Inhibiting the PI3K Pathway: Buparlisib, BYL719, and Taselisib Emerge as Contenders

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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.
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.

Genentech BioOncology is investigating the effect of the novel oral selective PI3K pathway inhibitor taselisib (GDC-0032), designed to target the PI3Kα mutant. The hypothesis is that isoform-specific PI3K inhibitors will result in greater target inhibition, allowing higher doses to be given with fewer adverse events.10

In January 2015, a global phase 3 randomized trial of fulvestrant plus taselisib or placebo was initiated in postmenopausal women with estrogen receptor-positive and HER2-negative PIK3CA-mutant unresectable, locally advanced or metastatic breast cancer with disease recurrence or progression during or after aromatase inhibitor therapy. Anticipated study duration is approximately 3.5 years.10

Approximately 30% to 40% of women have breast cancer with PI3K mutations, Dr. Cantley said, with responses to date skewing towards those with wild-type mutations.

He predicts that, as with trastuzumab, PI3K inhibitors will be approved first in late-stage disease, with responses contributing to an understanding of their mechanisms of action.

However, “I really do think it would be when we go into adjuvant and neoadjuvant therapy we will see the biggest impact.”

One intriguing finding of research with the PI3K inhibitors, underscoring the complexity of ongoing research, is that they increase insulin levels so high “that they override the inhibition of PI3K in the liver,” impairing “the ability to inhibit PI3 kinase in the tumor.”

For that reason, he said an endocrine consultant was brought in on the Novartis trials, who recommended metformin and other sodium glucose transporter agents be used to keep insulin levels as low as possible.

Dr. Cantley pointed to recent research that argues that “insulin resistance—more so than obesity—is driving incidence of breast cancer.” This suggests that breast tumors may be responding to high levels of insulin, even in the absence of PI3K mutation.

RELATED: Breast Cancer Risk Prediction Models

“One should be very worried about that,” he said, adding that one of the take-home messages of his decades of research is to “avoid sugar. Sugar is the worst culprit. If you can do a single thing that won't mean you are hungry all the time, avoid sugar.”

In 2010, a global phase 3 study was initiated to compare invasive disease-free survival in patients with early-stage breast cancer treated with metformin versus placebo in addition to standard adjuvant therapy.

More than 3,500 patients have been randomized to oral metformin or placebo twice daily for up to 5 years in the absence of disease progression.

Data from this study, which is ongoing but no longer recruiting participants, is expected in late 2016.11

References

  1. Cantley LC, Auger KR, Carpenter C, et al. Oncogenes and signal transduction. Cell. 1991;64(2):281-302.
  2. Toker A, Cantley LC. Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature. 1997;387(6634):673-676.
  3. Mayer IA, Abramson VG, Balko JM et al. SU2C phase Ib study of the PI3Kα inhibitor BYL719 with letrozole in ER+/HER2– metastatic breast cancer (MBC). J Clin Oncol. 2014;32:5s(suppl; abstr 516^).
  4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001; 344(11):783-792.
  5. Fritsch C, Huang A, Chatenay-Rivauday C, et al. Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther. 2014;13(5):1117-11129.
  6. Bendell JC, Rodon J, Burris HA, et al. Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012;30(3):282-290.
  7. www.ClinicalTrials.gov. A phase 1b trial of BYL719 (an α-specific PI3K inhibitor) in combination with endocrine therapy in post-menopausal patients with hormone receptor-positive metastatic breast cancer. NCT01791478. Available at: https://clinicaltrials.gov/ct2/show/NCT01791478. Accessed March 10, 2015.
  8. www.ClinicalTrials.gov. A phase II randomized, double-blind placebo controlled, study of letrozole with or without BYL719 or buparlisib, for the neoadjuvant treatment of postmenopausal women with hormone receptor-positive HER2-negative breast cancer. NCT01923168. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01923168. Accessed March 10, 2015.
  9. www.ClinicalTrials.gov. A randomized, double-blind, placebo controlled, phase II/III study of BKM120 plus paclitaxel in patients with HER2 negative inoperable locally advanced or metastatic breast cancer, with or without PI3K pathway activation. NCT01572727. Available at: https://clinicaltrials.gov/ct2/show/NCT01572727. Accessed March 10, 2015.
  10. www.ClinicalTrials.gov. A phase III, double-blind, placebo controlled, randomized study of taselisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with estrogen receptor-positive and HER2-negative locally advance or metastatic breast cancer who have disease recurrence or progression during or after aromatase inhibitor therapy. NCT02340221. Available at: https://clinicaltrials.gov/ct2/show/NCT02340221. Accessed March 10, 2015.
  11. www.ClinicalTrials.gov. A phase III randomized trial of metformin versus placebo on recurrence and survival in early stage breast cancer. NCT01101438. Available at: https://clinicaltrials.gov/ct2/show/study/NCT01101438. Accessed March 10, 2015.
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