tigozertinib (BLU-945)

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.

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.

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.

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.

P1, N=177, Terminated, 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

P1/2, N=190, Active, not recruiting, Blueprint Medicines Corporation | Recruiting --> Active, not recruiting

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.

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.

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).

The in vivo antitumor activities of BLU-945 and BLU-701 as single agents suggest both BLU-945 and BLU-701 have the potential to be used as 1L therapy in patients with EGFR L858R-driven NSCLC. The superior in vivo antitumor activity of BLU-945 or BLU-701 in combination with osimertinib in prolonging the DOR or increasing tumor growth inhibition in these models may have clinical application in improving outcomes of patients with EGFR L858R-driven NSCLC in 1L settings.

In the case of first- and second-generation TKIs, up to 60% of patients will develop an EGFR T790M mutation, while third-generation irreversible TKIs, like osimertinib, lead to C797S as the primary on-target resistance mutation. BLU-945 (compound 30) is a potent, reversible, wild-type-sparing inhibitor of EGFR+/T790M and EGFR+/T790M/C797S resistance mutants that maintains activity against the sensitizing mutations, especially L858R. Pre-clinical efficacy and safety studies supported progression of BLU-945 into clinical studies, and it is currently in phase 1/2 clinical trials for treatment-resistant EGFR-driven NSCLC.