Blueprint Medicines Announces BLU-945 Proof-of-Concept Data Supporting Initiation of Comprehensive Combination Development Strategy in EGFR-mutant Non-Small Cell Lung Cancer
-- Early dose escalation data show dose-dependent reductions in ctDNA and tumor burden --
-- Generally well-tolerated with most AEs Grade 1 or 2, supporting continued dose escalation --
-- Initiating SYMPHONY trial cohort to evaluate BLU-945 in combination with osimertinib --
-- Clinical trial supply agreement signed with
Early data from the ongoing Phase 1 dose escalation part of the SYMPHONY trial showed dose-dependent decreases in circulating tumor DNA (EGFR variant allele fractions) and radiographic tumor reductions, including a partial response (PR) in a patient treated with 400 mg once daily (QD), the highest dose tested as of the data cutoff date. Pharmacokinetic results showed BLU-945 exposures at higher doses were associated with broad EGFR mutation coverage, including the activating L858R mutation with or without the osimertinib-resistant C797S mutation. BLU-945 was generally well-tolerated, with no significant adverse events (AEs) associated with wild-type EGFR inhibition. The maximum tolerated dose and recommended Phase 2 dose have not yet been identified, and dose escalation is continuing.
"Today, targeted therapies are the mainstay treatment for EGFR-mutant lung cancer, but tumor resistance emerges in the majority of patients, driving mutational heterogeneity and disease progression. Innovative treatment strategies, including targeted therapy combinations, are urgently needed to prevent or treat this mutational heterogeneity and prolong patient benefit," said
"We believe BLU-945 is distinguished from other EGFR-directed therapies, based on its ability to inhibit the most difficult-to-target EGFR mutations while maintaining a wide therapeutic index over wild-type EGFR, a known driver of toxicity. As a result, BLU-945 has significant potential as a combination partner with other targeted therapies and broad-acting agents," said Fouad Namouni, M.D., President, Research & Development at
BLU-945: Data from the Phase 1/2 SYMPHONY Trial
As of a data cutoff date of
BLU-945 was generally well-tolerated at all doses tested. The most common AEs (regardless of relationship to BLU-945; ≥10 percent) were nausea, headache, fatigue, cough, dyspnea, vomiting, hyponatremia, dry mouth and anemia. Reported AEs associated with wild-type EGFR inhibition were infrequent and low grade, including rash (one patient; Grade 1) and diarrhea (three patients; all Grade 1). One dose-limiting toxicity (Grade 3 transaminitis) occurred in the 400 mg QD cohort, which improved with dose interruption. There were no treatment discontinuations due to AEs.
Pharmacokinetic data showed dose-proportional plasma concentrations, with exposures at increasing doses consistent with broad EGFR mutation coverage, based on preclinical activity thresholds. Mean plasma exposures at doses of 100 mg QD or higher exceeded the IC90 for mutants harboring the T790M and C797S resistance mutations, regardless of activating mutation. In addition, mean plasma exposure at 400 mg QD exceeded the IC90 for mutants harboring the activating L858R mutation with or without the C797S mutation.
The SYMPHONY trial is one of the first oncology studies to analyze plasma ctDNA via real-time next-generation sequencing to assess tumor biology and early drug activity. Results for patients with detectable T790M and C797S allele fractions at baseline and available post-baseline assessments showed dose-dependent reductions in both variant allele fractions. In patients treated with 400 mg QD, all detectable T790M and C797S allele fractions declined, including three that fell below the limit of detection (clearance).
Patients with measurable target lesions at baseline and at least one post-baseline scan were evaluable per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In a heavily pre-treated population, higher BLU-945 doses led to increased antitumor activity. Tumor shrinkage was observed in patients treated with 200-400 mg QD, including an unconfirmed PR1 in a patient treated with 400 mg QD. This patient had NSCLC harboring exon 19 deletion, T790M and C797S mutations, and previously received platinum-based chemotherapy, erlotinib and osimertinib with a best response of stable disease.
Investor Conference Call Information
BLU-701 and BLU-945 were designed to provide broad coverage of common activating and on-target resistance mutations, spare wild-type EGFR and other kinases to help limit off-target toxicities, and prevent or treat central nervous system (CNS) metastases. These preclinical profiles may enable BLU-701 and BLU-945 to become the backbones of a range of combination strategies across lines of therapy. The Phase 1/2 SYMPHONY trial (NCT04862780) of BLU-945 and the Phase 1/2 HARMONY trial (NCT05153408) of BLU-701 are currently ongoing for patients with EGFR-mutant NSCLC.
BLU-451 is a selective and potent inhibitor of EGFR exon 20 insertion-positive NSCLC. Based on preclinical data, BLU-451 potently inhibited all common EGFR exon 20 insertion variants with marked selectivity over wild-type EGFR and off-target kinases, and has shown CNS penetration.
To learn about ongoing or planned clinical trials, contact Blueprint Medicines at firstname.lastname@example.org or 1-888-BLU-PRNT (1-888-258-7768). Additional information is available at blueprintclinicaltrials.com or clinicaltrials.gov.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding
About Blueprint Medicines
Blueprint Medicines is a global precision therapy company that invents life-changing therapies for people with cancer and blood disorders. Applying an approach that is both precise and agile, we create medicines that selectively target genetic drivers, with the goal of staying one step ahead across stages of disease. Since 2011, we have leveraged our research platform, including expertise in molecular targeting and world-class drug design capabilities, to rapidly and reproducibly translate science into a broad pipeline of precision therapies. Today, we are delivering approved medicines directly to patients in the United States and Europe, and we are globally advancing multiple programs for systemic mastocytosis, lung cancer and other genomically defined cancers, and cancer immunotherapy. For more information, visit www.BlueprintMedicines.com and follow us on Twitter (@BlueprintMeds) and LinkedIn.
1 An unconfirmed PR is a PR in which tumor reduction ≥30% has occurred, but has not yet been confirmed via a subsequent scan.
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