Syros Pharmaceuticals announced new data from the dose-escalation portion of the Phase 1 clinical trial of SY-5609, its highly selective and potent oral cyclin-dependent kinase 7 (CDK7) inhibitor, demonstrating clinical activity at tolerable doses as a single agent across multiple tumor types. The data is being presented in an oral presentation at the 2021 ESMO Congress. The Phase 1 multi-center, open-label dose-escalation study of SY-5609 enrolled patients with advanced breast, colorectal, lung, ovarian and pancreatic cancers, as well as patients with solid tumors of any histology harboring Rb pathway alterations. Patients were treated in cohorts exploring continuous daily dosing as well as intermittent dosing regimens, including seven days on treatment and seven days off (7d on/7d off) and five days on treatment and two days off (5d on/2d off). As of July 6, 54 patients treated with single-agent SY-5609 in the study were eligible for a safety analysis and 45 patients were evaluable for clinical response. The median age of patients enrolled in the study was 65.5. Patients had been heavily pre-treated with as many as eight prior therapies and a median of four prior therapies. Safety, Tolerability, Dose and Schedule: Across all doses and schedules, the majority of adverse events (AEs) were low-grade and reversible. The most common treatment-emergent AEs were nausea, diarrhea, thrombocytopenia, fatigue and anemia. Low rate of discontinuations due to AEs. Tolerability was optimized with 7d on/7d off schedule, which had lowest rates of treatment-emergent AEs, while demonstrating comparable rates of stable disease (SD) as seen with more dose-intense regimens, supporting the selection of this schedule for further development of SY-5609. The maximum tolerated dose (MTD) of the 7d on/7d off schedule has not yet been reached. Changes in POLR2A mRNA expression, a pharmacodynamic (PD) marker for CDK7 inhibition, were associated with anti-tumor activity and were sustained for at least three days following drug cessation, supporting intermittent dosing. Early Clinical Activity Data: Thirteen patients (28.9%) achieved SD, with tumor regressions of up to 20% in six of those patients, across multiple tumor types. The most substantial clinical activity was observed in heavily pre-treated patients with advanced pancreatic cancer. Five of 13 (38.5%) evaluable patients achieved SD, with tumor reductions in two of those patients. Reductions in the CA 19-9 tumor marker, which is used in clinical practice to monitor tumor progression, were observed in three of four pancreatic cancer patients with serial CA 19-9 data. These reductions ranged from 32% to 72%. Notably, one metastatic pancreatic cancer patient who had failed two prior lines of therapy and relapsed after a third line of treatment experienced prolonged SD of up to 10 months. Analysis of clinical activity by tumor type and mutational status supports the mechanistic rationale for SY-5609 in Rb-altered and KRAS-mutant cancers.