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

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

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

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

BLU-945 suppresses ABCB1-mediated drug efflux and restores chemosensitivity in multidrug-resistant cancer cells. (PubMed, Eur J Pharmacol) - "Together, these findings reveal a previously unrecognized property of BLU-945 as a functional inhibitor of ABCB1-mediated drug transport. In addition to its activity as a mutant-selective EGFR inhibitor, BLU-945 may therefore serve as a dual-function agent capable of targeting oncogenic signaling while mitigating transporter-mediated chemoresistance, supporting its potential reprofiling in combination chemotherapy for ABCB1-overexpressing tumors."

Journal • Oncology • ABCB1

Recent advances in synthetic strategies of fourth-generation EGFR tyrosine kinase inhibitors under clinical trials for the treatment of resistant non-small cell lung cancer (NSCLC). (PubMed, Bioorg Chem) - "The present review summarizes recent advances in the synthetic strategies and biological profiles of fourth-generation EGFR-TK inhibitors currently undergoing clinical investigation for resistant Non-Small Cell Lung Cancer (NSCLC) to overcome the C797S mutation associated with Osimertinib. Representative clinical candidates, including TQB-3804, BPI-361175, BLU-945, BBT-176, BDTX-1535, QLH11811, HS-10375, and H002, are discussed with particular emphasis on synthetic route design, key intermediates, medicinal chemistry optimization, and pharmacological activity...In addition, advances in scaffold design, phosphine oxide incorporation, and conformationally optimized heterocyclic frameworks have contributed significantly to the development of next-generation mutant-selective inhibitors. Overall, this review provides a contemporary overview of synthetic innovations in fourth-generation EGFR inhibitor development and highlights emerging strategies for overcoming..."

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

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

Structure-guided identification and biological evaluation of reversible EGFR C797S inhibitors. (PubMed, Sci Rep) - "In an EGFR T790M/C797S/L858R xenograft model, oral administration of the reversible inhibitor BLU-945 produced significant tumor growth inhibition, confirming the in vivo tractability of C797S-driven EGFR signaling. In contrast, the structurally related tool compound F471-0411 exhibited limited antitumor efficacy following intratumoral delivery, suggesting that pharmacokinetic or exposure constraints, rather than lack of intrinsic cellular activity likely limited its in vivo potency. Collectively, these findings highlight the utility of structure-guided screening for identifying novel EGFR C797S-active scaffolds and provide translational insights to inform the design of next-generation EGFR inhibitors."

Journal • Oncology

Novel syngeneic models for evaluating therapies targeting EGFRL858R/T790Mand EGFRL858R/T790M/C979Sresistance mutations in NSCLC (AACR 2026) - "Therefore, our laboratory generated conditional knock-in C57BL/6 mice harboring human EGFRL858R/T790M or EGFRL858R/T790M/C979S, which quickly develop spontaneous NSCLC and yield primary tumor cell lines.In syngeneic, immune-competent C57BL/6 hosts, the fourth-generation TKI under research, BLU-945, markedly inhibited both EGFRL858R/T790M and EGFRL858R/T790M/C979S tumor growth. In contrast, osimertinib was effective only against EGFRL858R/T790M, but failing against the EGFRL858R/T790M/C979S mutation. This demonstrates how our novel mouse models faithfully recapitulate and allow the reversal of osimertinib resistance in vivo."

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

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

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

Elucidating the role of the T790M mutation in BLU-945 selectivity for mutant EGFR: structural and energetic insights. (PubMed, J Comput Aided Mol Des) - No abstract available

Journal • EGFR

The Fourth-Generation EGFR Tyrosine Kinase Inhibitor BLU-945 Resensitizes ABCG2-Overexpressing Multidrug-Resistant Non-Small Cell Lung Cancer Cells to Cytotoxic Anticancer Drugs. (PubMed, Eur J Pharm Sci) - "These findings reveal a previously unrecognized pharmacological property of BLU-945 as an inhibitor of ABCG2-mediated drug efflux, supporting its potential role in combination therapies aimed at overcoming MDR in patients with ABCG2-overexpressing tumors. Further preclinical and clinical studies are warranted to validate the translational relevance of this approach and to identify patient populations that may benefit most from this combinatorial strategy."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCG2 • EGFR

Deep mutational scanning reveals EGFR mutations conferring resistance to the 4th-generation EGFR tyrosine kinase inhibitor BLU-945. (PubMed, NPJ Precis Oncol) - "DMS library-expressing cells were exposed to osimertinib or BLU-945 to identify escape mutations. Another with baseline EGFR L858R, T790M, and C797S acquired an L718V mutation at progression. This study demonstrate how comprehensive resistance profiling of targeted therapies can predict clinically relevant mutations and guide rational combinations to delay or prevent resistance."

Journal • EGFR

EGFR mutations in non-small cell lung cancer: Classification, characteristics and resistance to third-generation EGFR-tyrosine kinase inhibitors (Review). (PubMed, Oncol Lett) - "Third-generation EGFR-TKIs (such as osimertinib) markedly improve patient survival by selectively targeting the T790M mutation, but novel resistance mutations, such as C797S, limit their long-term efficacy. Combination therapies (such as MET proto-oncogene, receptor tyrosine kinase/EGFR dual-target inhibitors) and fourth-generation TKIs (such as BLU-945) offer novel directions to overcome resistance. Future research should focus on precise subtyping, dynamic monitoring of resistance mechanisms and regulation of the immune microenvironment to advance personalized treatment for NSCLC."

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

Novel potent and selective fourth-generation inhibitors targeting EGFR for NSCLC therapy. (ASCO 2025) - " We have characterized the efficacy of two novel fourth-generation EGFR inhibitors, CCM-205 and CCM-308, which are potent against both mutational and non-mutational tumor resistance to Osimertinib. Novel fourth-generation EGFR inhibitors have been developed that can potentially overcome both on-target and off-target resistance in NSCLC and have potential clinical applications."

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

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

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

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

(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