tigozertinib (BLU-945) / Blueprint Medicines, ZAI Lab - LARVOL DELTA

Over 200! The largest BaF3-EGFR engineering cell lines collection, a useful platform for novel drug discovery (AACR 2025) - "Recognizing EGFR as a driver gene has accelerated the development of targeted anticancer therapies, such as monoclonal anti-EGFR antibodies (cetuximab, panitumumab) and small molecule receptor tyrosine kinase inhibitors (TKIs). The first generation of EGFR TKIs, like gefitinib and erlotinib, specifically target mutations such as L858R and exon 19 deletions. To address resistance to these early inhibitors, second-generation EGFR TKIs (afatinib, dacomitinib) were developed...Osimertinib, a third-generation TKI, was approved for use in EGFR-mutated NSCLC following the failure of first- and second-generation TKIs, although the EGFR C797S mutation limits its effectiveness. Fourth-generation EGFR TKIs, including BLU-945 and BBT-176, are under clinical evaluation but are not yet approved.We have created more than 200 Ba/F3-EGFR engineered cell lines, making this the largest in vitro and in vivo platform for drug discovery with the widest range of mutant cells. These cell lines..."

Preclinical • Brain Cancer • Breast Cancer • Colon Cancer • Colorectal Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • EGFR • EPGN • ERBB3 • ERBB4 • HBEGF • HER-2 • TGFA

Targeting exon mutations in NSCLC: clinical insights into LAG-3, TIM-3 pathways, and advances in fourth-generation EGFR-TKIs. (PubMed, Med Oncol) - "Advanced inhibitors, including BBT-176, BLU-945, and BLU-701, have effectively targeted resistant mutations and reduced disease progression. Such combination regimens aim to optimize PFS, OS, and ORR while minimizing adverse effects and addressing the limitations of current therapies. This study explores the landscape of EGFR mutations, their clinical significance, and the integration of innovative fourth-generation EGFR-TKIs with immunotherapies, emphasizing the potential of precision medicine in advancing the management of EGFR-mutated NSCLC."

IO biomarker • Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HAVCR2 • LAG3 • PD-L1

Next-generation NSCLC drug development powered by PDCs and PDOs: Mimicking real responses (AACR 2025) - "The models response to afatinib sensitively. Another example is YUO-143, which harbors EGFR mutations E19del/T790M/C797S and was derived from a patient resistant to gefitinib and mavelertinib. YUO-143 was used in the development of the 4th gen TKI, BLU-945, and showed an IC50 of 43 nM.Conclusions : Patient-derived models could serve as a crucial tool in developing novel therapeutic strategies and next-generation drugs for NSCLC."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • CD74 • EML4 • KRAS • MET • ROS1

Characterization of EGFR C797S-mutant, osimertinib-resistant non-small cell lung cancer cells (AACR 2025) - "Originally, it was developed to target the T790M gatekeeper mutation which arises as acquired resistance mechanism to first-generation EGFR inhibitors such as gefitinib. In contrast, the fourth-generation EGFR inhibitors BLU-945 and JBJ-09-063 reduced viability of the parental and C797S-mutant clones with similar potency. While potencies in the clones were similar between 2D culture and 3D spheroids, BLU-945 and JBJ-09-063 reached a higher maximum effect in 3D spheroids compared to 2D culture.The successful generation and characterization of the NCI-H1975 C797S-mutant clones provides a valuable in vitro model in which additional next-generation EGFR inhibitors and drug combinations can be profiled to identify therapeutic strategies to overcome osimertinib resistance."

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

Deep Mutational Scanning Reveals Novel EGFR Mutations Conferring Resistance to Osimertinib and BLU-945 (JSMO 2025) - No abstract available

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • EGFR

Identification of novel inhibitors for epidermal growth factor receptor tyrosine kinase using absolute binding free-energy simulations. (PubMed, Int J Biol Macromol) - "The result shows that the top candidate exhibits a binding affinity of -15.8 kcal/mol towards the EGFR™ mutant, surpassing BLU-945, a state-of-the-art fourth-generation inhibitor with a binding free energy of -12.6 kcal/mol...Targeting lysine has emerged as a promising strategy, especially in cases where the C797S mutation renders traditional covalent inhibitors ineffective. We propose that these novel inhibitors represent promising drug candidates for non-small cell lung cancer treatment and offer new strategies to overcome drug resistance caused by EGFR mutation."

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

(SYMPHONY) Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC (clinicaltrials.gov) - P1 | N=177 | Terminated | Sponsor: Blueprint Medicines Corporation | Phase classification: P1/2 ➔ P1 | Trial completion date: Jan 2025 ➔ Oct 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jan 2025 ➔ Oct 2024; Sponsor decision, not related to safety concerns

Phase classification • Trial completion date • Trial primary completion date • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Thoracic Cancer

BLU-945, a potent and selective next-generation EGFR TKI, has antitumor activity in models of osimertinib-resistant non-small-cell lung cancer. (PubMed, Ther Adv Med Oncol) - P1/2 | "BLU-945 also demonstrated tumor shrinkage in patients from the SYMPHONY trial. Our findings demonstrate the preclinical and early clinical activity of BLU-945 in EGFRm NSCLC progressing on previous EGFR-TKIs."

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

Modeling the Relationship of Clinical Safety Profile of EGFR Inhibitors with Wild-Type EGFR Inhibition in Cellular Model (IASLC-WCLC 2024) - "The EGFR inhibitors include commercially available proxy compounds of gefitinib, afatinib, osimertinib, mobocertinib, sunvozertinib, zipalertinib, BLU-945, BDTX-1535, etc. Clinical safety data are obtained from drug labels or publications, including all grades AEs and Grades ≥3 rash and diarrhea. The potency of inhibition of WT EGFR in a uniform nonclinical assay strongly correlated with overall rates and severity of rash and diarrhea observed in the clinical setting. These results may be useful in enhancing the understanding of the potential clinical safety profile of novel EGFR targeted therapies at the nonclinical development stage."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Characterization of fourth-generation EGFR inhibitors in binding experiments with C797S mutant EGFR and cell-based assays with osimertinib-resistant non-small cell lung cancer cell lines (AACR 2024) - "Fourth-generation EGFR inhibitors and combinations with other targeted agents are potential strategies to overcome osimertinib resistance or to increase its efficacy.Three fourth-generation EGFR inhibitors were profiled in biochemical and cell-based assays: BDTX-1535, BLU-945, and JBJ-09-063. Profiling results of the three fourth-generation EGFR inhibitors in the osimertinib-resistant cell lines and on a panel of more than one hundred human cancer cell lines will be presented.Reference: [1] Bertran-Alamillo et al. Nature Communications 10, 1812; 2019"

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MET

PH009-1, a highly potent, selective and brain-penetrable fourth-generation EGFR-TKI that overcome classic and resistant EGFR mutations in NSCLC (AACR 2024) - "Background: Epidermal growth factor receptor (EGFR) inhibitors, especially 3rd Gen inhibitor such as osimertinib (Osi), have become the first line therapy for non-small cell lung cancer (NSCLC) patients with EGFR activating mutations...In recent years, 4th Gen EGFR inhibitors have been developed such as BLU-945 and PH009-1... Our data suggested that PH009-1 overcome T790M/C797S resistant mutations, and also have potential to become a potent and safe approach for first line therapy of NSCLC with EGFR mutations."

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

Patient-derived cells (PDCs) and organoids (PDOs) as critical platforms for developing next therapeutic strategies for NSCLC (AACR 2024) - "IC50 of YUO-139 and YU-1092 to afatinib were 2.1 nM and 23.8 nM respectively. YUO-143 is a PDO model that harbors EGFR E19del/T790M/C797S which was derived from gefitinib and mavelertinib resistant patient revealed sensitivity to BLU-945 (IC50, 43 nM), a novel fourth-generation EGFR-TKI.Conclusions : Patient derived models could be a critical tool for developing therapeutic strategies for NSCLC."

Clinical • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • MET

(SYMPHONY) Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC (clinicaltrials.gov) - P1/2 | N=190 | Active, not recruiting | Sponsor: Blueprint Medicines Corporation | Recruiting ➔ Active, not recruiting

Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Thoracic Cancer

Blueprint Medicines Highlights 2024 Corporate Strategy and Business Priorities at 42nd Annual J.P. Morgan Healthcare Conference (PRNewswire) - "Discontinue further investment in the early clinical-stage therapies BLU-945 and BLU-451 for EGFR-mutant NSCLC and explore strategic options, including potential out-licensing, based on the evolving external landscape and emerging clinical data....Present data for BLU-222 in combination with ribociclib and fulvestrant in patients with HR+/HER2- breast cancer in the first half of 2024. Provide update on BLU-222 registration plan in HR+/HER2- breast cancer in the second half of 2024."

Discontinued • P1/2 data • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Binding Thermodynamics of Fourth-Generation EGFR Inhibitors Revealed by Absolute Binding Free Energy Calculations. (PubMed, J Chem Inf Model) - "We compared the binding affinities of BLU-945, BLU-945 analogues, CH7233163 (another fourth-generation TKI), and erlotinib (a first-generation TKI) using absolute binding free energy calculations. Furthermore, we discovered that the incorporation of piperidinol and sulfone groups in BLU-945 substantially enhanced its binding capacity to EGFR mutants. Our study offers valuable theoretical insights for optimizing fourth-generation EGFR TKIs."

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

"Ideally a trial pt -Patritumab Dxd or BLU 945 Other trial options - BL-B01D1 bispecific , Ami or Teliso depending on MET expression . Else carbo Pem ." (@RenoHemonc)

MET

Binding mechanism of ATP and EGFR inhibitors revealed by absolute binding free energy calculations (ACS-Fall 2023) - "The resistance of erlotinib happens after the T790M mutation of EGFR, because this mutation causes the binding of adenosine triphosphate (ATP) to EGFR more favorable than erlotinib. Although osimertinib, a third-generation tyrosine kinase inhibitor (TKI), against the T790M mutation have been in active development, most patients will eventually develop resistance to osimertinib due to the new mutation (C797S)...Additionally, we also found that the introduction of piperidinol and sulfone groups in BLU-945 significantly enhanced its binding ability to EGFR mutants. We hope the drug-resistance mechanism proposed in this study will provide valuable guidance for the design of drugs for NSCLC."

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

BLU-945 monotherapy and in combination with osimertinib (OSI) in previously treated patients with advanced EGFR-mutant (EGFRm) NSCLC in the phase 1/2 SYMPHONY study. (ASCO 2023) - P1/2 | "BLU-945 mono and combo with OSI were generally well tolerated and showed robust on-target EGFR ctDNA reduction, with tumor shrinkage in genomically heterogeneous, heavily pretreated pts. Combo showed responses at BLU-945 doses lower than in mono, consistent with additive benefit. The combo safety profile and on-target activity provide rationale for further development in front line."

Clinical • Combination therapy • Metastases • Monotherapy • P1/2 data • Cardiovascular • Fatigue • Heart Failure • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pain • Pneumonia • Solid Tumor • EGFR

Blueprint Medicines Highlights Clinical Progress Across Precision Oncology Pipeline at 2023 ASCO Annual Meeting (PRNewswire) - P1/2 | N=190 | SYMPHONY (NCT04862780) | Sponsor: Blueprint Medicines Corporation | "Updated results from the dose escalation part of the SYMPHONY trial showed the safety and clinical activity of BLU-945 as a monotherapy (n=112) and in combination with osimertinib (n=55) in patients with late-line, osimertinib-refractory, EGFR-mutant NSCLC...Updated results from the dose escalation part of the SYMPHONY trial showed the safety and clinical activity of BLU-945 as a monotherapy (n=112) and in combination with osimertinib (n=55) in patients with late-line, osimertinib-refractory, EGFR-mutant NSCLC....Updated results from the dose escalation part of the SYMPHONY trial showed the safety and clinical activity of BLU-945 as a monotherapy (n=112) and in combination with osimertinib (n=55) in patients with late-line, osimertinib-refractory, EGFR-mutant NSCLC."

P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A phase 1/2 study of BLU-945 in patients with common activating EGFR-mutant non–small cell lung cancer (NSCLC): SYMPHONY trial in progress. (ASCO 2022) - P1/2 | "Preclinically it has shown activity as monotherapy in osimertinib-resistant patient-derived xenograft (PDX) models. Patients may receive treatment until disease progression or unacceptable toxicity. Recruitment has started and approximately 30 sites will be open for enrollment across North America, Europe, and Asia."

Clinical • P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Blueprint Medicines to Present New Clinical Data Across Broad Precision Therapy Pipeline at 2023 ASCO Annual Meeting (PRNewswire) - "Blueprint Medicines Corporation...announced the acceptance of clinical abstracts for multiple programs across its precision therapy portfolio at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, June 2 to 6...The datasets to be reported at the ASCO Annual Meeting include: Results from the ongoing dose escalation part of the VELA trial of BLU-222 in breast cancer and other cancers vulnerable to CDK2 inhibition, showing evidence of monotherapy safety and pathway modulation. Updated results from the dose escalation part of the SYMPHONY trial showing the safety and tolerability of BLU-945 as a monotherapy and in combination with osimertinib in patients with late-line, EGFR-mutant non-small cell lung cancer (NSCLC). Results from the ongoing dose escalation part of the CONCERTO trial of BLU-451 in EGFR exon 20 insertion-positive NSCLC showing early safety and clinical activity."

P1/2 data • Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • CDK2 • EGFR

Patient-derived cells (PDCs) and organoids (PDOs) as platforms for screening novel therapeutics for NSCLC (AACR 2023) - "Osimertinib-resistant YU-1097 harboring EGFR resistance mutation (E19del/T790M/C797S) revealed sensitivity to BLU-945 (IC50, 108nM), a novel fourth-generation EGFR-TKI. A similar inhibition of cell viability was observed with repotrectinib (IC50, 21nM), a next-generation ROS1-TKI and lorlatinib (IC50, 9nM) in YU-1078 harboring CD74-ROS1, whereas more robust tumor regression was seen with repotrectinib in YU1078-derived xenograft model. Amivantamab, a EGFR-MET bispecific antibody, showed a robust activity in YU-1163 and YUO-036 in vitro and in vivo. PDC/PDO models can be utilized for evaluating activity of novel agents and will accelerate novel drug development in NSCLC."

Clinical • Colon Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • CD74 • MET • ROS1

Poorer outcomes in EGFR L858R-driven NSCLC treated with osimertinib may be addressed with novel combination of BLU-945 and osimertinib (AACR 2023) - P1/2 | "Poorer outcomes with L858R have also been reported with other 3rd-gen TKIs aumolertinib and lazertinib. In both RWDs, 1L osimertinib-treated patients with L858R-driven NSCLC had poorer outcomes vs ex19del, consistent with osimertinib’s weaker activity on L858R. Preclinically, BLU-945 in combination with osimertinib increased L858R inhibition, resulting in more durable antitumor activity in L858R xenografts vs osimertinib alone, supporting rationale for combination treatment in patients with L858R mutations. This combination is being evaluated in 1L patients with L858R in the SYMPHONY study (NCT04862780)."

Late-breaking abstract • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • TP53

[VIRTUAL] A phase 1/2 study of BLU-945, a highly potent and selective inhibitor of epidermal growth factor receptor (EGFR) resistance mutations, in patients with EGFR-mutant non-small cell lung cancer (NSCLC) (AACR-NCI-EORTC 2021) - No abstract available

Clinical • P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Zai Lab Announces Full-Year 2022 Financial Results and Recent Corporate Updates (GlobeNewswire) - "Clinical data update for the innovaTV 207 study in head and neck cancer in the first half of 2023. Clinical data update for the innovaTV 205 study in first-line+ r/m cervical cancer in the second half of 2023....Repotrectinib...Anticipated 2023 Zai Milestones; Discuss regulatory pathway with the NMPA at a pre-NDA meeting in the first quarter of 2023. Submit an NDA to the NMPA for ROS1+ advanced NSCLC in 2023....Provide an initial clinical data update on SYMPHONY trial expansion of BLU-945 in combination with osimertinib in first-line EGFR L858R-positive NSCLC in the second half of 2023..."

Clinical data • Non-US regulatory • P1/2 data • P2 data • Cervical Cancer • Gynecologic Cancers • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Thoracic Cancer