BLU-945 Shows Early Antitumor Activity in EGFR-Mutated NSCLC Models

In preclinical models of triple-mutated EGFR-positive non–small cell lung cancer (NSCLC), the investigational agent, BLU-945 induced robust antitumor responses, according to results presented at the 2020 European Society of Medical Oncology (ESMO) Virtual Congress.1

Additionally, the findings showed that BLU-945 potently and selectively inhibited triple-mutant EGFR, harboring the most common on-target resistance mutations to standard EGFR-targeted therapies, including the third-generation EGFR TKI osimertinib (Tagrisso). Specifically, BLU-945 inhibited triple-mutant EGFR with sub-nanomolar potency and it also showed a greater than 900-fold selectivity over wild-type EGFR plus overall kinome selectivity.

Curently, no FDA-approved treatments are available for patients with EGFR-mutant NSCLC who develop resistance to osimertinib, which is available for the first-line treatment of patients with EGFR-mutant NSCLC, and as a second-line treatment for patients with EGFR-mutant disease who acquire the T790M mutation. Therefore, there is an unmet need for novel therapies that can address this tumor resistance, according to Blueprint Medicines, the developer of BLU-945.2 For example, C797S is the most frequent on-target resistance mechanism to osimertinib.

BLU-945 is a fourth-generation EGFR TKI that potently inhibits triple-mutant EGFR that harbors either activated L858R or exon 19 deletion mutations, plus acquired T790M and C797S mutations, and selective to wild-type EGFR and kinome. BLU-945 is found to inhibit 1% of the kinome at more than 90% at a concentration of 3 μM, and a selectivity profile that enables combinations to cover a wide spectrum of resistant mechanisms.

In a virtual poster presentation during the 2020 ESMO Virtual Congress, the investigators noted that the EGFR TKI is designed to target these triple-mutant models following a frontline first-generation EGFR TKI and second-line osimertinib, and that a second fourth-generation EGFR TKI aims to target double-mutant EGFR patients following frontline osimertinib. BLU-945 also inhibits the EGFR pathway in models with exon 10 deletion/T790M/C797S mutations and L858R/T790M/C797S mutation–driven Ba/F3 cell lines.

Additional data showed that oral administration of BLU-945 has antitumor activity on EGFR-positive/T790M and EGFR-positive/T790M/C797S–driven cancers. The agent led to significant tumor regression in an NCI-H1975 NSCLC CDX (L858R/T790M) model similar to covalent osimertinib, and an osimertinib-resistant Ba/F3 CDX (exon 19 deletion/T790M/C797S) model.

Single-agent BLU-945 also resulted in robust antitumor 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 (Iressa) was associated with significant tumor regression in a triple-mutant EGFR NSCLC PDX model, which was derived from a patient with progressive disease following 5 lines of previous treatment. The novel agent was also found to be highly active in an NCI-H1975 L858R/T790M-luc intracranial model, suggesting that it has intracranial activity when administered orally.

BLU-945 was also examined in combination with gefitinib, and also with the third-generation EGFR TKI osimertinib. These data showed that these combinations both had enhanced antitumor activity compared with single-agent BLU-945 in an EGFR-positive/T790M/C797S-driven PDX model, which the investigators noted suggest potential for both monotherapy and combination therapy in the clinical setting.

"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," Marion Dorsch, PhD, chief scientific officer of Blueprint Medicines, stated in the press release. "The recent FDA approval of pralsetinib (Gavreto) 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."

Based on these findings, BLU-945 will move forward in drug development and be tested as a single agent and in combination with other therapies for the treatment of patients with osimertinib-resistant EGFR-positive NSCLC. Blueprint Medicines stated that it plans to initiate an international dose-escalation phase 1 trial of BLU-945 in the first half of 2021.

Moreover, the company added that it expects to nominate a brain-penetrant development candidate that targets double-mutant EGFR harboring activating L858R or exon 19 deletion mutations, and the acquired C797S mutation, in the fourth quarter of 2020. This candidate is expected to be explored as both a monotherapy and in combination with BLU-945.

_References

_{1. Schalm S, Dineen T, Lim SM, et al. BLU-945, a highly potent and selective 4th generation EGFR TKI for the treatment of EGFR T790M/C797S resistant NSCLC. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 1296P.}

_{2. Blueprint Medicines presents foundational preclinical data for BLU-945 showing robust anti-tumor activity in treatment-resistant EGFR-mutated lung cancer at ESMO Virtual Congress 2020. News release. Blueprint Medicines. September 17, 2020. September 19, 2020. https://prn.to/3iOSqFx.}