Opening New Doors for Colorectal Cancer Patients

Posted By David Roth, MD, CMO, Syros

August 31, 2021

By David Roth, MD, CMO, Syros

Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. Although early diagnosis has significantly improved outcomes, many patients aren’t diagnosed until the cancer has already spread, or metastasized, to other parts of the body, making it very difficult to treat.

Adding to the complexity is that different genetic mutations cause the cancer to grow in different patients. Mutations in the BRAF gene, which are found in about 10% of patients with metastatic CRC, are associated with a particularly dismal prognosis, with a median survival of less than 12 months.[1] As is the case with many cancers, these patients need and deserve better therapies.

Exploring the Potential of CDK7 Inhibition + Immunotherapy in BRAF-mutant CRC patients
We recently entered into an agreement with Roche to evaluate SY-5609, our highly selective and potent oral CDK7 inhibitor, in combination with atezolizumab, a PD-L1 inhibitor, in BRAF-mutant CRC patients as part of Roche’s ongoing Phase 1/1b INTRINSIC trial. Notably, this marks the first-ever clinical investigation of a CDK7 inhibitor with an immunotherapy, and we believe this novel combination has the potential to provide a profound benefit for patients with this difficult-to-treat disease.

There is strong mechanistic rationale and preclinical data to support combining SY-5609 with atezolizumab. By selectively inhibiting CDK7, SY-5609 disrupts two fundamental processes that cancer cells use to survive: transcription and uncontrolled cell cycle progression. In doing so, SY-5609 attacks the cancer in multiple ways and at multiple points. Meanwhile, by inhibiting PD-L1, Roche’s atezolizumab re-activates T-cells, triggering immune cells to attack and infiltrate the tumor to fight the cancer.

In preclinical studies, CDK7 inhibition enhances tumor response to anti-PD1 immunotherapy, increasing tumor-infiltrating immune cells and prolonging overall survival.[2] Additionally, as we reported at ASCO 2020, our preclinical data show that SY-5609 inhibits tumor growth at well-tolerated doses in CRC models, with deeper responses observed more frequently in models with BRAF mutations.[3]

What we learn from this clinical trial could not only help advance much-needed new therapies for BRAF-mutant CRC patients but also pave the way for other potential combinations of SY-5609 and immunotherapies to benefit patients with other difficult-to-treat cancers.

[1] Caputo F, Santini C, Bardasi C, et al. BRAF-Mutated Colorectal Cancer: Clinical and Molecular Insights. Int J Mol Sci. 2019;20(21):5369. Published 2019 Oct 28. doi:10.3390/ijms20215369

[2] Zhang et al., CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer, Cancer Cell (2019),

[3] Data presented at ASCO 2020 meeting