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DRUG:

tigozertinib (BLU-945)

i
Other names: BLU-945, ZL-2313
Company:
Blueprint Medicines, ZAI Lab
Drug class:
EGFR inhibitor
Related drugs:
11ms
(SYMPHONY) Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC (clinicaltrials.gov)
P1/2, N=190, Active, not recruiting, Blueprint Medicines Corporation | Recruiting --> Active, not recruiting
Enrollment closed
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EGFR mutation • EGFR T790M • EGFR C797S • EGFR T790M + EGFR C797S
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Tagrisso (osimertinib) • tigozertinib (BLU-945)
over1year
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)
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 • P1/2 data • Combination therapy • Metastases
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EGFR (Epidermal growth factor receptor)
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EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR wild-type • EGFR C797S
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Tagrisso (osimertinib) • tigozertinib (BLU-945)
over1year
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
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BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CD74 (CD74 Molecule)
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BRAF V600E • EGFR mutation • BRAF V600 • EGFR exon 19 deletion • MET amplification • EGFR T790M • EGFR exon 20 insertion • ALK fusion • EGFR C797S • ALK mutation • ROS1 fusion • EGFR exon 20 mutation • ROS1 G2032R • ALK G1202R • ALK-ROS1 fusion • EGFR fusion
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Tagrisso (osimertinib) • Lorbrena (lorlatinib) • Augtyro (repotrectinib) • Rybrevant (amivantamab-vmjw) • tigozertinib (BLU-945) • NVL-655
over1year
Poorer outcomes in EGFR L858R-driven NSCLC treated with osimertinib may be addressed with novel combination of BLU-945 and osimertinib (AACR 2023)
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
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EGFR (Epidermal growth factor receptor) • TP53 (Tumor protein P53)
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TP53 mutation • EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR G719X
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Tagrisso (osimertinib) • Ameile (aumolertinib) • Lazcluze (lazertinib) • tigozertinib (BLU-945)
2years
BLU-945 or BLU-701 as single agents versus their combination with osimertinib in EGFR L858R driven tumor models (AACR-NCI-EORTC 2022)
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.
Preclinical
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EGFR (Epidermal growth factor receptor)
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EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR wild-type • EGFR C797S
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Tagrisso (osimertinib) • tigozertinib (BLU-945) • BLU-701
over2years
Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer. (PubMed, J Med Chem)
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.
Journal
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EGFR (Epidermal growth factor receptor)
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EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR wild-type • EGFR C797S
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Tagrisso (osimertinib) • tigozertinib (BLU-945)
over2years
Phase 1/2 Study of BLU-945 in Patients With Common Activating EGFR-Mutant Non-Small Cell Lung Cancer (IASLC-WCLC 2022)
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 is ongoing and approximately 30 sites will be open for enrollment across North America, Europe, and Asia.
Clinical • P1/2 data
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EGFR (Epidermal growth factor receptor)
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EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR exon 20 insertion • EGFR C797S • EGFR exon 20 mutation • EGFR T790M + EGFR C797S
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Tagrisso (osimertinib) • tigozertinib (BLU-945)
over2years
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)
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
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EGFR (Epidermal growth factor receptor)
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EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR exon 20 insertion • EGFR C797S • EGFR exon 20 mutation • EGFR T790M + EGFR C797S
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Tagrisso (osimertinib) • tigozertinib (BLU-945)
over2years
Emerging evidence of activity of BLU-945 in patients with advanced EGFR-mutant NSCLC utilizing circulating tumor DNA (ctDNA) in the phase 1/2 SYMPHONY study (AACR 2022)
Background: Despite recent advances in the treatment of EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), most patients treated with third-generation (3G) EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, experience disease progression. As of the data cut, BLU-945 was generally well tolerated in heavily pre-treated patients with EGFRm NSCLC. There was also early evidence of a reduction in EGFR mutation allele fractions by ctDNA.
P1/2 data • Clinical • Circulating tumor DNA
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EGFR (Epidermal growth factor receptor)
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EGFR mutation • EGFR T790M • EGFR C797S • EGFR T790M + EGFR C797S
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FoundationOne® Liquid CDx
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Tagrisso (osimertinib) • tigozertinib (BLU-945)
almost3years
BLU-945-1101: (SYMPHONY) Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC (clinicaltrials.gov)
P1/2, N=190, Recruiting, Blueprint Medicines Corporation | N=120 --> 190
Preclinical • Enrollment change
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EGFR (Epidermal growth factor receptor)
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EGFR mutation • EGFR T790M • EGFR C797S • EGFR T790M + EGFR C797S
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Tagrisso (osimertinib) • tigozertinib (BLU-945)
almost3years
BLU-701 tumour suppression and intracranial activity as a single agent and in combination with BLU-945 in models of non-small cell lung cancer (NSCLC) driven by EGFR mutations (BTOG 2022)
Consistent with its brain penetration properties, BLU-701 exhibited dose-dependent brain tumour inhibition that surpassed gefitinib and erlotinib in an EGFR ex19del PC9-luc CDX model in which cells were implanted intracranially or inoculated in the carotid artery (followed by migration to the brain). The in vivo activity of BLU-701 supports its potential as a treatment for patients with EGFR-mutated NSCLC, including those with the C797S mutation resistant to covalent 3rd-generation TKIs, such as osimertinib. Its intracranial penetrance and brain tumour response suggest potential benefits in treating and/or preventing brain metastases. Broader EGFR mutational coverage could be achieved with BLU-701 and BLU-945 in combination, which could potentially prolong responses.
Combination therapy
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EGFR (Epidermal growth factor receptor)
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EGFR mutation • EGFR exon 19 deletion • EGFR T790M • EGFR wild-type • EGFR C797S
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Tagrisso (osimertinib) • erlotinib • gefitinib • tigozertinib (BLU-945) • BLU-701
over3years
Clinical • New P1/2 trial • Preclinical
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EGFR (Epidermal growth factor receptor)
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EGFR mutation • EGFR T790M • EGFR C797S • EGFR T790M + EGFR C797S
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tigozertinib (BLU-945)