tegtociclib (PF-07104091) / Pfizer - LARVOL DELTA

Discovery of NKT5097: a first-in-class, highly potent and selective, orally bioavailable CDK2/4 dual degrader for cancer therapy (SABCS 2025) - "NKT5097 also demonstrates a 68-fold increase in selectivity for CDK2 over CDK1 in comparison to PF-07104091, and a 33-fold increase in selectivity for CDK4 over CDK6 compared to PF-07220060 in functional cellular assays...Additionally, combination of NKT5097 with fulvestrant leads to deeper degradation of CDK2 and CDK4 in vitro, resulting in better tumor growth inhibition in HR+ breast cancer models...Therefore, as the first-in-class CDK2/4 dual degrader, NKT5097 presents a unique opportunity to serve as a backbone therapy for HR+HER2- breast cancer and other cancers with CDK2 and/or CDK4 dysregulation. NKT5097 is currently being investigated in a phase I clinical study."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • CCNE1 • CDK1 • CDK2 • CDKN2A • HER-2

Gdc-4198, a next-generation CDK4/2 inhibitor, induces durable cell cycle arrest and overcomes CDK2-driven adaptation to CDK4 inhibition (SABCS 2025) - "While CDK4/6 inhibitors (CDK4/6i) have changed the therapeutic landscape of hormone receptor-positive (HR+) breast cancer, resistance to these therapies is a major challenge limiting their clinical benefit...Immunofluorescence data from HR+ breast cancer cells revealed that the shift in cell cycle distribution induced by GDC-4198 was differentiated from the effects of CDK4/6i and can most closely be reproduced by a combination of atirmociclib (a CDK4 inhibitor) and tagtociclib (a CDK2 inhibitor)...Additional studies in patient-derived cell lines obtained in the setting of metastatic HR+ breast cancer following progression on letrozole/ribociclib, as well as in patient-derived cell lines with acquired in vitro resistance to palbociclib, confirmed the enhanced antitumor activity of GDC-4198 compared to current CDK4/6i or atirmociclib...Pharmacokinetic and pharmacodynamic analyses indicated favorable drug exposure and pharmacodynamic modulation in tumor tissues consistent..."

Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • CCNE1 • CDK2

Investigating CDK2 and CDK4 Inhibition in IDH-Mutant Glioma with CDKN2A Deletion (SNO 2025) - "To test this, we assessed the response of IDH-mutant glioma cell lines (with and without CDKN2A deletion) to CDK2 inhibitors (INX-315, Tagtociclib), a CDK4 inhibitor (Atirmociclib), and their combination. Broader inhibitors, including Abemaciclib and PF-06873600 (CDK4/6 and CDK2/4/6 inhibitors, respectively), we measured the effect of the drug on cell viability and confirmed the impact of the drug on pathway activity by western blot mediators of CDK-Rb activity...These results suggest that CDK6 activity, or synergistic inhibition across CDK2/4/6, may be critical for efficacy. The lack of efficacy with selective inhibitors highlights on non-redundant roles of CDK in G1/S checkpoint regulation and underscores the complexity of CDK targeting in glioma."

Brain Cancer • Glioma • Solid Tumor • CDKN2A

Investigating CDK2 and CDK4 Inhibition in IDH-Mutant Glioma with CDKN2A Deletion (WFNOS 2025) - "To test this, we assessed the response of IDH-mutant glioma cell lines (with and without CDKN2A deletion) to CDK2 inhibitors (INX-315, Tagtociclib), a CDK4 inhibitor (Atirmociclib), and their combination. Broader inhibitors, including Abemaciclib and PF-06873600 (CDK4/6 and CDK2/4/6 inhibitors, respectively), we measured the effect of the drug on cell viability and confirmed the impact of the drug on pathway activity by western blot mediators of CDK-Rb activity...These results suggest that CDK6 activity, or synergistic inhibition across CDK2/4/6, may be critical for efficacy. The lack of efficacy with selective inhibitors highlights on non-redundant roles of CDK in G1/S checkpoint regulation and underscores the complexity of CDK targeting in glioma."

Brain Cancer • Glioma • Solid Tumor • CDKN2A

Combined treatment with CDK4/6, CDK2, and CXCR1/2 inhibitors effectively halts the growth of BRAF wild-type melanoma tumors. (PubMed, Front Oncol) - "In this study, we evaluated the effectiveness of the CDK4/6 inhibitor, palbociclib, the CDK2 inhibitor, PF-07104091, the dual CXCR1 and CXCR2 (CXCR1/2) antagonist, SX-682, and the combination of these inhibitors for effective treatment of melanoma in preclinical models. This combination also decreased the percentage of CD8+ T cells that expressed PD-1 or TIM-3 and increased the ratio of MHCII+F4/80+ M1-like macrophages to CD206+F4/80+ M2-like macrophages. These data suggest that inhibiting CDK4/6 and CDK2, combined with antagonism of CXCR1/2, may be an effective treatment for BRAF wild-type melanoma tumors and NRAS mutant melanoma tumors that express Rb and are resistant to immune checkpoint inhibitors."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • BRAF • CCNA2 • CCND1 • CCNE1 • CD4 • CD8 • CXCR1 • CXCR2 • FOXP3 • HAVCR2 • IFNG • IL10 • MRC1 • NRAS • PD-1

PF-07104091 as a Single Agent and in Combination Therapy (clinicaltrials.gov) - P2 | N=154 | Active, not recruiting | Sponsor: Pfizer | Phase classification: P1/2 ➔ P2 | Trial completion date: Mar 2025 ➔ Mar 2026 | Trial primary completion date: Mar 2025 ➔ Mar 2026

Phase classification • Trial completion date • Trial primary completion date • Breast Cancer • HER2 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

YF550 is a potent and selective inhibitor of KIF18A, specifically targeting CIN+ cancer cells (AACR 2025) - "In contrast to the Eg5 inhibitor Ispinesib, YF550 does not inhibit normal PBMC proliferation...YF550 has demonstrated synergistic effects when combined with various agents, including Olaparib (PARP inhibitor), PF-07104091 (CDK2 inhibitor), Elimusertib (ATR inhibitor), Volasertib (PLK1 inhibitor), and MMAE, in cellular proliferation assays. In the OVCAR3 ovarian cancer xenograft model, YF550 has shown superior efficacy compared to KIF18A inhibitor AMG650 at a 5 mg/kg dose, with no significant impact on body weight. Furthermore, YF550 induced tumor regression in both the OVCAR8 ovarian and JIMT-1 HER2 positive breast cancer xenograft models. YF550 exhibits superior ADME and PK property suitable for clinical development for CIN+ cancers with high aneuploidy score and has the potential for combination therapy with PD-1/L1 antibodies, PARP1 inhibitors, and MMAE based ADC."

IO biomarker • Late-breaking abstract • Breast Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2 • KIF18A

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