puxitatug samrotecan (AZD8205) / AstraZeneca - LARVOL DELTA

Phase II Trial of Puxitatug Samrotecan (AZD8205) in Advanced, Recurrent or Metastatic (R/M) Aggressive Adenoid Cystic Carcinoma Subtype I (ACC-I) (clinicaltrials.gov) - P2 | N=28 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

New P2 trial • Adenoid Cystic Carcinoma • Oncology

Puxitatug Samrotecan (AZD8205) Monotherapy vs Chemotherapy in B7-H4-selected Endometrial Cancer (Bluestar-Endometrial01) (clinicaltrials.gov) - P3 | N=700 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • Monotherapy • Endometrial Cancer • Oncology • Solid Tumor

Puxitatug samrotecan: Data from P1/2 trial (NCT05123482) for solid tumors post 2026 (AstraZeneca) - H1 & Q2 2025 Results

P1/2 data • Oncology • Solid Tumor

Puxitatug Samrotecan (AZD8205) Monotherapy vs Chemotherapy in B7-H4-selected Endometrial Cancer (Bluestar-Endometrial01) (clinicaltrials.gov) - P3 | N=700 | Not yet recruiting | Sponsor: AstraZeneca

Monotherapy • New P3 trial • Endometrial Cancer • Oncology • Solid Tumor

Puxitatug samrotecan (P-Sam, AZD8205) in patients (pts) with HR+/HER2– breast cancer (BC): A first-in-human phase I/IIa dose escalation and expansion study (ESMO-BC 2025) - P1/2 | "P-Sam had a manageable safety profile and showed preliminary efficacy in heavily pre-treated pts with advanced/recurrent HR+/HER2‒ BC; further P-Sam development is ongoing."

Clinical • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • VTCN1

B7 Homolog 4 (B7-H4)-Directed Agents in Oncology Clinical Trials: A Review. (PubMed, J Immunother Precis Oncol) - "B7-H4-directed agents, particularly antibody-drug conjugates (ADCs) like puxitatug samrotecan (AZD8205), felmetatug vedotin (SGN-B7H4V), and GSK5733584, have demonstrated early clinical activity with promising response rates in triple-negative breast cancer (TNBC). Combination strategies, such as ADCs with anti-PD-1 or PARP inhibitor therapies, have also shown enhanced tumor regression in preclinical models and are the subject of several ongoing clinical trials. This review highlights the current landscape of B7-H4-targeted agents, their progress in clinical trials, and the potential for combination approaches to improve outcomes in B7-H4-expressing cancers."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • VTCN1

Puxitatug samrotecan: Data from P1/2 trial (NCT05123482) for solid tumors in 2026 (AstraZeneca) - Q4 2024 Results

P1/2 data • Oncology • Solid Tumor

Puxitatug Samrotecan Demonstrates Efficacy, Manageable Safety in Advanced/Metastatic Endometrial Cancer (OncLive) - P1/2a | N=370 | BLUESTAR (NCT05123482) | Sponsor: AstraZeneca | "Among evaluable patients treated with puxitatug samrotecan at 2.0 mg/kg (n = 26) and 2.4 mg/kg (n = 26), the objective response rates (ORRs) were 34.6% and 38.5%, respectively; the respective 12-week disease control rates were 80.8% (95% CI, 60.6%-93.4%) and 84.6% (95% CI, 66.1%-95.6%)....At a median follow-up of 4.1 months (range, 1.2-12.7) for the 2.0-mg/kg cohort and 4.0 months (range, 0-12.5) for the 2.4-mg’kg cohort, the median progression-free survival was 7.0 months (95% CI, 4.5-9.0) and 7.0 months (95% CI, 5.5-9.2), respectively....The majority of treatment-related adverse effects (TRAEs) were gastrointestinal and hematologic in nature."

P1/2 data • Endometrial Cancer

Safety and preliminary efficacy of puxitatug samrotecan (P-Sam, AZD8205) in patients (pts) with endometrial cancer (EC): a first-in-human Phase 1/2a study (SGO 2025) - No abstract available

Clinical • Late-breaking abstract • P1/2 data • Endometrial Cancer • Oncology • Solid Tumor

BLUESTAR: A Phase I/IIa Study of AZD8205 Given Alone or in Combination With Anticancer Drugs, in Participants With Advanced or Metastatic Solid Malignancies (clinicaltrials.gov) - P1/2 | N=370 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jun 2026 ➔ May 2027 | Trial primary completion date: Jun 2026 ➔ May 2027

Monotherapy • Trial completion date • Trial primary completion date • Biliary Cancer • Biliary Tract Cancer • Breast Cancer • Endometrial Cancer • Hepatology • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor

Detailed Structural Elucidation of Antibody-Drug Conjugate Biotransformation Species Using High Resolution Multiple Reaction Monitoring Mass Spectrometry with Orthogonal Dissociation Methods. (PubMed, ACS Pharmacol Transl Sci) - "The reported orthogonal analytical approaches highly complement and fortify the intact protein LC-HRMS data. This study sheds further light on detailed structural characterization of various ADC species and validates the proposed biotransformation pathways explaining the stability of AZD8205 in vivo."

Journal • VTCN1

BLUESTAR: A Phase I/IIa Study of AZD8205 Given Alone or in Combination With Anticancer Drugs, in Participants With Advanced or Metastatic Solid Malignancies (clinicaltrials.gov) - P1/2 | N=340 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2025 ➔ Jun 2026 | Trial primary completion date: Dec 2025 ➔ Jun 2026

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Biliary Cancer • Biliary Tract Cancer • Breast Cancer • Endometrial Cancer • Hepatology • Oncology • Ovarian Cancer • Solid Tumor

Extensive Biotransformation Profiling of AZD8205, an Anti-B7-H4 Antibody-Drug Conjugate, Elucidates Pathways Underlying Its Stability In Vivo. (PubMed, Anal Chem) - P1/2 | "The comprehensive nature of this work increases our confidence in the understanding of these processes. We hope this analytical approach can inform future development of bioconjugate drug candidates."

Journal • Preclinical • Oncology • Solid Tumor • VTCN1

Initial results from a first-in-human study of the B7-H4-directed antibody-drug conjugate (ADC) AZD8205 (puxitatug samrotecan) in patients with advanced/metastatic solid tumors (ESMO 2024) - P1/2 | "AZD8205 had a manageable safety profile consistent with other Top1i ADCs and showed preliminary efficacy in heavily pre-treated pts with prior progression on standard treatment. Phase 2 expansion cohorts are ongoing in ovarian, breast, endometrial and biliary tract cancer."

Clinical • Metastases • P1 data • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Endometrial Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Solid Tumor • VTCN1

AZD8205: “AZD8205 - promising efficacy in heavily pre-treated patients with ovarian, breast and endometrial cancer”; Solid tumors (AstraZeneca) - ESMO 2024: “20.5% ORR with doses ≥1.6 mg/kg across B7-H4 levels”

P1/2 data • Breast Cancer • Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor

ESMO: Novel ADC AZD8205 demonstrates manageable safety profile and preliminary efficacy in first-in-human trial (MD Anderson Press Release) - P1/2a | N=340 | NCT05123482 | Sponsor: AstraZeneca | "The antibody-drug conjugate (ADC) puxitatug samrotecan (AZD8205) demonstrated a manageable safety profile consistent with similar ADCs and initial efficacy in heavily pretreated patients with advanced or metastatic solid tumors...Of the 44 patients treated at 1.6 mg/kg dose or higher, nine had partial responses, including patients with ovarian, breast or endometrial cancer...Because this patient population was heavily pretreated, while 91.5% of patients experienced treatment-related adverse events of any grade and 55.3% of patients experienced adverse events above grade three, the fact that only two patients had to discontinue treatment due to toxicities is promising. The most common adverse effects at grade three or higher were neutropenia (34%), anemia (17%) and a decrease in white blood cell count (17%) and were managed with with dose delays and dose reductions."

P1/2 data • Breast Cancer • Endometrial Cancer • Ovarian Cancer • Solid Tumor

AstraZeneca advances ambition to improve standards of care in multiple cancer types at WCLC and ESMO 2024 (AstraZeneca Press Release) - "AstraZeneca advances its ambition to revolutionise cancer care with new data across its diverse, industry-leading portfolio and pipeline at the IASLC 2024 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer, 7 to 10 September 2024 and the European Society for Medical Oncology (ESMO) Congress, 13 to 17 September 2024. Across the two meetings, more than 130 abstracts will feature 17 approved and potential new medicines from AstraZeneca including five Presidential Symposia and 41 oral presentations."

Late-breaking abstract • P1/2 data • P2 data • P3 data • Bladder Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Hepatocellular Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Non Small Cell Lung Cancer • Ovarian Cancer • Small Cell Lung Cancer • Solid Tumor

A Phase I/IIa Study of AZD8205 Given Alone or in Combination With Anticancer Drugs, in Participants With Advanced or Metastatic Solid Malignancies (clinicaltrials.gov) - P1/2 | N=340 | Recruiting | Sponsor: AstraZeneca | N=248 ➔ 340 | Trial completion date: Jun 2025 ➔ Dec 2025 | Trial primary completion date: Jun 2025 ➔ Dec 2025

Combination therapy • Enrollment change • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Biliary Cancer • Biliary Tract Cancer • Breast Cancer • Endometrial Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Ovarian Cancer • Solid Tumor

AZD8205: Data from P1/2 trial (NCT05123482) for solid tumors post 2025 (AstraZeneca) - Q1 2024 Results

P1/2 data • Oncology • Solid Tumor

AZD8205: Data from P1/2 trial (NCT05123482) for solid tumors in 2025 (AstraZeneca) - Q4 & FY2023 Results

P1/2 data • Biliary Tract Cancer • Breast Cancer • Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor

Development of the Novel Topoisomerase 1i Linker-Payload AZ14170133 (ADC-USA 2023) - "Outlining key challenges in linker-payload development; Reviewing the key steps in the development of anti-B7-H4 ADC AZD8205; Highlighting the exciting future directions of AZ14170133"

Oncology • VTCN1

Spatial Immunoprofiling of Adenoid Cystic Carcinoma Reveals B7-H4 Is a Therapeutic Target for Aggressive Tumors. (PubMed, Clin Cancer Res) - "Spatial analysis revealed that ACC subtypes have distinct TMEs, with enrichment of ACC-I immune cells that are restricted to the stroma. B7-H4 is highly expressed in poor-prognosis ACC-I subtype and is a potential therapeutic target."

Journal • Adenoid Cystic Carcinoma • Immune Modulation • Oncology • VTCN1

Preclinical evaluation of a novel B7-H4 targeted antibody-drug conjugate AZD8205 as a single agent and in combination with novel PARP inhibitor and checkpoint blockade (AACR 2023) - P1/2 | "To further exploit the DNA damage elicited by the specific delivery of the TOP1i warhead, the combination of AZD8205 with a novel poly-ADP ribose polymerase 1 (PARP1) selective inhibitor, AZD5305, was investigated. These data demonstrate that AZD8205 is a promising therapeutic candidate for the treatment of B7-H4 positive solid tumors. A first in human phase I/IIa study in patients with advanced solid tumors is currently ongoing (NCT05123482)."

Checkpoint block • Checkpoint inhibition • Combination therapy • IO biomarker • Preclinical • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Endometrial Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • HRD • VTCN1

AstraZeneca advances its pipeline and highlights progress in immuno-oncology, ADCs, cell therapy and epigenetics at AACR (AstraZeneca Press Release) - "Preclinical data for AZD8205, an ADC targeting B7-H4, will also be presented both as monotherapy and in combination with the PARP-1 selective inhibitor, AZD5305. Robust anti-tumour activity is evident in preclinical models across multiple B7-H4 positive tumour types, including ovarian and cholangiocarcinoma tumours, with combination therapy resulting in higher anti-tumour activity than monotherapy....At AACR, the first preclinical data will be presented for the novel lead epigenetics molecule, AZ-PRMT5i-1, a potent methylthioadenosine phosphorylase (MTAP)-selective PRMT5 inhibitor with anti-tumour activity in MTAP-deleted tumours."

Preclinical • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

Discovery and first disclosure of AZD8205, a B7-H4-targeted antibody-drug conjugate utilizing a novel topoisomerase I linker-warhead (AACR 2022) - P1/2 | "These data suggest that AZD8205 is a promising therapeutic candidate for the treatment of B7-H4 positive solid tumors. A first in human phase 1 study in patients with advanced solid tumors is currently ongoing (NCT05123482)."

Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Endometrial Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • BRCA • TOP1 • VTCN1