On September 17, 2020 Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, reported preclinical proof-of-concept data for BLU-945, an investigational precision therapy for patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) (Press release, Blueprint Medicines, SEP 17, 2020, View Source [SID1234565299]). The new preclinical data showed BLU-945 potently and selectively inhibited triple-mutant EGFR harboring the most common on-target resistance mutations to standard treatments for EGFRm NSCLC, resulting in robust anti-tumor activity in multiple lung cancer models. The data were made available today in a poster presentation at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020.
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Currently, there are no approved therapies for patients with osimertinib-resistant EGFRm NSCLC, and there is an urgent need for new therapies to address tumor resistance. BLU-945 was designed to potently inhibit triple-mutant EGFR harboring either the activating L858R or exon 19 deletion mutations combined with the acquired T790M and C797S mutations, the most common on-target resistance to standard EGFR inhibitors. In addition, BLU-945 was designed to be wild-type EGFR and kinome selective with the potential for improved tolerability and combination strategies.
"Our scientists at Blueprint Medicines specifically engineered BLU-945 to tackle treatment resistance in patients with EGFR-mutated lung cancer, and the preclinical proof-of-concept data we’re reporting today highlight the potential of BLU-945 to offer clinical benefit to patients along with a safety profile that enables combinations with other EGFR-targeted therapies across multiple treatment lines," said Marion Dorsch, Ph.D., Chief Scientific Officer of Blueprint Medicines. "The recent FDA approval of GAVRETO (pralsetinib) combined with our rapidly advancing EGFR research program highlight our broad commitment to patients with lung cancer, as well as the potential of our research platform to address the evolution of cancer and enable durable patient outcomes."
In preclinical data presented at the ESMO (Free ESMO Whitepaper) congress, BLU-945 inhibited triple mutant EGFR with sub-nanomolar potency and demonstrated greater than 900-fold selectivity over wild-type EGFR along with excellent overall kinome selectivity. In a triple mutant EGFR cell-line, BLU-945 potently inhibited the EGFR pathway, while osimertinib demonstrated limited activity. BLU-945 monotherapy resulted in robust anti-tumor activity in multiple cell line-derived and patient-derived xenograft (PDX) models of triple mutant EGFR NSCLC. In addition, BLU-945 treatment in combination with osimertinib or gefitinib resulted in tumor regression in a triple mutant EGFR NSCLC PDX model derived from a patient with progressive disease following five lines of prior therapy. BLU-945 was also highly active in an intracranial disease model.
Based on these preclinical proof-of-concept data, Blueprint Medicines plans to develop BLU-945 as a monotherapy and in combination with other agents for the treatment of patients with osimertinib-resistant EGFR NSCLC. The company plans to initiate an international Phase 1 dose-escalation trial of BLU-945 in the first half of 2021.
In addition, Blueprint Medicines expects to nominate a brain-penetrant development candidate targeting double mutant EGFR harboring the activating L858R or exon 19 deletion mutations and the acquired C797S mutation, the most common on-target resistance profile following first-line osimertinib, in the fourth quarter of 2020. The company plans to develop this candidate as both a monotherapy and in combination with BLU-945.
About EGFRm NSCLC
Lung cancer is the leading cause of cancer death worldwide. Among the 80 to 85 percent of lung cancers classified as NSCLC, about 10 to 15 percent of cases in the US and Europe and about 40 to 50 percent of cases in Asia are caused by activating EGFR mutations. In recent years, the introduction of EGFR targeted therapies including osimertinib has dramatically improved outcomes in patients with EGFRm NSCLC. However, the emergence of tumor resistance represents an urgent medical need and there are no approved therapies for osimertinib-resistant EGFRm NSCLC.
About BLU-945
Derived from Blueprint Medicines’ proprietary research platform, BLU-945 is designed to treat patients with osimertinib-resistant EGFRm NSCLC. In preclinical studies, BLU-945 potently inhibited triple-mutant EGFR harboring either the activating L858R or exon 19 deletion mutations combined with the acquired T790M and C797S mutations, the most common on-target resistance to first-generation EGFR inhibitors and the third-generation EGFR inhibitor osimertinib, respectively. In addition, BLU-945 demonstrated excellent selectivity for triple-mutant EGFR over wild-type EGFR and other clinically relevant kinases, potentially enabling well-tolerated combinations with other EGFR inhibitors. Blueprint Medicines owns worldwide development and commercialization rights for BLU-945.