ebvaciclib (PF-06873600) / Pfizer - LARVOL DELTA

First-In-Human Phase 1/2a Study of the First-In-Class CDK2/4/6 Inhibitor PF-06873600 Alone or with Endocrine Therapy in Patients with Breast Cancer. (PubMed, Clin Cancer Res) - P1/2 | "PF-06873600 demonstrated a benefit-risk profile consistent with the CDK4/6 inhibitor class of drugs, with preliminary clinical activity in HR+/HER2- mBC."

Journal • P1/2 data • Breast Cancer • Fatigue • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2

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

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

Individualized Pooled CRISPR/Cas9 Screenings Identify CDK2 as a Druggable Vulnerability in a Canine Mammary Carcinoma Patient. (PubMed, Vet Sci) - "A comparison of essential genes for tumor cells survival identified CDK2 as a functional vulnerability in canine mammary tumors (CMTs) that can be targeted with the PF3600 inhibitor. Additional potential targets were also uncovered, providing insights for personalized cancer treatments in dogs."

Journal • Breast Cancer • Oncology • Solid Tumor • CDK2

C3661001: A Study of PF-06873600 in People With Cancer (clinicaltrials.gov) - P1/2 | N=155 | Terminated | Sponsor: Pfizer | Phase classification: P2 ➔ P1/2 | Active, not recruiting ➔ Terminated; Per business decision, but not due to safety concerns or regulatory request.

Phase classification • Trial termination • Breast Cancer • Fallopian Tube Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Male Breast Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2

Discovery of targeted therapies for cancer patients: CDK2/4/6 inhibitor Ebvaciclib and EZH2 inhibitor PF-06821497 (ACS-Fall 2023) - "Ebvaciclib, is a CDK2/4/6 inhibitor designed to be co-dosed with hormone therapy (letrozole or fulvestrant) to treat HR+ breast cancer. PF-06821497 is an EZH2 inhibitor currently being evaluated alone and in combination with enzalutamide to treat patients with castration resistant prostate cancer who have received either abiraterone and/or enzalutamide treatment and have evidence of prostate cancer progression. Discovery, synthesis, and early clinical results will be presented."

Clinical • Breast Cancer • Genito-urinary Cancer • Hormone Receptor Breast Cancer • Oncology • Prostate Cancer • Solid Tumor

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

Cells rapidly adapt to CDK2 inhibitors via plasticity of the CDK2/4/6-Rb-E2F axis (AACR 2023) - "Here, application of a novel small molecule CDK2/4/6 inhibitor, PF-06873600, enabled in-depth interrogation of CDK2 substrate phosphorylation, cell-cycle progression, and drug adaptation in preclinical models...CDK2 inhibition reveals latent CDK4/6 activity throughout S phase that backstops the proliferative program by maintaining Rb1 hyperphosphorylation, active E2F transcription, and Cyclin A2 expression, enabling re-activation of CDK2. Our results augment our understanding of CDK plasticity and indicate that co-inhibition of CDK2 and CDK4/6 is required to suppress adaptation to CDK2 inhibitors."

Oncology • CCNA2 • CDK1 • RB1

Synthesis and biological evaluation of novel pteridin-7(8H)-one derivatives as potent CDK2 inhibitors. (PubMed, Bioorg Med Chem Lett) - "Taking the CDK2/4/6 inhibitor Ebvaciclib as the positive control and an in-house library compound (23) as the lead compound, three classes of 30 target compounds with pteridin-7(8H)-one as the core structure were designed to establish structure-activity relationships (SAR)...After the above compounds were tested for CDK2/4/6 kinase selectivity, we found that compound KII-21 was about 3 and 4 times more selective to CDK2-cyclinE2 than CDK4-cyclinD1 and CDK6-cyclinD3, respectively. This work also provides a reference basis for the subsequent research on CDK2 inhibitors."

Journal • Oncology • CCND1 • CCND3 • CCNE2

Cell cycle intervention beyond palbociclib; preclinical discovery of the CDK2/4/6 inhibitor PF-06873600 (EORTC-NCI-AACR 2018) - P2; "Palbociclib resistance models derived from either expression of CDK2-activating cyclin E or deletion of RB1 are sensitive to genetic interruption of CDK2 signaling. Pharmacokinetic, safety and translational discovery data for PF-06873600, generated as rationale for a phase I clinical investigation (ClinicalTrials.gov Identifier: NCT03519178), will be discussed in detail.*All procedures performed on animals were in accordance with regulations and established guidelines and were reviewed and approved by an Institutional Animal Care and use committee"

Preclinical • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

C3661001: A Study of PF-06873600 in People With Cancer (clinicaltrials.gov) - P2 | N=155 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: Apr 2023 ➔ Nov 2024

Combination therapy • Trial completion date • Breast Cancer • Fallopian Tube Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Male Breast Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2

A first-in-human phase 1/2a dose escalation/expansion study of the first-in-class CDK2/4/6 inhibitor PF‑06873600 alone or with endocrine therapy in patients with breast or ovarian cancer (SABCS 2021) - P2 | "This first-in-human dose escalation/expansion study (NCT03519178) is evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of the first-in-class selective CDK2/4/6 inhibitor PF-06873600 (PF-3600) as monotherapy and combined with ET... This is a phase 1/2a, open-label, non-randomized, study of PF-3600 as monotherapy and combined with letrozole or fulvestrant (F)... PF-3600 can be combined with ET with a manageable AE profile and demonstrates promising preliminary antitumor activity in heavily pretreated pts, including those with HR+/HER2– BC progressing on ET + CDK4/6i and Cx. Dose expansion in combination with ET in pts with HR+/HER2– BC with and without prior CDK4/6i Tx is ongoing."

Clinical • P1/2 data • Breast Cancer • HER2 Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2

C3661001: A Study of PF-06873600 in People With Cancer (clinicaltrials.gov) - P2 | N=155 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: Jan 2024 ➔ Apr 2023

Combination therapy • Trial completion date • Breast Cancer • Fallopian Tube Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Male Breast Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2

C3661001: A Study of PF-06873600 in People With Cancer (clinicaltrials.gov) - P2 | N=155 | Active, not recruiting | Sponsor: Pfizer | N=69 ➔ 155

Combination therapy • Enrollment change • Breast Cancer • Fallopian Tube Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Male Breast Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2

CONCURRENT INHIBITION OF CDK2 ADDS TO THE ANTI-TUMOR ACTIVITY OF CDK4/6 INHIBITION IN GIST (CTOS 2022) - "The impact of inhibitors of CDK2 (CDK2 inhibitor-II, PF-07104091), CDK4/6 (palbociclib, abemaciclib), and CDK2/4/6 (PF-06873600) was determined through cell proliferation and protein detection assays in vitro and in vivo. These studies establish the biologic rationale for CDK2 and CDK4/6 co-inhibition as therapeutic strategy in patients with advanced GIST, including metastatic GIST progressing on tyrosine kinase inhibitors. In addition, these findings expand the spectrum of potential CDK inhibitor resistance mechanisms with translational potential for improving cell cycle targeted therapies in other cancer types."

Breast Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Hormone Receptor Breast Cancer • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor • Targeted Protein Degradation • CCND1 • RB1

C3661001: A Study of PF-06873600 in People With Cancer (clinicaltrials.gov) - P2 | N=69 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | N=160 ➔ 69 | Trial completion date: Oct 2025 ➔ Jan 2024

Combination therapy • Enrollment change • Enrollment closed • Trial completion date • Breast Cancer • Fallopian Tube Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Male Breast Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2

Response and resistance to CDK2 and CDK4/6 inhibition in GIST (AACR 2022) - "The impact of various CDK perturbants using CDK2i (CDK2 inhibitor-II), CDK4/6i (palbociclib or abemaciclib), and CDK2/4/6i (PF-06873600) was determined through cell proliferation and protein detection assays in GIST cell lines and murine xenografts. We show that co-inhibition of CDK2 and CDK4/6 is synergistic in GIST and highlight RB1 inactivation and a novel oncogenic cyclin D1 as mechanisms of acquired CDKi resistance. Hence, combination therapies targeting CDK2 and CDK4/6 with correlative biomarkers predictive of response should be evaluated in patients with metastatic or TKI-resistant GIST."

Breast Cancer • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor • CCND1 • CDKN2A • KIT • PDGFRA • RB1

NP-ALT, a liposomal:peptide drug, blocks p27Kip1 phosphorylation to cause cell death in CDK4i-resistant breast cancer (AACR 2022) - "This RIPK1/RIPK3-dependent cell death is more specific for HR+ lineages, but the combination of NP-ALT and palbociclib in TNBC cells causes synergy to induce necroptosis...We tested other CDK2i, including CYC065, a CDK2/9 inhibitor and PF-06873600, a CDK4/6/2 inhibitor, and and found that while they were able to block DNA replication, only NP-ALT was able to induce ROS-dependent death in the resistant lines...Thus, NP-ALT and p27 targeting has several differentiators, which might provide clinical advantages: a) its low toxicity due to the tight specificity of the peptide for the p27 target and b) its ability to kill tumor cells as opposed to just causing cytostasis. Concarlo is currently developing NP-ALT into a therapeutic lead for the treatment of drug-resistant breast cancer."

Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDKN1B • CDKN2A • FAT1 • FGFR • RIPK1

A platform of CDK4/6 inhibitor-resistant patient-derived breast cancer organoids illuminates mechanisms of resistance and therapeutic vulnerabilities (SABCS 2021) - "We successfully established 16 PDOs out of 32 biopsies (50% efficiency) of metastates from patients with ER+ MBC progressing on CDK4/6i (palbociclib or abemaciclib) + antiestrogens (letrozole or fulvestrant; median response to combination = 9 months)...Finally, treatment of 10 resistant PDOs with the CDK2/4/6 inhibitor PF-06873600 revealed that the CCNE1 (cyclin E1)-amplified PDO was highly sensitive (IC50=130 nM vs >1000 nM), supporting that CCNE1 -amplified tumors are vulnerable to CDK2 inhibition. PDOs can be successfully established from ER+ MBC biopsies, maintain the resistant phenotype in culture, retain driver alterations found in tumors from which they were derived, and fail to suppress E2F targets following treatment with CDK4/6i. Therefore, these PDOs represent valuable models to understand and explore diverse mechanisms of CDK4/6i resistance and therapeutic vulnerabilities."

Clinical • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ARID1A • CCNE1 • CDK1 • ER • HER-2 • NF1 • PIK3CA • PLK1 • PTEN

Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor. (PubMed, Cancer Cell) - "The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR/HER2 breast cancer when combined with anti-hormonals...We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models...Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • HER-2

Restoring order at the cell cycle border: Co-targeting CDK4/6 and CDK2. (PubMed, Cancer Cell) - "study mechanisms of resistance to CDK4/6 inhibitors by employing a CRISPRa screen. They identify the cyclin E-CDK2 axis and Myc signaling as key pathways of resistance and develop PF-06873600, a selective CDK2/4/6 inhibitor."

Journal • Oncology • CDK2 • CDK4

Discovery of PF-06873600, a CDK2/4/6 Inhibitor for the Treatment of Cancer. (PubMed, J Med Chem) - "Further, we detail the use of molecular dynamics simulations to provide insights into the basis for selectivity against CDK9. Based on overall potency, selectivity, and ADME profile, PF-06873600 (22) was identified as a candidate for the treatment of cancer and advanced to phase 1 clinical trials."

Journal • Breast Cancer • Oncology • Solid Tumor • CDK9

A Safety, Pharmacokinetic, Pharmacodynamic and Anti-Tumor Study of PF-06873600 as a Single Agent and in Combination With Endocrine Therapy (clinicaltrials.gov) - P2; N=157; Recruiting; Sponsor: Pfizer; Trial completion date: May 2024 ➔ Jul 2025; Trial primary completion date: Nov 2022 ➔ Feb 2023

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Breast Cancer • Fallopian Tube Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Male Breast Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2

A Safety, Pharmacokinetic, Pharmacodynamic and Anti-Tumor Study of PF-06873600 as a Single Agent and in Combination With Endocrine Therapy (clinicaltrials.gov) - P2; N=220; Recruiting; Sponsor: Pfizer

Clinical • Combination therapy • New P2 trial • Breast Cancer • Fallopian Tube Cancer • Gynecologic Cancers • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Male Breast Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2

A Safety, Pharmacokinetic, Pharmacodynamic and Anti-Tumor Study of PF-06873600 as a Single Agent and in Combination With Endocrine Therapy (clinicaltrials.gov) - P2; N=220; Recruiting; Sponsor: Pfizer; Trial completion date: Mar 2023 ➔ Nov 2023; Trial primary completion date: Mar 2023 ➔ Nov 2023

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Breast Cancer • Fallopian Tube Cancer • Gynecologic Cancers • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Male Breast Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2