tagtociclib (PF-07104091) / Pfizer - LARVOL DELTA

A comparative study of CDK2 inhibitors (AACR 2025) - "Using PF3600 and PF4091 (tagtociclib), we previously showed that upon CDK2 inhibition, cells exhibit a rapid drop in substrate phosphorylation that rebounds within several hours ('drop-rebound'). We hypothesize that durable cell-cycle arrest requires forcing Rb kinase activity below a specific threshold where the Rb-E2F positive feedback loop is broken. Our results are timely given the increasing interest in CDK2 inhibitors across a variety of cancer types."

Oncology

ODY-CDK, a brain-penetrant, selective CDK2 inhibitor that demonstrates antitumor activity in an intracranial CCNE1-amplified breast tumor model (AACR 2025) - "Daily oral dosing of ODY-CDK resulted in tumor regression in 8 out of 11 mice, while PF-07104091 showed modest activity with regression in only a single mouse. These data demonstrate that ODY-CDK is a selective brain-penetrant CDK2 inhibitor with differentiating intracranial antitumor activity to existing clinical-stage CDK2 inhibitors and support the evaluation of ODY-CDK in patients with brain metastases that have a high unmet medical need."

Preclinical • Breast Cancer • Eye Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Cell Lung Cancer • Solid Tumor • Triple Negative Breast Cancer • CCNA2 • CCNE1 • CDK1 • RB1

Discovery of a novel and selective CDK2 inhibitor for targeted cancer therapy (AACR 2025) - "Compared to the clinically advanced CDK2 inhibitor PF-07104091, VB18214 demonstrated 5-fold greater potency in inhibiting CDK2 kinase activity, 16-fold higher affinity for CDK2 in NanoBRET assays, 2-fold greater selectivity over CDK1 in both biochemical and intracellular assays, and 9-fold higher antiproliferative activity in OVCAR3 cells.These findings position VB18214 as a potent and selective CDK2 inhibitor with significant potential for clinical development in cancers driven by CDK2/cyclin E dysregulation, as well as CDK4/6 treatment progressed mBC. More characterization data for VB18214 will be updated at the meeting."

Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • CCNB1 • CCND1 • CCND3 • CCNE1 • CDK1 • CDK6 • CDK7 • CDK9

Cyclin-Dependent Kinase 2 is a potential target for cholangiocarcinoma treatment under diabetogenic glucose condition (APASL 2025) - "Tagtociclib, a selective CDK2 inhibitor, was tested for its cytotoxicity... CDK2 and its cyclin partners were upregulated in HG condition, and thus, they are a promising target for CCA treatment under diabetogenic glucose. Inhibition of CDK2 led to CCA cell apoptosis via inhibition of STAT3 pathways and decreased anti-apoptotic protein expression, in addition to controlling the cell cycle progression. These findings suggested the benefits of using CDK2 inhibitors as therapeutic agents in CCA, particularly in the condition that CDK2 is upregulated such as under diabetogenic glucose condition."

Biliary Cancer • Cholangiocarcinoma • Diabetes • Oncology • Solid Tumor • ANXA5 • CASP3 • CASP9 • CCNA2 • CDK2 • XIAP

18F-FLT PET, a Non-Invasive Pharmacodynamic Biomarker of Tumor Cell Proliferation, Detected Differential Response to Various Cyclin Dependent Kinase (CDK) Inhibitors. (PubMed, Mol Cancer Ther) - "Consistent with this observation, 18F-FLT PET was able to differentiate the resistance to Palbociclib from sensitivity to PF-06873600 (CDK2/4/6 inhibitor) and PF-07104091 in OVCAR-3 model. This work highlights the utility of 18F-FLT PET as a quantitative, non-invasive biomarker which provides whole-body information. 18F-FLT PET has potential to be a biomarker in novel CDK inhibitor clinical trials to evaluate Palbociclib resistance and identifying responding and non-responding patients."

Biomarker • Journal • PK/PD data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • HER-2

Cyclin Dependent Kinase 2 (CDK2) Inhibitors in Oncology Clinical Trials: A Review. (PubMed, J Immunother Precis Oncol) - "Common side effects observed include nausea, vomiting, diarrhea, anemia, and fatigue. This clinical review summarizes past and current CDK2 inhibitors in clinical trials."

Journal • Review • Fatigue • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology

Targeting CDK2 Confers Vulnerability to Lenvatinib Via Driving Senescence in Anaplastic Thyroid Cancer. (PubMed, Adv Sci (Weinh)) - "Combination of CDK2 inhibitors in clinical trials (Dinaciclib or PF-07104091) and lenvatinib markedly suppressed growth of xenograft tumors from the lenvatinib-resistant patient. The findings support the combination therapy strategy of lenvatinib and CDK2 inhibitor for lenvatinib-resistant ATC patients with high CDK2 expression."

Journal • Endocrine Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • CDK2 • FBXW7 • RACK1

Discovery of NKT3964: a first-in-class, highly potent and selective, orally bioavailable CDK2 PROTAC degrader for cancer therapy (EORTC-NCI-AACR 2024) - "In CDK2-dependent cancer cells, NKT3964 potently inhibited Rb phosphorylation and cell proliferation, with 3-to-100-fold higher potency than the clinical CDK2 inhibitor PF-07104091. These results demonstrate that NKT3964 is a potent and selective CDK2 degrader with distinct properties and mechanism of action and has great potential to effectively treat patients with aberrant CDK2/Cyclin E activation in a variety of cancer types. NKT3964 is currently being investigated in a Phase 1 clinical trial in patients with advanced solid tumors."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CDK1 • CDK2 • HER-2

C4391002: A Study to Learn About the Study Medicine (Called PF-07220060 in Combination With PF-07104091) In Participants With Breast Cancer and Solid Tumors (clinicaltrials.gov) - P1/2 | N=192 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2026 ➔ Aug 2026 | Trial primary completion date: Dec 2026 ➔ Aug 2026

Combination therapy • Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Synergistic preclinical efficacy through combination of the CDK4 and CDK2 selective inhibitors, PF-07220060 and PF-07104091, respectively, in HR+ HER2- breast cancer (ESMO 2024) - P1/2 | "Combining the highly selective CDK2i (PF-07104091) and CDK4i (PF-07220060) for HR+/HER2- breast cancer circumvents inhibition of CDK6, resulting in less hematologic toxicity. Further, increased anti-tumor efficacy and tumor regression seen with this combination (unlike with the single agents, or the combination of CDK2i and palbociclib) provide the rationale for the current clinical trial NCT05262400."

Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CCNE1 • CDK4 • CDKN2A • HER-2 • RB1

Phase Ib/II first-in-class novel combination trial of next generation CDK4-selective inhibitor PF-07220060 and next generation CDK2-selective inhibitor PF-07104091 in HR+ HER2- metastatic breast cancer and advanced solid tumors (ESMO 2024) - P1/2 | "BC pts could start fulvestrant at Cycle 3. PF-60/PF-91 combination was generally well tolerated with promising antitumor activity in heavily pretreated post-CDK4/6i mBC pts, including 5 PRs in mBC pts with ESR1 mutations and mPFS 8.3 months. Dose expansions are enrolling CDK4/6i-treated and naïve mBC pts."

Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

PF-07104091 as a Single Agent and in Combination Therapy (clinicaltrials.gov) - P1/2 | N=154 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | N=320 ➔ 154 | Trial completion date: Jan 2026 ➔ Mar 2025

Combination therapy • Enrollment change • Enrollment closed • Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Cell Lung Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2

PF-07104091, a first-in-class CDK2-selective inhibitor for the treatment of HR+/HER2- breast cancer and CCNE1high ovarian cancer (AACR 2024) - "Whole genome CRISPR KO and CRISPR activation screens in conjunction with CDK46 inhibition establish CDK2 KO as a primary sensitizer to CDK46 inhibition, and support Cyclin ECDK2 complexes as the driver of resistance to CDK46 inhibitors in ER+ breast models. PF-07104091 combined with CDK46 inhibitor Palbociclib or CDK4-selective inhibitor PF-0060 synergistically controls proliferation of ER+ BC cells in vitro and induces tumor regression in ER+ BC xenograft models, including PDX models with acquired resistance to CDK46 inhibitors and endocrine therapy."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • CCNE1 • HER-2 • RB1

Elucidation of the fates of CDK2 inhibited aneuploid and residual lung cancers (AACR 2024) - "To elucidate cell fates of progeny with multipolar mitosis after CDK2/9 inhibition with CYC065 (0.2 µM) treatment, a panel of murine and human lung cancer cells underwent time-lapse fluorescent microscopy...To confirm these effects were through CDK2 inhibition, the selective CDK2 inhibitor Tagtociclib (PF-07104091, at the 2 µM dosage) was used...CDK2 inhibition of aneuploid lung cancers yields distinct cell fates. This is linked to resistance to CDK2 antagonism and to formation of residual in vivo tumors."

Lung Cancer • Oncology • Solid Tumor

A Study to Learn About the Study Medicine (Called PF-07220060 in Combination With PF-07104091) In Participants With Breast Cancer and Solid Tumors (clinicaltrials.gov) - P1/2 | N=240 | Recruiting | Sponsor: Pfizer | Trial completion date: Sep 2026 ➔ Dec 2026 | Trial primary completion date: Sep 2026 ➔ Dec 2026

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

A Study to Learn About the Study Medicine (Called PF-07220060 in Combination With PF-07104091) In Participants With Breast Cancer and Solid Tumors (clinicaltrials.gov) - P1/2 | N=240 | Recruiting | Sponsor: Pfizer | Phase classification: P1b/2 ➔ P1/2

Combination therapy • Metastases • Phase classification • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

A Study to Learn About the Study Medicine (Called PF-07220060 in Combination With PF-07104091) In Participants With Breast Cancer and Solid Tumors (clinicaltrials.gov) - P1b/2 | N=240 | Recruiting | Sponsor: Pfizer | N=144 ➔ 240

Combination therapy • Enrollment change • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

A Study to Learn About the Study Medicine (Called PF-07220060 in Combination With PF-07104091) In Participants With Breast Cancer and Solid Tumors (clinicaltrials.gov) - P1b/2 | N=144 | Recruiting | Sponsor: Pfizer | Trial completion date: Jul 2027 ➔ Sep 2026

Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

First-in-human phase 1/2a study of a potent and novel CDK2-selective inhibitor PF-07104091 in patients (pts) with advanced solid tumors, enriched for CDK4/6 inhibitor resistant HR+/HER2- breast cancer. (ASCO 2023) - P1/2 | "Treatment with PF-07104091 monotherapy was generally well tolerated and showed antitumor activity in heavily pretreated HR+ HER2- mBC pts who progressed on prior CDK4/6i. Dose expansions of PF-07104091 are ongoing as monotherapy in pts with ovarian cancer and in combination with fulvestrant in pts with breast cancer. Clinical trial information: NCT04553133."

Clinical • Metastases • P1/2 data • Anemia • Anorexia • Breast Cancer • Fatigue • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • HER-2

Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity. (PubMed, Cell) - "CDK4/6 activity backstops inhibition of CDK2 and sustains the proliferative program by maintaining Rb1 hyperphosphorylation, active E2F transcription, and cyclin A2 expression, enabling re-activation of CDK2 in the presence of drug. Our results augment our understanding of CDK plasticity and indicate that co-inhibition of CDK2 and CDK4/6 may be required to suppress adaptation to CDK2 inhibitors currently under clinical assessment."

Journal • Oncology • CCNA2 • CDK1 • RB1

Pfizer Presents Scientific Advancements from its Leading Oncology Portfolio at ASCO 2023 Annual Meeting (Businesswire) - "Pfizer’s commitment to advancing scientific innovation will be on display at ASCO 2023 with more than 40 company-sponsored abstracts. Highlights include: For the first time, the primary efficacy and safety results from the Phase 2 PHAROS trial exploring BRAFTOVI® (encorafenib)...given in combination with MEKTOVI® (binimetinib)...in patients with metastatic non-small cell lung cancer harboring a BRAF V600E mutation; Advancements across Pfizer’s leading breast cancer portfolio and pipeline, including a new analysis of real-world evidence for IBRANCE...as a first-line treatment of metastatic breast cancer. In addition, the first Phase 1 data for the CDK4-selective inhibitor PF-07220060, the CDK2-selective inhibitor PF-07104091 and the KAT6 inhibitor PF-07248144, all investigational agents for advanced or metastatic hormone-receptor positive breast cancer, will be presented."

P1 data • P2 data • Real-world evidence • Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • CDK2 • CDK4

A Study to Learn About the Study Medicine (Called PF-07220060 in Combination With PF-07104091) In Participants With Breast Cancer and Solid Tumors (clinicaltrials.gov) - P1b/2 | N=144 | Recruiting | Sponsor: Pfizer | Trial completion date: Dec 2027 ➔ Jul 2027 | Trial primary completion date: Dec 2026 ➔ Jul 2026

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

PF-07104091 as a Single Agent and in Combination Therapy (clinicaltrials.gov) - P1/2 | N=320 | Recruiting | Sponsor: Pfizer | Phase classification: P2 ➔ P1/2 | N=240 ➔ 320 | Trial completion date: Nov 2027 ➔ Jan 2026 | Trial primary completion date: Nov 2026 ➔ Jan 2025

Combination therapy • Enrollment change • Phase classification • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Cell Lung Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2

A Phase 1b/2 Study of PF-07220060 in Combination with PF-07104091 Plus Endocrine Therapy in Participants with BC and other Advanced Solid Tumors (clinicaltrialsregister.eu) - P2 | N=144 | Ongoing | Sponsor: Pfizer Inc.

Combination therapy • Metastases • New P2 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Combined Inhibition of CDK2 and BCL2 Overrides Resistance to Targeting BTK and CDK4/6 in Mantle Cell Lymphoma Therapy (ASH 2022) - "Unrestrained proliferation of MCL cells is mainly driven by aberrant cyclin D1 expression and dysregulated CDK4 activity that promotes cell cycle progression from G1 to S. In our phase 1 clinical trial inhibiting CDK4/6 with palbociclib and BTK with ibrutinib (PALIBR) in recurrent MCL, the complete response rate (CR) was 42% compared to 21% in response to ibrutinib alone, despite a comparable 67% overall response rate...Indeed, combined inhibition of CDK2 with PF-07104091 and BCL2 with venetoclax (PF-VEN) cooperatively impaired growth and killed ibrutinib-resistant MAVER-1 cells, more effectively in the isogenic derivative MAVER-1R cells which we generated to recapitulate cCNV in PALIBR resistance – depletion of RB protein through translational termination mutation (W99, AAF 75%) in RB1, loss of CDKN2A and gain of CDK4...In summary, by longitudinal genomic analysis, we have provided the first evidence that 1) resistance to CDK4/6i and BTKi stems from MCL intrinsic cCNV;..."

IO biomarker • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • BCL2 • BCL2L1 • CCND1 • CDK4 • CDKN2A • IRF4 • PMAIP1 • RB1 • TK1