1. PI3K Pathway Inhibitors
Scott Kopetz, MD, PhD

2. DISCLOSURES
Consultant
Amgen
AstraZeneca
Bayer
GlaxoSmith Kline
Roche

3. PI3K pathway: Growth Signaling
SU2C PI3K Team

4. Inside the “Blue Box”
Growth Factors
ATP AA
Grow

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

6. 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

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

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

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

10. No responses in any GI tumors
Single Agent, Unselected Patients: Minimal Clinical Activity in GI Adenocarcinomas
XL147 n=75
GDC n=139
XL765 n=83
BKM120 n=66
BAY n=47
CH n=31
PX-866 n=84
BEZ235 n=75
GSK n=129
GDC n=74
SF n=39
PF n=33
PF 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

11. 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

12. 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