ESMO: Syros targets KRAS-mutant cancer as CDK7 inhibitor shows early promise

CDK4/6 inhibitors like Pfizer’s Ibrance have changed the treatment of HR-positive, HER2-negative breast cancer. Syros Pharmaceuticals hopes its investigational drug targeting another member of the CDK family could add a new weapon to the treatment arsenal, and it has promising early data in humans and animals to support its plans.

Syros’ oral CDK7 inhibitor, coded SY-5609, controlled or shrank tumors in heavily pretreated patients with different cancer types in a phase 1 clinical trial. It also showed robust antitumor activity in mouse models of KRAS-mutant pancreatic cancer and non-small cell lung cancer, as well as ovarian cancer, the company reported at the European Society for Medical Oncology 2021 virtual congress.

The ongoing phase 1 trial has been testing SY-5609 as a single agent in different solid tumors or in combination with AstraZeneca’s estrogen receptor degrader Faslodex in HR-positive, HER2-negative breast cancer. 

With the positive early results, Syros plans to expand the trial to evaluate SY-5609 alongside chemotherapy in pancreatic cancer later this year. It also intends to test the drug with a BTK inhibitor in mantle cell lymphoma early next year. 

CDK7 levels are elevated in several cancer types and are linked to clinical outcomes. By inhibiting CDK7, SY-5609 has shown potential to treat cancer by reining in uncontrolled cell proliferation and suppressing the expression of cancer-promoting genes, according to Syros.

Previously, SY-5609 showed activity in mouse models of colorectal cancer that had BRAF and KRAS mutations. Because KRAS mutations are prevalent in pancreatic cancer and NSCLC, Syros scientists went on to test the drug in those settings.

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In mice carrying RAS-mutant pancreatic tumors derived from previously treated patients, SY-5609 shrank tumors in four of eight animals, and the regression lasted beyond two weeks after treatment stopped. In mice with xenografts of KRAS-G12D cancer, SY-5609 monotherapy or the chemotherapy gemcitabine alone inhibited tumors somewhat, but the combo of the two drugs showed nearly complete (97%) tumor inhibition and was well-tolerated, Syros reported. The researchers recorded similar results for the combo when SY-5609 was dosed every other week. A separate study in mouse models of ovarian cancer produced similar results.

In NSCLC, SY-5609 and the chemotherapy docetaxel blocked tumor growth better than the CDK7 inhibitor alone in mice with KRAS G12S tumors. By comparison, SY-5609 alone achieved near-complete regressions in KRAS G12C models, and the addition of docetaxel sealed the deal, as rodents on the combo saw their tumors completely disappear, the researchers said. Tumors did not come back for at least four weeks after treatment stopped, they added.

Syros also offered an updated look at its ongoing phase 1 study. Thirteen of 45 patients (28.9%) achieved stable disease across multiple tumor types, and six saw their tumors shrink. Pancreatic cancer patients appeared to have experienced the best responses. Five of 13 evaluable pancreatic patients achieved stable disease on SY-5609, with tumor reductions in two patients.

What’s more, the seven-day intermittent dosing regimen was associated with the lowest rates of treatment-related side effects, while maintaining comparable rates of disease stabilization compared with other more frequent dosing regimens, the researchers said. The finding supports selecting it for further development of SY-5609, Syros said.

“[T]he prolonged stable disease and tumor shrinkage seen in pancreatic cancer patients is distinct from what you would expect to see in this highly refractory patient population—particularly when treated with a single agent,” START Midwest researcher Manish R. Sharma, M.D., an investigator of the phase 1 study, said in a statement.

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In addition to testing SY-5609 in its phase 1 trial, Syros is offering the drug to Roche for a phase 1/1b trial dubbed Intrinsic, which will test the CDK7 inhibitor with the Swiss pharma’s PD-L1 inhibitor Tecentriq in BRAF-mutant colorectal cancer.

SY-5609 isn’t Syros’ first attempt at CDK7 inhibition; the Massachusetts biotech   canned an intravenous CDK7 inhibitor called SY-1365 midway through a phase 1 trial in 2019 and decided to focus on the oral option, SY-5609, instead.

That earlier setback put Syros behind Carrick Therapeutics, which is working on the CDK7 blocker samuraciclib (CT7001). At ESMO, Carrick reported that in patients with HR-positive, HER2-negative breast cancer that had failed after treatment with a CDK4/6 inhibitor, combining samuiraciclib with Faslodex reduced tumor burden, including one partial response, in a phase 1 trial. The company also reported positive data from other solid tumors, including triple-negative breast cancer and prostate cancer.