PI3K and mTOR inhibitors

Question 1

GOG248 Study Question?

Answer 1

Hormonal therapy and mTOR inh are active, is there synergy?

Question 2

Study design GOG 248?

Answer 2

RCT temsirolimus 25 mg IV weekly or TEM + megace (alternating with tamoxifen)

Question 3

Inclusion criteria GOG 248?

Answer 3

Advanced, persistent or recurrent EC, no prior chemo unless prior CR/PFS for 6+mo; ORR

Question 4

GOG 248 results

Answer 4

Combo arm closed due to VTE 7 in 22 pts
Unacceptable VTE risk, not active enough to offset the risk

TEM arm continued 22% ORR!

Question 5

What was the study question of GOG 3007?

Answer 5

Blocking PI3K/AKT/mTOR path may suppress and/or overcome endocrine therapy resistance for solid tumors; everolimus and letrozole has been effective -

Question 6

Study design of GOG 3007?

Answer 6

everolimus/letrozole vs. tamoxifen/megace

Question 7

ORR of GOG 3007?

Answer 7

ORR 22 vs. 25%; chemo naïve patients with improved PFS (had higher response rate) 28 vs 4 mo

Question 8

Theory behind Konstantinopoulos 2022 study - Letrozole and Abemaciclib

Answer 8

Extensive cross-talk between ER, PI3K, and RTK/RAS/CTNNB1 pathways leads to both ligand-dependent and ligand-independent ER transcriptional activity as well as upregulation of cyclin D1 which, in complex with cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), is a critical regulator of cell cycle progression and a key mediator of resistance to hormonal therapy. We hypothesized that the combination of the aromatase inhibitor letrozole and CDK4/6 inhibitor abemaciclib

Question 9

Study design of Konstantinopoulos?

Answer 9

Single arm abemaciclib + letrozole, with OR via RECIST or PFS
Abemaciclib - 150 mg BID
Letrozole 2.5 mg PD qd

Question 10

Results of Konstantinopoulos study?

Answer 10

ORR 30%; PFS 9 mo; DOR 7.4 mo
Ph III trial is planned
p53 mut was neg predictor of response