PI3Kinase

Disease Target Area: Breast, Lung and Ovarian Cancer

About PI3 Kinase (PI3K)

The PI3K pathway is an essential mechanism by which cells maintain homeostasis, which controls cell proliferation, survival and transcription. Alterations in the PI3K pathway are one of the most frequent in solid cancers and has been linked to tumor initiation and growth. Alterations leading to pathway activation include mutations in the gene that encodes p110-alpha PIK3CA, mutations in AKT1, as well as loss of the tumor suppressor gene PTEN.

About the Program & What we learned:

We learned that targeting the PI3K pathway through inhibition of multiple p110 subunits (ie, alpha, beta, gamma and delta) has a narrow therapeutic index. As such, the development of drug candidates that are more active on the mutant form of p110alpha (versus the non-mutant form in healthy, non-cancerous tissue) is likely essential to expand the therapeutic window. As such, molecules that specifically target the p110a subunit like GDC-0077 and alpelisib are expected to have only modest activity in patients whose tumors do not have a PIK3CA mutation (which was, in fact, demonstrated in the Phase III SOLAR-1 study of alpelisib in patients with metastatic HR+ breast cancer, which validated this hypothesis). On the other hand, molecules that target the PI3K pathway downstream of p110, such as ipatasertib (AKT inhibitor) and everolimus (mTOR inhibitor) are likely to be active in HR+ breast cancer patients independent of the status of PIK3CA when combined with endocrine therapies.

Reverse Translation:

The PI3K program has made numerous contributions to the ipatasertib, GDC-9545 (SERD) and GDC-0077 programs.

ESR1 mutation analysis in the FERGI and the SANDPIPER studies demonstrated that fulvestrant (and, by extension, GDC-9545) activity is not associated with ESR1 status

PI3K inhibitors, pictilisib and taselisib, further reduced Ki67 in HR+ eBC (LORELEI and OPPORTUNE studies), which was not limited to PIK3CA mutant tumors.

Taselisib Basket cohort comprising of pts with PIK3CA mutant tumors demonstrated that taselisib has activity across a range of solid tumor types.

Patients with double PIK3CA mutations appear to be particularly sensitive to PI3K inhibitors, which lead to the inclusion GDC-0077 in patients with double mutants in TAPESTRI basket study.

Through the analysis of paired biopsies demonstrated on the pictilisib program, we observed that inadequate pathway inhibition didn’t translate to clinically meaningful benefit.

PTEN mutations appear to be a resistance mechanism in PIK3CA mutant patients (taselisib Basket cohort and SANDPIPER ctDNA analysis).

In lung cancer, we observed that patients without activating mutations in RAS pathway components is associated with improved PFS outcomes in patients that are treated with a PI3K inhibitor in combination with chemotherapy, which suggests that activation of the RAS pathway is a mechanism of resistance to PI3K inhibitors.