AZD8421 / AstraZeneca - LARVOL DELTA

Targeting RB-deficient small cell lung cancer with selective CDK2 inhibition by AZD8421 (AACR 2026) - "In contrast, 6 RB-deficient PDX models demonstrated more profound and sustained responses with monotherapy, achieving an average TGI of 90%. Pharmacodynamic studies confirm dose-dependent target engagement via p-NPM1 suppression and evidence of apoptosis in vivo.These findings support further evaluation of CDK2 inhibition as a possible targeted strategy for RB-mutant SCLC that could offer a precision-medicine approach for a historically refractory disease subtype."

Eye Cancer • Lung Cancer • Oncology • Retinoblastoma • Small Cell Lung Cancer • Solid Tumor • CASP3 • CASP7 • CCNA2 • CCNE1 • NPM1 • RB1

Targeting the cell cycle with AZD8421, a potent and highly selective CDK2 inhibitor (AACR 2024) - "In vivo PD marker suppression and efficacy was demonstrated in CDK4/6 inhibitor resistant breast PDXs in combination with palbociclib (CDK4/6i). Monotherapy activity and combination benefit in vivo with standard of care agents was also observed in ovarian PDX models with elevated levels of CCNE1. AZD8421 is a potent and highly selective CDK2 inhibitor, with double digit nM potency in cells, as well as suitable physical and pharmacokinetic properties for progression into the clinic."

Breast Cancer • Oncology • Solid Tumor • CCNE1 • CDK1 • CDK9

First disclosure of AZD8421, a highly selective CDK2 inhibitor to address resistance to CDK4/6 inhibitors in breast and CCNE1-high cancers (AACR 2024) - P1/2 | "AZD8421 showed robust monotherapy activity in a CCNE1 amplified ovarian model OVCAR3 with regressions seen with monotherapy and in combination with palbociclib. These data, along with suitable physical and pharmacokinetic properties"

Breast Cancer • Oncology • Solid Tumor • CCNE1 • CDK1 • CDK9

CYCAD-1: A First-in-human Dose Escalation and Expansion Study to Evaluate the Safety, and Tolerability of AZD8421 Alone or in Combination in Participants With Selected Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=564 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Aug 2026 ➔ Aug 2027 | Trial primary completion date: Aug 2026 ➔ Aug 2027

First-in-human • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • High Grade Serous Ovarian Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor

CYCAD-1: A First-in-human Dose Escalation and Expansion Study to Evaluate the Safety, and Tolerability of AZD8421 Alone or in Combination in Participants With Selected Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=564 | Recruiting | Sponsor: AstraZeneca | N=348 ➔ 564

Enrollment change • First-in-human • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • High Grade Serous Ovarian Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor

Discovery of AZD8421: A Potent CDK2 Inhibitor with Selectivity Against Other CDK Family Members and the Human Kinome. (PubMed, J Med Chem) - "AZD8421 demonstrates favorable pharmacokinetic properties, including excellent solubility and robust in vitro stability. Demonstrated efficacy in an ovarian cancer patient-derived xenograft model further supports its potential as a therapeutic agent."

Journal • Oncology • Ovarian Cancer • Solid Tumor • CDK1

Discovery of PARP1- and CDK2-selective inhibitors for targeted therapy in cancer (ACS-Fall 2025) - "The first program targeted homologous recombination repair deficient tumors, such as those harboring a BRCA mutation (BRCAm), through PARP1 inhibition, structure-based drug design campaign that led to the discovery of new generation, selective PARP1 inhibitor and DNA trapper Saruparib (AZD5305) and CNS-penetrant PARP1-selective inhibitor and DNA trapper AZD9574. The second campaign targeted cyclin E (CCNE)-amplified or overexpressed tumors through inhibition of CDK2 activity, which led to the discovery of CDK2-selective inhibitor AZD8421. AZD8421 is highly selective for CDK2 over other members of the CDK family as well as the broader kinome and demonstrated efficacy in CCNE-amplified ovarian PDX models."

Oncology • BRCA • HRD

CYCAD-1: A First-in-human Dose Escalation and Expansion Study to Evaluate the Safety, and Tolerability of AZD8421 Alone or in Combination in Participants With Selected Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=348 | Recruiting | Sponsor: AstraZeneca | N=204 ➔ 348

Enrollment change • Breast Cancer • HER2 Breast Cancer • High Grade Serous Ovarian Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor

CYCAD-1: A First-in-human Dose Escalation and Expansion Study to Evaluate the Safety, and Tolerability of AZD8421 Alone or in Combination in Participants With Selected Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=204 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jun 2025 ➔ May 2026 | Trial primary completion date: Jun 2025 ➔ May 2026

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • High Grade Serous Ovarian Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor

CYCAD-1: A First-in-human Dose Escalation and Expansion Study to Evaluate the Safety, and Tolerability of AZD8421 Alone or in Combination in Participants With Selected Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=204 | Recruiting | Sponsor: AstraZeneca

Metastases • New P1/2 trial • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor