volrustomig (MEDI5752) / AstraZeneca - LARVOL DELTA

First-line (1L) trastuzumab deruxtecan (T-DXd) with volrustomig and fluoropyrimidine in patients with HER2-low gastric cancer (GC), gastroesophageal junction adenocarcinoma (GEJA), or esophageal adenocarcinoma (EA): DESTINY-Gastric03 (DG-03) part 5. (ASCO-GI 2026) - "Funded by AstraZeneca The full, final text of this abstract will be available on Jan 05 at 05:00 PM EST."

Clinical • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2

Volrustomig drives superior CTLA-4 blockade, induces sustained PD-1 degradation, and enhances T cell function ex vivo (ESMO-IO 2025) - "PBMCs, disaggregated tumor cells (DTCs), or human tumor slice cultures (TSCs) were treated with volrustomig or a co-formulation of a bivalent monospecific anti-PD-1 (clone LO115) and anti-CTLA-4 (tremelimumab) antibodies in the presence or absence of exogenous anti-CD3 stimulation. Ex vivo, volrustomig enhanced TIL functionality as detected by increased IFNγ secretion from non-small cell lung cancer DTCs and gastric TSCs.Conclusions Volrustomig demonstrates cooperative binding, induces sustained PD-1 degradation, and enhances IFNγ secretion in vitro, and ex vivo. These findings support volrustomig's unique mechanistic properties and underscore its differentiation from co-formulations of bivalent monospecific anti-PD-1 and anti-CTLA-4 antibodies.Legal entity responsible for the study AstraZeneca."

IO biomarker • Preclinical • Gastric Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • IFNG • NCAM1

Volrustomig co-operatively binds to PD-1 and CTLA-4 and causes PD-1 degradation in tumour antigen specific T cells (ESMO-IO 2025) - "Furthermore, we demonstrated that this MoA has functional consequences regarding antigen specific killing and cytokine release. We have also demonstrated V mediated PD-1 degradation and confirmed this further differentiates V from conventional bivalent monospecific anti-CTLA-4/anti-PD-1 antibodies.Legal entity responsible for the study The authors."

IO biomarker • Oncology • CTLA4 • MLANA • PD-1

eVOLVE-RCC02: A Study to Investigate the Efficacy and Safety of Volrustomig ± Casdatifan vs Nivolumab + Ipilimumab as 1L Treatment for Advanced ccRCC (clinicaltrials.gov) - P3 | N=1116 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

eVOLVE-Meso: MEDI5752 in Combination With Carboplatin Plus Pemetrexed in Unresectable Pleural Mesothelioma (clinicaltrials.gov) - P3 | N=825 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2028 ➔ Nov 2028 | Trial primary completion date: Mar 2027 ➔ Nov 2027

Trial completion date • Trial primary completion date • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor

GEMINI-Hepatobiliary: Study of Novel Immunomodulators as Monotherapy and in Combination With Anticancer Agents in Participants With Advanced Hepatobiliary Cancer (clinicaltrials.gov) - P2 | N=294 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2026 ➔ Oct 2027 | Trial primary completion date: Dec 2025 ➔ Oct 2026

Monotherapy • Trial completion date • Trial primary completion date • Biliary Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Volrustomig: Data from P2 CANTOR trial (NCT06792695) for metastatic CRC post 2026 (AstraZeneca) - Q3 2025 Results: Data from P1 trial (NCT03530397) for advanced solid tumors in H1 2026

P1 data • P2 data • Colorectal Cancer • Oncology • Solid Tumor

Volrustomig: Data from P3 eVOLVE-Cervical trial (NCT06079671) in patients with high-risk locally advanced cervical cancer post 2026 (AstraZeneca) - Q3 2025 Results: Data from P3 eVOLVE-Lung02 trial (NCT05984277) for 1L metastatic NSCLC with PD-L1 <50% post 2026

P3 data • Cervical Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Volrustomig: Data from P3 eVOLVE-Meso trial (NCT06097728) for 1L unresectable malignant pleural mesothelioma post 2026 (AstraZeneca) - Q3 2025 Results: Data from P3 eVOLVE-HNSCC trial (NCT06129864) for locally advanced HNSCC post 2026

P3 data • Malignant Pleural Mesothelioma • Oncology • Squamous Cell Carcinoma of Head and Neck

Volrustomig: Data from P2 eVOLVE-02 trial (NCT06535607) for advanced/metastatic solid tumors in post 2026 (AstraZeneca) - Q3 2025 Results

P2 data • Oncology • Solid Tumor

Development and utilization of a humanized mouse tumor model to dissect the mechanism of action of the monovalent bispecific anti-CTLA-4/PD-1 antibody (volrustomig). (SITC 2025) - "We developed a 25-marker spectral flow cytometry antibody panel to assess major immune cell lineage populations, the amount of T-cell activation and expression levels of immune checkpoint markers. In parallel, bulk RNA sequencing of tumor samples was conducted to characterize the genetic changes associated with the immune response following antibody treatment (figure 1).Results Our in vivo analysis revealed that 1) antigen recognition favors the recruitment of immune cells in tumors and this infiltration is potentiated with volrustomig in comparison with anti-PD-1 monotherapy, 2) high dimensional flow cytometry revealed that volrustomig gives rise to distinct infiltrating T cell subsets but alters myeloid recruitment in tumors and 3) transcriptomic analyses showed a distinct program triggered by volrustomig with significant up-regulation of genes encoding for IFNγ-signaling pathway and a specific set of transcription factors.Conclusions Overall, using in vivo tumor with..."

IO biomarker • Preclinical • Esophageal Cancer • Oncology • Solid Tumor • CD34 • IFNG

Ph1b/2 Study of the Safety and Efficacy of T-DXd Combinations in Advanced HER2-expressing Gastric Cancer (DESTINY-Gastric03) (clinicaltrials.gov) - P2 | N=413 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jul 2026 ➔ Jun 2027 | Trial primary completion date: Jul 2026 ➔ Jun 2027

Monotherapy • Trial completion date • Trial primary completion date • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Oncology • Solid Tumor • HER-2

eVOLVE-02: Study of Volrustomig as Monotherapy or in Combination With Anti- Cancer Agents in Participants With Advanced/Metastatic Solid Tumors (clinicaltrials.gov) - P2 | N=110 | Recruiting | Sponsor: AstraZeneca | N=257 ➔ 110

Enrollment change • Monotherapy • Cervical Cancer • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Concurrent binding to PD-1 and CTLA-4 mechanistically differentiates volrustomig from the combination of monospecific antibodies ex vivo (ESMO 2025) - "PBMCs or disaggregated primary human tumours were treated with volrustomig or a co-formulation of a bivalent monospecific anti-PD-1 (LO115) and anti-CTLA-4 (tremelimumab) antibodies. Through concurrent and cooperative engagement of PD-1 and CTLA-4, volrustomig demonstrates mechanistic biology distinct from the combination of anti-PD-1 and anti-CTLA-4 monospecific antibodies. Legal entity responsible for the study AstraZeneca UK Ltd."

IO biomarker • Preclinical • Oncology • CD80 • CD86 • CTLA4 • PD-1

eVOLVE-02: Study of Volrustomig as Monotherapy or in Combination With Anti- Cancer Agents in Participants With Advanced/Metastatic Solid Tumors (clinicaltrials.gov) - P2 | N=257 | Recruiting | Sponsor: AstraZeneca | N=110 ➔ 257 | Trial completion date: Oct 2027 ➔ Nov 2028 | Trial primary completion date: Oct 2027 ➔ Nov 2028

Enrollment change • Monotherapy • Trial completion date • Trial primary completion date • Cervical Cancer • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

SEVERE PULMONARY ARTERIAL HYPERTENSION POSTLOBECTOMY FOR LUNG CANCER (CHEST 2025) - "His prior chemotherapies (paclitaxel, carboplatin, and volrustomig) have not previously been associated with PH, and TTE was normal after drug exposure...He was subsequently started on sildenafil 20 mg three times daily, digoxin 125 mcg daily, and furosemide 20 mg daily...Macitentan was discontinued with improvement in peripheral edema and sildenafil was also subsequently weaned... PH post-MLR is an important contributor to morbidity and mortality. Future research will help better risk stratify those who are at risk of developing severe PH and to understand the impact of early PH therapy initiation on reversal pulmonary vasculopathy."

Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Immunology • Lung Cancer • Oncology • Pulmonary Arterial Hypertension • Respiratory Diseases • Solid Tumor • Squamous Cell Carcinoma

eVOLVE-Meso: A Global Phase 3 Study of First-line Volrustomig Plus Chemotherapy in Unresectable Pleural Mesothelioma (IMIG 2025) - P1, P3 | "Approximately 825 patients will be randomized in a 1:1 ratio to: volrustomig + carboplatin + pemetrexed; or investigator's choice of (a) nivolumab + ipilimumab, or (b) for epithelioid histologies only, pemetrexed + carboplatin or cisplatin. Exploratory biomarker analyses will also be conducted. Enrollment opened in November 2023."

Clinical • IO biomarker • P3 data • Immunology • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Pleural Mesothelioma • Sarcoma • Solid Tumor

CANTOR: A Study of Novel Study Interventions and Combinations in Participants With Colorectal Cancer (clinicaltrials.gov) - P2 | N=120 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jan 2028 ➔ Jun 2028

Trial completion date • Colorectal Cancer • Oncology • Solid Tumor

Phase 3 eVOLVE-Lung02 Trial of Volrustomig + Chemotherapy (CT) vs Pembrolizumab + CT in Metastatic NSCLC With PD-L1 TC <50% (IASLC-WCLC 2025) - P1, P3 | "Approximately 1200 patients will be randomized 1:1 to receive histology-specific CT (squamous: paclitaxel plus carboplatin; non-squamous: pemetrexed plus carboplatin + pemetrexed maintenance) in combination with either volrustomig or pembrolizumab 200 mg Q3W for 4 cycles; after this volrustomig (Q3W) or pembrolizumab (200 mg Q3W or 400 mg Q6W where locally approved) will be administered until completion of 24 months of treatment or disease progression, or other discontinuation criteria are met. Key secondary endpoints are PFS and OS in all randomized patients; other secondary endpoints include objective response rate, duration of response, PFS2 (progression after starting first subsequent therapy or death), safety and tolerability, patient-reported outcomes (including NSCLC Symptom Assessment Questionnaire on disease-related symptoms), pharmacokinetics, and immunogenicity. Enrollment is ongoing at approximately 26 sites in 25 countries/regions."

IO biomarker • Metastases • P3 data • Cardiomyopathy • Cardiovascular • CNS Disorders • Congestive Heart Failure • Heart Failure • Hypertension • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • EGFR • NTRK • PD-L1 • ROS1

TROPION-Lung04: Phase 1b Study of Dato-DXd in Combination With Immunotherapy With or Without Carboplatin in Advanced or Metastatic Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=165 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting | N=371 ➔ 165 | Trial completion date: Jan 2026 ➔ Apr 2026 | Trial primary completion date: Jan 2026 ➔ Apr 2026

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • PD-L1

DESTINY-Lung03: Phase Ib Study of the Safety of T-DXd and Immunotherapy Agents With and Without Chemotherapy in Advanced or Metastatic HER2+, Non-squamous NSCLC (clinicaltrials.gov) - P1 | N=244 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2025 ➔ Jun 2027 | Trial primary completion date: Dec 2025 ➔ Jun 2027

IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

eVOLVE-01: Volrustomig Priming Regimens Exploratory Phase II Platform Study (clinicaltrials.gov) - P2 | N=180 | Recruiting | Sponsor: AstraZeneca | N=120 ➔ 180

Enrollment change • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

eVOLVE-RCC02: A Study to Investigate the Efficacy and Safety of Volrustomig ± Casdatifan vs Nivolumab + Ipilimumab as 1L Treatment for Advanced ccRCC (clinicaltrials.gov) - P3 | N=1116 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • Monotherapy • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

TAYLOR: MEDI5752 in Patients With Mature Tertiary Lymphoid Structures Solid Tumors. (clinicaltrials.gov) - P2 | N=102 | Not yet recruiting | Sponsor: Institut Bergonié | Trial completion date: Sep 2027 ➔ Sep 2028

Trial completion date • Oncology • Solid Tumor

MEDI5752 in Japanese Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=6 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion • Oncology • Solid Tumor