Abstract 13P
Background
Mutational KRAS activation drives oncogenic processes including aberrant cell cycle progression. CDK7 inhibition has been shown to target two fundamental processes in cancer: transcription and cell cycle control. SY-5609 is a CDK7 inhibitor in development in patients with solid tumors including pancreatic and lung cancers (NCT04247126). Here we report on SY-5609 preclinical activity in models of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small-cell lung cancer (NSCLC).
Methods
SY-5609 was evaluated as a single agent (SA) and in combination with chemotherapies. PDAC studies were done in RAS-mutant (7 KRAS, 1 NRAS) patient derived xenograft (PDX) models, and Panc-1 (KRAS-G12D) cells and xenografts +/- gemcitabine (Gem). NSCLC studies were done in A549 (KRAS G12S) cells and xenografts, and ST2972 (KRAS G12C) PDX tumors +/- docetaxel (Doc).
Results
In RAS-mutant PDAC PDX models derived from previously treated patients, SA SY-5609 (6mpk QD x28) induced regressions in 50% (4/8) of models and was well-tolerated (average body weight change [avg-BWC] 0%); regressions were sustained ≥2 weeks (wks) after drug discontinuation. In Panc-1 cells, SY-5609 inhibited proliferation (IC50, 0.7nM) and was synergistic with Gem. In vivo, SA SY-5609 (3 mpk QD x21) and SA Gem (100 mpk QW) each induced partial TGI; the combination induced nearly complete TGI (97%) and was well-tolerated (avg-BWC +2%). Similar combination results (94.3% TGI) were seen with a SY-5609 dosing regimen of 3 mpk QD, every other wk for 28d. In A549 cells, SY-5609 inhibited proliferation (IC50, 10nM) and was synergistic with Doc. In vivo, the combination of SY-5609 (3 mpk) and Doc (5 mpk QW) enhanced TGI. In ST2972 tumors, SA SY-5609 (3 mpk QD x21) induced near complete regressions, and with Doc (10 mpk QW) induced complete regressions with no tumor regrowth for ≥ 4 wks post drug discontinuation. Both regimens were well-tolerated (avg-BWC +3.6% to -6%).
Conclusions
SY-5609 shows robust antitumor activity in RAS-mutant PDAC and NSCLC preclinical models. Results support clinical evaluation of SY-5609 in combination with Gem in PDAC and Doc in NSCLC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Syros Pharmaceuticals.
Funding
Syros Pharmaceuticals.
Disclosure
S.H. Henry, L. Johannessen, P. Sawant, A. Lefkovith, N. Ke, W. Dworakowski, G. Hodgson: Financial Interests, Institutional, Full or part-time Employment: Syros Pharmaceuticals.