BI-4020 / Boehringer Ingelheim - LARVOL DELTA

Exploration of Acquired Resistance Mechanisms to the 4th-Generation EGFR-TKI in EGFR-Mutated Lung Cancer - An in Vitro Study (IASLC-WCLC 2024) - "We found that HCC827 resistant to BI-4020 (HCC827BIR) had MET gene amplification (2.97 times) and that it was sensitive to a combination of capmatinib (MET-TKI) and BI-4020. Conclusions : The on-target resistance through the secondary EGFR mutation was not detected. Instead, MET gene alterations and EMT known for the mechanisms to 1 st - 3 rd generation EGFR-TKIs, were recurrently observed."

Preclinical • Lung Cancer • Oncology • Solid Tumor • CDH1 • MET • VIM

Potential Utility of a 4th-Generation EGFR-TKI and Exploration of Resistance Mechanisms-An In Vitro Study. (PubMed, Biomedicines) - "Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib)...HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020...This study suggests that erlotinib may be more suitable than 4G TKIs to overcome secondary mutations after front-line osimertinib. We found that off-target mechanisms that cause resistance to earlier-generation TKIs will also cause resistance to 4G TKIs."

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

A macrocyclic kinase inhibitor overcomes the compound mutations that cause the resistance to all approved EGFR inhibitors in EGFR-positive lung cancer (AACR 2024) - "In our previous study, we experimentally demonstrated that brigatinib with anti-EGFR antibody was effective against osimertinib-resistant EGFR-C797S and EGFR-T790M+C797S mutants, and is currently undergoing clinical studies. Microsecond molecular dynamics simulations revealed the binding mode and affinity between BI-4020 and the EGFR mutants. This study identified potential therapeutic strategies using new-generation macrocyclic EGFR inhibitor to overcome the emerging resistance mutants."

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

Structural analysis of the macrocyclic inhibitor BI-4020 binding to EGFR kinase. (PubMed, ChemMedChem) - "Structures show that BI-4020 is likely rendered selective due to interactions with the kinase domain hinge region as well as T790M, akin to Osimertinib. Additionally, BI-4020 is also rendered more potent due to its constrained macrocycle geometry as well as additional H-bonds to conserved K745 and T845 residues in both active and inactive conformations. These findings taken together show how this novel macrocyclic inhibitor is both highly potent and selective for mutant EGFR in a reversible mechanism and motivate structure- inspired approaches to developing targeted therapies in medicinal oncology."

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

A macrocyclic kinase inhibitor overcomes triple resistant mutations in EGFR-positive lung cancer. (PubMed, NPJ Precis Oncol) - "Brigatinib-based therapy was effective against osimertinib-resistant EGFR C797S mutants and is undergoing clinical studies. Molecular dynamics simulation revealed the binding mode and affinity between BI-4020 and EGFR mutants. This study identified potential therapeutic strategies using the new-generation macrocyclic EGFR inhibitor to overcome the emerging ultimate resistance mutants."

Journal • Lung Cancer • Oncology • Solid Tumor • EGFR

Exploration of Secondary Resistant Mutations against Mobocertinib - in Vitro Study with Various EGFR Exon 20 Insertion Models (IASLC-ACLC 2022) - "We also examined growth inhibitory effect of poziotinib, afatinib, CLN-081, erlotinib, osimertinib, brigatinib and BI4020 using the same Ba/F3 models. These findings indicate that T790M or C797S, depending on the activating mutations, will cause acquired resistance to mobocertinib in NSCLCs with EGFR exon 20 mutations. We also found a novel secondary mutation (F856V) that may confer acquired resistance to mobocertinib."

EGFR exon 20 • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

[PREPRINT] Structural analysis of the macrocyclic inhibitor BI-4020 binding to EGFR kinase (bioRxiv) - “A novel macrocyclic inhibitor of mutant EGFR (BI-4020) has shown promise in pre-clinical studies of T790M and C797S drug-resistant non-small cell lung cancer. To better understand the molecular basis for BI-4020 selectivity and potency, we have carried out biochemical activity assays and structural analysis with X-ray crystallography. Biochemical potencies agree with previous studies indicating that BI-4020 is uniquely potent against drug-resistant L858R/T790M and L858R/T790M/C797S variants. Structures show that BI-4020 is likely rendered selective due to interactions with the kinase domain hinge region as well as T790M, akin to Osimertinib. Additionally, BI-4020 is also rendered more potent due to its constrained macrocycle geometry as well as additional H-bonds to conserved K745 and T845 residues in both active and inactive conformations.”

Preclinical • Preprint • Non Small Cell Lung Cancer • Oncology

In vitro Activity and Potential Resistance Mutations Against BI-4020, a 4th-generation EGFR-TKI (IASLC-WCLC 2022) - "BI-4020, a 4G EGFR-TKI, will be able to overcome both of T790M/C797S exon 20 mutations. However, acquisition of exon 18 mutations (E709G and L718Q) may cause resistance to BI-4020 when L858R is a sensitizing mutation."

Preclinical • EGFR