaking4; now, the agent is considered a standard of care for early-stage, HER2-positive breast cancer.
They hoped to find agents that target solid tumors such as breast cancer carrying PIK3CA gene alterations that work first in the metastatic setting, with the goal of moving use to the neoadjuvant setting.
Over 4 years, they tested more than 20 PI3K pathway-targeted agents as well as 7 drugs targeting interacting pathways in 57 breast cancer cell lines to determine if potentially novel biomarkers could be identified.
Two agents emerged as candidates for the ongoing phase 2/3 trials: buparlisib (BKM120) and BYL719, both synthesized by Novartis (Basel, Switzerland), which have been shown in phase 1 trials to target solid tumors that carry PIK3CA gene alterations.5,6
Ingrid A. Mayer, MD, MSCI, Co-Leader and Clinical Director of the Breast Cancer Research Program at Vanderbilt-Ingram Cancer Center in Nashville, TN, and colleagues, presented results from the phase 1b trial of BYL719 (an α-specific PI3K inhibitor) in combination with letrozole in postmenopausal patients with estrogen receptor-positive/HER2-negative metastatic breast cancer7 at the 2014 Annual Meeting of the American Society of Clinical Oncology.3
They found the combination of BYL719 and letrozole to be safe and tolerable, with the grade 2 and 3 rash and hyperglycemia observed suggesting PI3K inhibition.
However, “a correlation of PIK3CA mutations with clinical benefit cannot yet be fully established,” they noted, and that “clinical activity was not restricted to patients with PIK3CA mutant tumors.” The recommended dose of BYL719 for phase 2 trials was found to be 300 mg/day.
SU2C, whose scientific partner is the American Association for Cancer Research, funded the phase 1b trial “with collaboration and help from Novartis, which will now pick up the cost of the phase 2 trial and take it worldwide,” Dr. Cantley said.
Dr. Mayer is continuing as lead investigator for the phase 2 trial, which will determine whether treatment with neoadjuvant buparlisib (BKM120), BYL719, or placebo in combination with letrozole leads to an increase in pathologic response compared with treatment with placebo plus letrozole.8
Also underway is the Novartis-sponsored randomized phase 2/3 BELLE-4 trial, which is studying the effect of BKM120 plus paclitaxel in patients with HER2-negative inoperable locally advanced or metastatic breast cancer, with and without PI3K pathway activation.9