PI3K Pathway Inhibitors

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Presentation transcript:

PI3K Pathway Inhibitors Scott Kopetz, MD, PhD

DISCLOSURES Consultant Amgen AstraZeneca Bayer GlaxoSmith Kline Roche

PI3K pathway: Growth Signaling SU2C PI3K Team

Inside the “Blue Box” Growth Factors ATP AA Grow

PI3K Pathway Primer Simple version: Bruton tyrosine kinase TEC kinase Serum/glucocorticoid kinases Phin et al Front. Oncol. ‘13

Genomic Dysregulation in GI Cancers Mutation PIK3CA PIK3R1 AKT PTEN MTOR Amplification Epigenetic PTEN loss CRC Esoph Panc Gastric HCC 20% 6% 2% 22% <1% 4% 1% 3% 7% 8% 19% ? 15% 14% 12% cBioPortal.org 3/14; Holander et al Nat Rev Cancer ‘11

Inhibitors for the Pathway Rodon, J. et al Nat. Rev. Clin. Oncol. ‘13

Over 50 agents in development Rodon, J. et al Nat. Rev. Clin. Oncol. ‘13

Bright Spot: MTOR inhibition in Pancreatic Neuroendocrine Tumors Yao et al NEJM ‘11

No responses in any GI tumors Single Agent, Unselected Patients: Minimal Clinical Activity in GI Adenocarcinomas XL147 n=75 GDC-0491 n=139 XL765 n=83 BKM120 n=66 BAY 80-9646 n=47 CH5132799 n=31 PX-866 n=84 BEZ235 n=75 GSK2126458 n=129 GDC-0980 n=74 SF-1126 n=39 PF-04691502 n=33 PF-05212384 n=53 BGT-226 n=57 PI3K Inhibitors N=985 patients treated in phase 1 studies No responses in any GI tumors Brana et al BMC Medicine ‘12

Single Agent, Selected Patients: Still Minimal Activity in GI Adenocarcinomas BYL719: PIK3CA mutations required 1 CRC response at first report KRAS and PIK3CA R88Q mutation But after 67 additional pts, no further responses in GI cancers No correlation of PIK3CA mutations and response to PI3K or AKT inhibitors seen in most other studies: BMK120: Bendell JCO ’12 Cohort: Oliviera ASCO ’12 MK2206: Yap JCO ’11 Cohort: Dienstmann MCT ‘12 PX-866: Jimeno ASCO ‘10

Reasons for limited response Inadequate degree of pathway inhibition? Unlikely just a PK issue given multiple agents If >90% inhibition is needed, is there a sufficient therapeutic window? Development of feedback/upregulation? Insufficient pt selection? Isoform selectivity? Perhaps PTEN loss and PI3Kβ inhibitors Needs combination therapy? Randomized phase II studies with combinations ongoing