October 15, 2021

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2021 ESMO: Safety and anti-tumor activities of CDK7 inhibitors

2021 ESMO: Safety and anti-tumor activities of CDK7 inhibitors

2021 ESMO: Safety and anti-tumor activities of CDK7 inhibitors



2021 ESMO: Safety and anti-tumor activities of CDK7 inhibitors

2021 ESMO: Safety and anti-tumor activity of CDK7 inhibitors, the latest research summary!

Looking back at the 2021 ESMO conference that has ended, in addition to immunotherapy is still a hot issue of concern from all walks of life, research results related to new drug targets are also emerging.

As we all know, CDK inhibitors will exceed the US$5 billion mark globally in 2020 by virtue of their first marketed species, and their family series of targets have gradually become research and development hotspots. For example, the application of CDK4/6 inhibitors such as piperazil has changed the HR positive, Current status of clinical treatment of HER2-negative breast cancer.

This 2021 ESMO not only highlighted the hottest CDK4/6, but also mentioned many CDK7-related research results. Tumor Jun summarized the research progress related to the CDK7 target for readers.

CDK7 was discovered in the early 1990s. It has the function of activating kinases. The CDK activated kinase (CAK) complex composed of CDK7, CyclinH and MATI can participate in the regulation of cell division, transcription and nuclear receptor functions after phosphorylation. Especially estrogen and androgen receptors.

CDK7 is mainly involved in the regulation of the transcription process. It can phosphorylate the Ser residues at positions 5 and 7 of the carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II to promote the initiation of transcription.

1.Samuraciclib (CT7001) is a small molecule, ATP-competitive and selective oral inhibitor of CDK7.

Samuraciclib’s first in vivo modularization study

Dr. Krebs and the research team [1] evaluated the tolerability, pharmacokinetics and efficacy of samuraciclib. They evaluated its escalating dose (M1A), paired tumor biopsy (PB) samples (M1A), the effect of food on bioavailability (M4), and an expanded cohort (M1B) for triple-negative breast cancer (TNBC).

In M1A, the researchers recruited 33 patients in 5 cohorts at doses of 120 mg, 240 mg, 360 mg, and 480 mg once a day, and 180 mg twice a day. In addition, 11 patients were dosed in a paired tumor biopsy cohort for pharmacodynamic evaluation. In M4, the researchers recruited 15 patients. In M1B, 23 patients were recruited.

When 120 mg, 240 mg, and 360 mg were administered once a day, the most common adverse drug reactions were grade 1-2 nausea, vomiting, and diarrhea. At 480 mg once daily, 3 out of 6 patients had dose-limiting toxicity, grade 3 diarrhea, grade 3 oral mucositis, and grade 3 vomiting. At 180 mg twice daily, 1 out of 7 patients had dose-limiting toxicity, grade 4 thrombocytopenia. No neutropenia and significant bone marrow suppression associated with other CDK inhibitors were observed.

240 mg and 360 mg once a day are determined as clinically relevant doses, and 360 mg once a day is the initial recommended phase II dose.

In fasting patients, the median Tmax is 1.5 to 4 hours, and the geomean T 1/2 is approximately 75 hours. A steady state is reached within 8 to 15 days. Plasma exposure is increased in proportion to the dose; the pharmacologically active exposure is achieved during the entire dosing period. Food has no clinically significant effect on exposure.

In the “All Participants” cohort of M1A and M4, it was observed that 57% (25/44) of reevaluable patients had evidence of disease control at the first post-baseline scan (FPBS), including the partial response of HR+ breast cancer patients ( PR).

A decrease in PSA was observed in the 4 castration-resistant prostate cancer patients recruited. Preliminary tumor biopsy data supports the involvement of tumor targets. A total of 20 TNBC patients can be evaluated by RECIST; these 12 patients reached the first stable condition after the baseline scan, and 3 patients were treated for more than 1 year.

The authors concluded that samuraciclib showed acceptable safety and had evidence of anti-tumor activity.

Samuraciclib combined with fulvestrant in the treatment of advanced HR+/HER2- breast cancer

Previous research results suggest that preclinical HR+ breast cancer models indicate that the CDK7 inhibitor samuraciclib may have a synergistic effect when combined with fulvestrant. The study [2] further evaluated the tolerability and effectiveness of samuraciclib combined with fulvestrant in the treatment of patients with advanced HR+ breast cancer; all patients had previously received aromatase inhibitors and CDK4/6 inhibitors.

The results showed that 31 HR+ breast cancer patients received standard doses of fulvestrant and samuraciclib in combination therapy. Six patients received 240 mg of samuraciclib once daily, and 25 patients received 360 mg once daily. The combination therapy is generally well tolerated, and noteworthy adverse drug reactions (AE) are G1-2 grade nausea, vomiting, and diarrhea; most patients continue to receive treatment until the disease progresses. The RECIST assessment showed evidence of reduced tumor disease burden, including a partial response from a patient who was treated for about 1 year.

Samuraciclib has been shown to have acceptable safety, and there is evidence that it has anti-tumor activity in combination with Fulvestrant and can be used for advanced HR+ breast cancer patients with previous CDK4/6i progression.


2. SY-5609 is another highly effective oral CDK7 inhibitor.

Exploration of the tolerability and preliminary clinical activity of SY-5609 in patients with advanced solid tumors

The research report [3] reported the results of SY-5609 related research and the intermittent dosing regimen. The evaluation included: safety according to CTCAE v5.0; clinical activities according to RECIST v1.1, tumor markers and clinical evaluation; and peripheral blood Induction of the PD marker POLR2A in mononuclear cells.

As of March 26, 21, 51 patients were enrolled, including 9 patients treated with fulvestrant. Both QD intermittent dosing regimens have passed the dose-limiting toxicity (DLT) assessments of 4 mg/d and 5 mg/d, and are currently undergoing activity evaluation and upgrading to higher doses.

Any causal (≥ 20%) single-agent AEs of SY-5609 include nausea, diarrhea, fatigue, decreased appetite, and thrombocytopenia; most are low-grade (1/2) and reversible. 30% (11/37) of the response can assess the patient’s stable disease (SD) as the best response. The tumors of 6 SD patients shrank by 8.7%-18.1%, and the median time of treatment was 198 days (range: 55-273). A PDAC patient with prolonged SD (> 8 months [ongoing]) had a 72% reduction in CA19-9 (5723 to 1609 U/mL), and a ovarian cancer patient had a reduction in CA-125 by 84% (1950 To 308 units/ml). A dose-dependent induction of POLR2A was observed during intermittent administration.

The intermittent administration of SY-5609 can tolerate continuous administration higher than the maximum tolerated dose (MTD), and evidence of a dose-dependent PD effect is observed. Early evidence of clinical activity, with durable SD and reduction in tumor size and markers, supports continuous dose escalation with intermittent administration.

Antitumor activity of SY-5609 in a preclinical model of KRAS mutant cancer

Research report [4] reported the preclinical activity of SY-5609 in KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) models.

The PDAC study was conducted in a xenograft (PDX) model derived from patients with RAS mutants (7 KRAS, 1 NRAS) and Panc-1 (KRAS-G12D) cells and xenograft +/- gemcitabine (Gem) models. The NSCLC study was conducted in A549 (KRAS G12S) cells and xenografts and ST2972 (KRAS G12C) PDX tumor +/- docetaxel (Doc) model.

In the RAS mutant PDAC PDX model derived from previously treated patients, SA SY-5609 (6mpk QD x28) induced regression in 50% (4/8) of the model and was well tolerated (average weight change [avg- BWC] 0 %); subsided lasting ≥ 2 weeks (wks) after stopping the drug.

In Panc-1 cells, SY-5609 inhibits proliferation (IC50, 0.7nM) and cooperates with Gem. In vivo, SA SY-5609 (3 mpk QD x21) and SA Gem (100 mpk QW) each induce partial TGI; this combination induces almost complete TGI (97%) and is well tolerated (avg-BWC +2% ).

Using the SY-5609 dosing regimen 3 mpk QD, dosing for 28 days every other week, a similar combination result (94.3% TGI) was observed. In A549 cells, SY-5609 inhibits proliferation (IC50, 10nM) and has a synergistic effect with Doc.

In the body, the combination of SY-5609 (3 mpk) and Doc (5 mpk QW) enhances TGI. In ST2972 tumors, SA SY-5609 (3 mpk QD x21) induces almost complete regression, while Doc (10 mpk QW) induces complete regression, and there is no tumor regeneration ≥ 4 weeks after stopping the drug. Both options are well tolerated (average BWC +3.6% to -6%).

The results suggest that SY-5609 shows strong anti-tumor activity in preclinical models of PDAC and NSCLC with RAS mutations. The results support the clinical evaluation of SY-5609 combined with Gem for PDAC and combined Doc for NSCLC.

Preclinical evaluation of SY-5609 anti-tumor and PD activity in ovarian cancer xenografts

Another preclinical study [5] reported on the effect of intermittent SY-5609 dosing regimen on tumor growth inhibition (TGI), pharmacodynamics (PD) activity and pharmacokinetics in high-grade serous ovarian cancer (HGSOC) xenograft models. The effect of kinetics (PK).

The results showed that SY-5609 induced dose-dependent TGI in all dosing regimens. The dose-dependent change of SY-5609 tumor PD markers lasted up to 72 hours above baseline. When BID and QD are given the same total daily dose, TGI is enhanced. Evaluation of the PK of SY-5609 during the BID and QD program showed that the anti-tumor activity associated with maintaining a high trough level of SY-5609 was increased. All regimens were well tolerated and there was no weight loss.

SY-5609 has shown strong anti-tumor activity in preclinical HGSOC xenografts. These programs combine higher doses with dosing holidays, and are supported by sustained PD effects in tumor tissues after the dose is stopped. Observed enhanced anti-tumor activity of SY-5609 between BID and QD (Controlled Dose) Supporting dose The sustained high level of CDK7 inhibits the contribution of anti-tumor activity, and informs patients of intermittent administration evaluation to optimize single or combination SY -5609 Dosage and schedule selection.

2021 ESMO: Safety and anti-tumor activities of CDK7 inhibitors

(source:internet, reference only)


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