tilatamig samrotecan (AZD9592) / AstraZeneca - LARVOL DELTA

AZD9592: Data from P1 EGRET trial (NCT05647122) for advanced solid tumors/NSCLC/HNSCC/CRC in H2 2025 (AstraZeneca) - Q1 2025 Results

P1 data • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

AZD9592, an EGFR/cMET bispecific antibody-drug conjugate (ADC), demonstrates target-dependent efficacy in colorectal cancer (CRC) patient-derived xenograft (PDX) models (AACR 2025) - "Despite recent advances in ADC development for CRC, such as the use of trastuzumab deruxtecan to treat HER2-positive CRC, a significant unmet need remains for novel therapeutic approaches, particularly for patients with limited targeted treatment options. We evaluated the antitumor efficacy of AZD9592 and explored biomarker-response relationships in CRC PDX models across a range of very low to high EGFR expression (optical density of membrane [OD] 6.7-162.6) and cMET expression (OD 18.5-142.6) measured by immunohistochemistry-quantitative continuous score (IHC-QCS), as well as other molecular features like oncogene drivers. AZD9592 demonstrated dose-dependent antitumor activity in CRC PDX models, including KRAS-mutant and KRAS-wildtype tumors. These responses suggest opportunities for clinical development of AZD9592 in CRC and the potential for biomarker-guided patient selection."

Clinical • Colorectal Cancer • Oncology • Solid Tumor • BRAF • HER-2 • KRAS • TOP1

Establishing preclinical activity of topoisomerase I inhibitor (TOPO1i) antibody-drug conjugate AZD9592 in patient-derived xenograft (PDX) models of metastatic colorectal cancer (mCRC) in context of irinotecan pretreatment and resistance (AACR 2025) - "We evaluated these models for aresponse to AZD9592 (administered in a single dose at 2, 4, or 8 mg/kg), irinotecan, or irinotecan plus oxaliplatin. AZD9592 was effective in mCRC PDX models, even at the lowest doses tested. AZD9592 was effective in mCRC PDX models that did not respond to irinotecan-based treatment. Ongoing research is evaluating whether multiple doses of AZD9592 can induce resistance in PDX models, and potential resistance mechanisms are being assessed by molecular characterization."

Metastases • Preclinical • Colorectal Cancer • Oncology • Solid Tumor • EGFR

KA-2886-LD38: a bispecific antibody-drug conjugate (ADC) targeting both EGFR and MET, incorporating a novel linker-payload that inhibits DNA topoisomerase I (AACR 2025) - "Compared to the benchmark ADC AZD9592, KA-2886-LD38 exhibits a similar internalization rate when binding to tumor cells but demonstrates significantly stronger cytotoxicity and bystander killing activity across different tumor cell lines in vitro...Moreover, KA-2886-LD38, when combined with osimertinib, also demonstrated a combination inhibitory effect on H1975 tumor growth. KA-2886-LD38 is well-tolerated at doses up to 30 mg/kg in EGFR and MET humanized genetically modified mice, and toxicity studies in monkeys are ongoing. These results suggest that KA-2886-LD38 has remarkable potential in the landscape of anti-EGFR/cMet therapies."

Breast Cancer • Colorectal Cancer • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • EGFR • TOP1

EGRET: First in Human Study of AZD9592 in Solid Tumors (clinicaltrials.gov) - P1 | N=228 | Recruiting | Sponsor: AstraZeneca | N=162 ➔ 228

Enrollment change • Monotherapy • Colorectal Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

Anti-MET Antibody Therapies in Non-Small-Cell Lung Cancer: Current Progress and Future Directions. (PubMed, Antibodies (Basel)) - " Amivantamab, a bispecific EGFR/MET antibody was approved to treat EGFR exon 20 insertion and now has recently been extended to target classical EGFR mutations with progression on osimertinib. Other important anti-MET targeted therapies in development include antibody drug conjugates such as telisotuzumab vedotin, REGN5093-M114, and AZD9592 and emibetuzumab, which is a humanized immunoglobulin G4 monoclonal bivalent MET antibody...Future research should focus on developing novel MET antibody drugs and exploring new therapeutic combinations to enhance treatment efficacy and overcome resistance in NSCLC. Refining biomarker-driven approaches to ensure precise patient selection is also critical to optimizing treatment outcomes."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A promising MET-EGFR bispecific nanobody-drug conjugate therapy for multiple solid tumours (ESMO 2024) - "KY-0301 was engineered with lower EGFR affinity (161-fold) and EGFR arm truncation, with the aim of reducing EGFR-driven toxicity in normal tissues. KY-0301 showed higher internalization rates than AZD9592 in HCT116 and NCI-H1975. Preclinical data has demonstrated promising efficacy and safety of KY-0301 in tumors expressing MET and EGFR, including but not limited to NSCLC, colorectal cancer, pancreatic cancer and kidney cancer."

Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Kidney Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • EGFR • MET

AZD9592: Data from P1 EGRET trial (NCT05647122) for advanced solid tumors/NSCLC/HNSCC/CRC in H2 2025 (AstraZeneca) - H1 & Q2 2024 Results

P1 data • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

VBC101-F11: An innovative EGFR/cMet bispecific antibody drug conjugate (ADC) targeting key oncogenic drivers in solid tumors (AACR 2024) - "This innovative design distinguishes VBC101-F11 from other EGFR/cMet-targeting agents on the market or in clinical trials (ABBV399 or AZD9592), optimizing both efficacy and safety.1. Further payload exploration, such as DNA replication inhibitor, has also yielded promising results, with VBC101-F11-new payload showing comparable efficacy to the same class ADC AZD9592 in models with low EGFR and high cMet expression (100% TGI) and in those with moderate EGFR/cMet expression (~ 60% TGI).In summary, VBC101-F11, with unique design and distinguished attributes, has demonstrated its remarkable potential in the landscape of anti-EGFR/cMet therapies. The encouraging efficacy observed in preclinical models supports the molecule's advancement into clinical development, positioning it as a best-in-class bispecific ADC for treating tumors in patients."

Late-breaking abstract • Lung Cancer • Oncology • Solid Tumor

EGRET: First in Human Study of AZD9592 in Solid Tumors (clinicaltrials.gov) - P1 | N=162 | Recruiting | Sponsor: AstraZeneca | N=108 ➔ 162

Combination therapy • Enrollment change • Metastases • Monotherapy • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

EGRET: First in Human Study of AZD9592 in Solid Tumors (clinicaltrials.gov) - P1 | N=108 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2025 ➔ Oct 2025 | Trial primary completion date: Mar 2025 ➔ Oct 2025

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

AZD9592: Data from P1 EGRET trial (NCT05647122) for advanced solid tumors/NSCLC/HNSCC in 2025 (AstraZeneca) - Q4 & FY2023 Results

P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

Maximizing Preclinical Data to Tailor Translational Plans for Bispecific ADC: Lessons From AZD9592, an EGFR-cMET Bispecific ADC (ADC-USA 2023) - "Exploring the characterization of internalization and cytotoxic properties of AZD9592, a bispecific ADC designed to selectively bind EGFR and c-MET on tumor cells and deliver a topoisomerase 1 inhibitor payload; Using in vivo PDX studies to explore relationship of target expression to tumor growth inhibition; Describing pharmacodynamic biomarkers supporting multi-faceted mechanism of action"

Preclinical • Oncology • EGFR • MET

In Vivo Efficacy of AZD9592, an EGFR-cMET Bispecific ADC, in a Broad Panel of NSCLC Patient-Derived Xenograft Models (IASLC-WCLC 2023) - "Comparable efficacy was observed across EGFR mutant (EGFRm) models previously treated with single or multiple lines of first- (gefitinib, erlotinib), second- (afatinib), and/or third-generation (osimertinib) EGFR TKIs. Additionally, TR was observed in 3/3 (100%) of models previously treated with an EGFR TKI in combination with the cMET TKI savolitinib; high cMET expression by IHC was seen in >90% of the cells in these three models. Notably, 4/5 (80%) of models with prior exposure to the ALK TKI crizotinib demonstrated TR... In vivo efficacy of AZD9592 was demonstrated in PDX models across a broad spectrum of NSCLC molecular profiles. These included EGFRwt and EGFRm tumours harbouring varied EGFR mutations; groups with and without prior chemotherapy; and groups with and without prior treatment with ALK, EGFR, and/or cMET TKI. These observations suggest that AZD9592 may provide clinical benefit in areas of unmet need, including in patients previously treated with..."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR

EGRET: First-in-human Study of the Novel Antibody-drug Conjugate AZD9592 ± Anti-cancer Agents in Advanced Solid Tumours (IASLC-WCLC 2023) - P1 | "Module 2 will evaluate AZD9592 in combination with osimertinib in patients with EGFRm mNSCLC. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting."

Metastases • P1 data • Cardiovascular • Head and Neck Cancer • Interstitial Lung Disease • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • EGFR • TOP1

AstraZeneca data at WCLC advance ambition to have an AstraZeneca medicine for more than half of all patients treated for lung cancer by 2030 (AstraZeneca Press Release) - "Two posters will feature AZD9592, an EGFR/cMET bispecific ADC designed to deliver targeted chemotherapy to cancer cells expressing both EGFR and cMET with a topoisomerase inhibitor 1 warhead using the Company’s proprietary linker technology. A trial-in-progress poster will describe the EGRET Phase I trial, a first-in-human study evaluating AZD9592 in patients with advanced solid tumours including in combination with Tagrisso in metastatic EGFRm NSCLC. In addition, a poster on translational results for AZD9592 suggests it may provide clinical benefit in areas of unmet need, including in patients with NSCLC previously treated with chemotherapy or targeted agents."

Clinical data • Trial status • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

EGRET: First in Human Study of AZD9592 in Solid Tumors (clinicaltrials.gov) - P1 | N=108 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Oct 2024 ➔ Jan 2025 | Trial primary completion date: Oct 2024 ➔ Jan 2025

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

EGRET: A first-in-human study of the novel antibody-drug conjugate (ADC) AZD9592 as monotherapy or combined with other anticancer agents in patients (pts) with advanced solid tumors. (ASCO 2023) - P1 | "Module 2 will evaluate AZD9592 in combination with osimertinib in pts with EGFRm mNSCLC. The study will include sites across the EU, USA, and Asia Pacific; sites in USA and Australia are currently open for enrollment. Clinical trial information: NCT05647122."

Clinical • Metastases • Monotherapy • P1 data • Cardiovascular • Head and Neck Cancer • Interstitial Lung Disease • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • EGFR • MET • TOP1

AZD9592, an EGFR-cMET Bispecific Antibody Drug Conjugate Engineered for Differentiation (PEGS 2023) - "The antibody is conjugated via a cleavable linker to a topoisomerase 1 inhibitor (TOP1i) payload (AZ14170132). AZD9592 is broadly active in PDX models representing clinical line-of-sight and shows a promising safety profile."

AstraZeneca (AZN.US) three new class 1 drugs approved for clinical trials in China [Google translation] (Sina Corp) - "On May 15, the official website of the Center for Drug Evaluation (CDE) of the State Food and Drug Administration of China announced that three new Class 1 drugs from AstraZeneca (AZN.US) have obtained implicit approval for clinical trials. AZD9592, intended to be used alone or in combination with anticancer drugs in the treatment of advanced solid tumors....Oral estrogen receptor degrader (SERD) AZD9833 tablets, intended for prolonged treatment of estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) early breast cancer patients at medium or high risk of recurrence."

New trial • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor

"The rationale behind AZD9592, anti-EGFR/cMet bispecific ADC, via $AZN Frank Comer #AACR23 (cf $JNJ Rybrevant)" (@JacobPlieth)

Oncology

Evaluation of the relationship between target expression and in vivo anti-tumor efficacy of AZD9592, an EGFR/c-MET targeted bispecific antibody drug conjugate (AACR 2023) - "Collectively, these results support the hypothesized mechanism of action of AZD9592: TOP1i induced tumor cell death due to formation of DNA DSB, and suggest opportunities in the treatment of tumors with a range of molecular features. AZD9592 is currently in a Phase 1 clinical trial in advanced solid malignancies."

Preclinical • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CASP3 • EGFR • MET • SLFN11

AZD9592: An EGFR-cMET bispecific antibody-drug conjugate (ADC) targeting key oncogenic drivers in non-small-cell lung cancer (NSCLC) and beyond (AACR 2023) - "MET amplification or protein overexpression has been established as the most common mechanism of clinical resistance to EGFR inhibitors such as osimertinib. Plasma pharmacokinetics in cynomolgus monkeys showed an acceptable profile at tolerated doses, in line with other EGFR and cMET directed antibodies. These results demonstrate that AZD9592 has a promising efficacy and safety profile in preclinical models representing diverse opportunities in multiple clinical settings."

Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • KRAS • MET

AstraZeneca advances its pipeline and highlights progress in immuno-oncology, ADCs, cell therapy and epigenetics at AACR (AstraZeneca Press Release) - "AstraZeneca will present new data across its diverse, industry-leading Oncology pipeline and portfolio at the American Association for Cancer Research (AACR) Annual Meeting, 14 to 19 April 2023....Two oral presentations will feature the first preclinical and translational results for AZD9592, a bispecific ADC designed to deliver targeted chemotherapy to cancer cells with a topoisomerase inhibitor 1 (TOP1i) warhead using the Company’s proprietary linker technology....In addition, the first preclinical results will be presented for another ADC, AZD5335, a promising therapeutic candidate for the treatment of certain ovarian cancers."

Preclinical • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

EGRET: First in Human Study of AZD9592 in Solid Tumors (clinicaltrials.gov) - P1 | N=108 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Metastases • Monotherapy • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck