tegtociclib (PF-07104091) / Pfizer - LARVOL DELTA

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

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=235 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: Aug 2026 ➔ Feb 2027 | Trial primary completion date: Aug 2026 ➔ Feb 2027

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

Process development of CDK2 selective inhibitor PF-07104091 (ACS-Fall 2026) - "Highlights of the synthesis include two telescoped sequences to improve synthetic efficiency and process mass intensity (PMI) and includes a novel enzymatic cascade that sets two stereocenters in one pot. This talk will share the story of the development of this chemistry and its optimization."

Study to Assess the Safety and Tolerability of PF-07220060 in Combination With PF-07104091 in Participants With Breast Cancers or Solid Tumors and to Assess the Safety and Tolerability of PF-07220060 and PF-07104091 in Combination With Endocrine Therapy in Participants With Breast Cancer. (clinicaltrials.gov) - P1b/2 | N=144 | Recruiting | Sponsor: Pfizer | Trial completion date: Oct 2027 ➔ Jan 2028 | Trial primary completion date: Oct 2026 ➔ Jan 2027

Combination therapy • 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) - 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

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

Study to Assess the Safety and Tolerability of PF-07220060 in Combination With PF-07104091 in Participants With Breast Cancers or Solid Tumors and to Assess the Safety and Tolerability of PF-07220060 and PF-07104091 in Combination With Endocrine Therapy in Participants With Breast Cancer. (clinicaltrials.gov) - P1b/2 | N=144 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • 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: 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

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) - 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

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

CDK2 Inhibition Exerts RB-Independent Antitumor Activity in CDK4/6 Inhibitor-Resistant HR+/HER2- Breast Cancer. (PubMed, Cancer Res) - "Here, by analyzing tumor and liquid biopsies from patients treated with the selective CDK2i PF-07104091, we observed that PF-07104091 monotherapy achieved disease stabilization in a cohort of CDK4/6i-resistant HR+/HER2- MBC patients...These findings indicate that CDK dependency shifts from CDK4/6 toward CDK2 as cells transition from CDK4/6i-sensitive to CDK4/6i-resistant state. The distinct mechanisms of CDK2i and CDK4/6i support enhanced synergistic activity in HR+/HER2- MBC with acquired resistance to CDK4/6i therapy."

Journal • 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 • RB1

Dual CDK2 and CDK4/6 inhibition suppresses Rb/E2F signaling and enhances anti-leukemic activity in acute myeloid leukemia. (PubMed, Haematologica) - "In contrast, clinical efficacy was observed for the combination of the dual CDK4/6 inhibitor, palbociclib, with chemotherapy in pediatric acute leukemia and lymphoma patients...We found the CDK2- targeting drug, tegtociclib, to be particularly effective in potentiating the inhibitory effects of CDK4/6 inhibitors against acute leukemia cells...Our results also demonstrate that synergy between these agents, as has been previously shown in breast cancer, is also observed in acute leukemia and correlates with suppression of the Rb/E2F axis and inhibition of cell cycle progression. The universality between the underlying mechanisms of synergy for CDK2 inhibitors combined with CDK4/6 inhibitors in breast cancer and AML warrants further evaluation in other malignancies characterized by dependencies on these CDK subtypes."

Journal • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Non-Genetic Mechanisms of Fractional Resistance to Abemaciclib in Dedifferentiated Liposarcoma. (PubMed, bioRxiv) - "Dedifferentiated liposarcoma is a rare mesenchymal malignancy driven by amplification of chromosome 12q13-15, which includes the oncogenes CDK4 and MDM2. These fractionally resistant cells were defined by selective enrichment of cyclin-dependent kinase 2 (CDK2), cyclin B1, and phosphorylated ribosomal protein S6 (pS6), and showed enhanced sensitivity to the CDK2 inhibitor, tagtociclib. Together, these findings reveal nongenetic cell cycle plasticity as a mechanism of escape from CDK4/6 inhibition in dedifferentiated liposarcoma and nominate CDK2 and the PI3K-mTOR pathway as candidate targets for combination therapy."

Journal • Eye Cancer • Liposarcoma • Oncology • Retinal Disorders • Sarcoma • Solid Tumor • CCNB1 • MDM2

Proteome-wide target engagement and selectivity profiling of CDK2 inhibitors using CETSA® (AACR 2026) - "Several CDK2-selective inhibitors have recently been developed, including Tagtociclib (PF-07104091), Cirtociclib (BLU-222), and INX-315. Here, we investigated the proteome-wide target engagement and selectivity profiles of these CDK2-selective kinase inhibitors and compared them with those of approved CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) and pan-CDK probes...Target engagement of CDK1 was restricted to CDK2-selective and pan-CDK inhibitors and was only observed at higher compound concentrations. Together, these data illustrate the utility of CETSA MS for mapping target engagement and selectivity across the proteome, as well as for characterizing the evolution of CDK inhibitors from early pan-CDK compounds to modern CDK2-selective agents."

Breast Cancer • Eye Cancer • Oncology • Retinoblastoma • Solid Tumor • CDK1 • RB1

Dual-targeting CDK4 and CDK2 overcomes resistance to CDK4/6 inhibitors in HR+ breast cancer (AACR 2026) - "The next generation of CDK inhibitors such as atirmociclib targeting CDK4 and tagtociclib targeting CDK2 have demonstrated encouraging early efficacy, and the combination of a selective CDK4 inhibitor and a selective CDK2 inhibitor has entered clinical trials...These results suggested that CDK4:CDK6 selectivity of Cpd-1308 was greater than that of palbociclib.Further kinetic characterization using surface plasmon resonance (SPR) spectroscopy revealed that Cpd-1308 has long residence time on CDK2 in comparison with tagtociclib...Cpd-1308 indeed showed superior potency on antiproliferation of derived palbociclib resistant MCF7 cells (MCF7-palbo-r) and derived abemaciclib resistant MCF7 cells (MCF7-abema-r)...Cpd-1308 demonstrated significant resistance-overcoming activity.Taken together, we demonstrate activity of Cpd-1308 in HR+ breast cancers and CDK4/6i-resistant breast cancers. Our research results indicate that co-targeting CDK4 and CDK2 with a small-molecule may..."

Breast Cancer • Eye Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Retinoblastoma • Solid Tumor • CD34 • CDK2 • CDK6

CDK2 controls RIPK2 ubiquitination and stability in prostate cancer cells (AACR 2026) - "This study aims to address this knowledge gap by investigating the regulation of RIPK2 ubiquitination and degradation in PC cells, with a particular focus on CDK2, which we identified as a key mediator of RIPK2 regulation of the c-Myc oncoprotein. PC cells—22Rv1 (androgen receptor-positive) and PC3 (androgen receptor-negative)—were treated with two clinically evaluated, CDK2-selective inhibitors, INX-315 and PF-07104091...Cell cycle synchronization was achieved by serum starvation or treatment with Ro-3306, hydroxyurea, thymidine, or monastrol... Kinase-active CDK2 inhibits the K48-linked ubiquitination of RIPK2 and protects it from proteasomal degradation. This protection is potentially mediated by regulating the association between RIPK2 and its deubiquitinase YOD1 in PC cells. The findings support further investigation into the molecular mechanisms by which CDK2 stabilizes RIPK2 in PC and other cancer types."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • CDK2 • MYC • RIPK2

PF-07104091 as a Single Agent and in Combination Therapy (clinicaltrials.gov) - P2 | N=157 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: Mar 2026 ➔ Dec 2026 | Trial primary completion date: Mar 2026 ➔ Dec 2026

Platinum resistant • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Cell Lung Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2

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

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

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

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

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 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

Pro-Tumorigenic Roles of Cyclin Dependent Kinase 2 and its Associated Cyclins in Cholangiocarcinoma Progression under High Glucose Condition. (PubMed, Arch Med Res) - "CCA cells with upregulated CDK2 and its cyclin partners in HG were more sensitive to tagtociclib at a higher dose. Cyclin E and cyclin A also regulated CCA metastasis by controlling epithelial-mesenchymal transition. Targeting CDK2 and its associated cyclins in CCA cells demonstrated therapeutic potential that requires further translational and clinical verification."

Journal • Biliary Cancer • Cholangiocarcinoma • Diabetes • Metabolic Disorders • Oncology • Solid Tumor • CCNA2 • CDK2