Conclusions:In the FLAURA China study, median OS was extended by 7.4 months in the osimertinib arm vs comparator EGFR-TKI arm in the first-line treatment of pts with EGFRm advanced NSCLC, consistent with the global population where osimertinib extended OS by 6.8 months. Safety data were comparable with the global population.Clinical trial identification: NCT02296125. Editorial acknowledgement:We thank Natalie Griffiths, PhD, from iMed Comms, who provided medical writing support funded by AstraZeneca.Legal entity responsible for the study: AstraZeneca.
BACKGROUND: Non-small cell lung cancer (NSCLC) represents 80% of lung cancers, the second leading cause of cancer deaths globally. Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are genomic drivers in a molecular sub-type of NSCLC that is sensitive to tyrosine kinase inhibitors (TKIs). Third-generation, irreversible TKIs, such as osimertinib and lazertinib, have become standard of care and are now widely used as first-line therapy in EGFR-driven metastatic NSCLC. However, resistance invariably arises during treatment. The C797S mutation is the most frequent on-target resistance mechanism in response to third-generation TKIs when used in the first-line setting. There are currently no approved therapies for patients who progress with a C797S mutation. Although first-generation TKIs inhibit EGFR with a C797S mutation, they carry liabilities of 1) insufficient selectivity over wild-type (WT) EGFR, which precludes maximal target coverage and results in dose-limiting adverse events; and 2) limited brain penetration. METHODS: BLU-701 activity was tested in biochemical assays for EGFR mutants and EGFR WT. Cellular activity was evaluated by a phosphorylation specific EGFR AlphaLisa assay in WT cell lines or those expressing EGFR mutations. The in vivo antitumor activity of BLU-701 was assessed in a PC9 ex19del cell line-derived tumor xenograft (CDX) model. RESULTS: We have developed an orally available, single-digit nanomolar, brain-penetrant, WT-sparing, reversible EGFR inhibitor that is active against the C797S resistance mutation. BLU-701 is equally potent against both the sensitizing mutations ex19del and L858R, and the resistance double mutants ex19del/C797S and L858R/C797S. BLU-701 is brain penetrant (Kpu,u >0.9) and demonstrates a selectivity over WT EGFR that compares favorably with osimertinib. Oral administration of BLU-701 to PC9 ex19del tumor-bearing mice resulted in strong and prolonged pathway suppression and tumor regression at tolerated doses. CONCLUSION: Due to its potent pharmacological activity and selectivity for mutant EGFR, BLU-701 has the potential to demonstrate activity in first-line and resistance settings as a single agent and in combination therapy, addressing potential tumor heterogeneity. The pre-clinical data described here supports the clinical development of BLU-701 in EGFR-driven NSCLC. Citation Format: Chiara Conti, John Campbell, Rich Woessner, Jian Guo, Yoav Timsit, Maria Iliou, Scott Wardwell, Alison Davis, Sharon Chicklas, John Hsieh, Meredith Eno, Omar Ahmad, Dilinie Fernando, Kevin Barvian, Joseph Kim, Steven Kazmirski, Emanuele Perola, Tom Dineen, Victoria Brown, Timothy Guzi, Ayşegül Özen, Faith Stevison, Caitlin Utt, Clare Medendorp, Robert Meissner, Marion Dorsch, Klaus Hoeflich. BLU-701 is a highly potent, brain-penetrant and WT-sparing next-generation EGFR TKI for the treatment of sensitizing (ex19del, L858R) and C797S resistance mutations in metastatic NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1262.
Background: EGFR-activating mutations (L858R and ex19del) are major drivers (15-47%) of lung adenocarcinoma. EGFR TKI development has changed the treatment paradigm for EGFR-mutant (EGFR+) NSCLC. However, tumors often develop acquired resistance mutations to current TKIs leading to clinical progression. EGFR+/T790M is the most prevalent acquired resistance mutation after first- and second-generation TKI treatment. Osimertinib, a third-generation TKI which targets EGFR+/T790M, can overcome this resistance, but faces further resistance within 10-18 months. EGFR+/C797S is the most significant on-target resistance mechanism to osimertinib, leading to EGFR+/T790M/C797S double resistant mutants. There are currently no approved targeted therapies for patients with EGFR+/T790M/C797S NSCLC. BLU-945 is a potent and highly selective inhibitor of the EGFR+/T790M/C797S and EGFR+/T790M mutations, with in vivo activity in subcutaneous and intracranial EGFR-mutant tumor models. Method: In vivo antitumor activity of BLU-945 was evaluated in engineered triple mutant cell line-derived xenograft (CDX) models and osimertinib-resistant patient-derived xenograft (PDX) models of NSCLC. Plasma and tumor samples were collected for future pharmacokinetic and pharmacodynamic analyses. In vivo activity was also evaluated in an intracranial implantation model using luciferase-expressing YU-1097 patient-derived-cells harboring EGFRex19del/T790M/C797S resistance mutations, with the tumor burden of intracranial lesions measured by bioluminescence imaging. Results: Oral administration of BLU-945 to tumor-bearing mice showed potent EGFR pathway inhibition and significant single-agent antitumor activity at well-tolerated doses in the engineered osimertinib-resistant EGFRL858R/T790M/C797S CDX model, and an EGFRex19del/T790M/C797S PDX model. In addition, combination of BLU-945 with osimertinib showed enhanced antitumor activity compared with single-agent treatment in the EGFRex19del/T790M/C797S PDX model. Pharmacodynamic assays revealed treatment with BLU-945 resulted in marked inhibition of EGFR, AKT and ERK phosphorylation in the EGFRL858R/T790M/C797S CDX and EGFRex19del/T790M/C797S PDX models. BLU-945 also demonstrated potent activity in a patient-derived model of EGFRex19del/T790M/C797S implanted intracranially. Conclusion: BLU-945 is a potent, selective, and orally available fourth-generation EGFR inhibitor with robust antitumor activity in osimertinib-resistant NSCLC models grown subcutaneously and intracranially. BLU-945 shows activity as a single agent and in combination with other EGFR inhibitors. Clinical development of BLU-945 is expected in 2021. Citation Format: Sun Min Lim, Chae Won Park, Zhuo Zhang, Rich Woessner, Tom Dineen, Faith Stevison, John Hsieh, Meredith Eno, Doug Wilson, John Campbell, Caitlin Utt, Faris Albayya, Nicolas Lamontagne, Marion Dorsch, Klaus Hoeflich, Byoung Chul Cho, Stefanie Schalm. BLU-945, a fourth-generation, potent and highly selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with intracranial activity, demonstrates robust in vivo antitumor activity in models of osimertinib-resistant non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1467.
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