On May 29, 2020 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported new preclinical data for SY-5609, its highly selective and potent oral inhibitor of cyclin-dependent kinase 7 (CDK7) (Press release, Syros Pharmaceuticals, MAY 29, 2020, View Source [SID1234558727]). The data show that SY-5609 inhibits tumor growth, including inducing sustained regressions, at well-tolerated doses in colorectal cancer models, supporting the inclusion of colorectal cancer patients in Syros’ ongoing Phase 1 clinical trial. These data were presented as part of the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program (ASCO20).

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"These data provide the first insights into the role of SY-5609 in driving anti-tumor activity in preclinical colorectal cancer models," said David A. Roth, M.D., Syros’ Chief Medical Officer. "Two hallmarks of colorectal cancer are increased expression of cancer-driving transcription factors and activating mutations in oncogenes that drive cell cycle progression. By inhibiting CDK7, SY-5609 attacks both of these processes. These new data add to the substantial body of scientific evidence that CDK7 inhibition is a potentially transformative targeted approach for difficult-to-treat cancers. We are actively enrolling patients, including those with colorectal cancer, in our Phase 1 trial and look forward to reporting initial dose-escalation data in the fourth quarter of 2020."

New Preclinical Data Highlight Therapeutic Potential of SY-5609 in Colorectal Cancer
Syros scientists conducted a series of preclinical studies of SY-5609 in colorectal cancer cell lines, as well as in 30 independent patient-derived xenograft (PDX) models of colorectal cancer, including BRAF-mutant, KRAS-mutant and wild-type models. The data show that SY-5609:

Potently inhibited proliferation and induced G2/M cell cycle arrest in KRAS- and BRAF-mutant colorectal cancer cell lines in vitro.
Induced dose-dependent tumor growth inhibition, including complete regressions that were sustained after treatment discontinuation, with repeated daily dosing at well-tolerated doses that were associated with dose-dependent expression changes in cell cycle markers E2F1 and CCNB1 and the transcriptional marker POLR2A in a BRAF-mutant PDX model.
Resulted in ≥ 50 percent tumor growth inhibition in 67 percent (20/30) of PDX models, and ≥ 90 percent tumor growth inhibition in 23 percent (7/30) of PDX models, including in models derived from heavily pre-treated patients, at well-tolerated doses.
Deeper responses, defined as ≥ 90 percent tumor growth inhibition, were observed more frequently in models with BRAF mutations (50 percent, 5/10) relative to KRAS-mutant or wild-type models (10 percent, 1/10 each).
Regressions were seen in two BRAF-mutant models and one KRAS-mutant model.
Design of the Ongoing Phase 1 Clinical Trial of SY-5609
In a separate presentation at ASCO (Free ASCO Whitepaper)20, Syros detailed the design of its ongoing Phase 1 trial of SY-5609. The multi-center, open-label, Phase 1 trial is expected to enroll approximately 60 patients with advanced breast, colorectal, lung or ovarian cancer, or solid tumors of any histology that harbor Rb pathway alterations. The primary objectives of the dose escalation are to assess safety and tolerability of escalating doses of SY-5609, with the goal of establishing a maximum tolerated dose (MTD). Additional objectives include assessments of anti-tumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and potential predictive biomarkers.

The trial is designed to move efficiently through dose escalation, initiating with a single-patient accelerated titration design before transitioning to a more traditional 3+3 dose escalation. To further characterize safety, PK and PD, and explore early signals of clinical activity, any dose level that has cleared the dose-limiting toxicity evaluation may be expanded to enroll up to 12 patients while dose escalation proceeds. Additionally, an amendment is planned to assess the safety of escalating doses of SY-5609 in combination with fulvestrant in HR-positive/HER2-negative metastatic breast cancer patients who have progressed after treatment with a CDK4/6 inhibitor.

Syros expects to report initial safety, tolerability, PK and PD data from the dose escalation in the fourth quarter of 2020. Additional dose-escalation data, including clinical activity data, are expected in mid-2021.

The posters are now available on the Publications and Abstracts section of the Syros website at www.syros.com.