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Treatment Resistance in EGFR-Mutant NSCLC & Acquired RET Fusion

doi: 10.1097/01.COT.0000547474.61589.24
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TORONTO—Two clinical cases demonstrating proof-of-concept for BLU-667 in combination with osimertinib in treatment-resistant, EGFR-mutant non-small cell lung cancer (NSCLC) were presented at the IASLC 19th World Conference on Lung Cancer. In both cases, the combined agents overcame resistance to standard treatment due to an acquired RET fusion, resulting in significant tumor reductions.

“The combination of two highly selective agents, BLU-667 and osimertinib, has the potential to become an important new tool to overcome treatment resistance in a subset of patients with EGFR-mutant NSCLC,” said Lecia V. Sequist, MD, PhD, Medical Oncologist at Massachusetts General Hospital Cancer Center; Associate Professor of Medicine, Harvard Medical School; and senior author of the oral presentation and paper.

“We found that two pre-treated patients with advanced disease, who acquired RET fusions resulting in resistance to standard therapy, each showed a meaningful response only 8 weeks after initiating the combination regimen. These results are highly encouraging and support further study of BLU-667 in combination with osimertinib in additional patients.”

BLU-667 is an investigational precision therapy designed to potently and selectively inhibit RET alterations including resistance mutations. It is currently being evaluated in the global phase I ARROW clinical trial in patients with RET-altered NSCLC, medullary thyroid cancer (MTC), and other solid tumors.

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Data Highlights

The conference presentation included preclinical data and two clinical cases highlighting the potential of combining BLU-667 and osimertinib to overcome treatment resistance in EGFR-mutant NSCLC.

The clinical cases included two patients treated with BLU-667 and osimertinib under investigator-sponsored protocols. The patients had advanced EGFR-mutant NSCLC that progressed on standard targeted therapy, with an acquired RET fusion identified via lung biopsy. Radiographic scans after 8 weeks showed both patients experienced a partial response (both pending confirmation), with each achieving a 78 percent reduction in target tumors per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The combination was well-tolerated, and all reported adverse events were grade 1 or 2. Both patients continued to receive treatment as of Sept. 26, 2018.

Based on these data, researchers plan to explore opportunities to evaluate the combination of BLU-667 and osimertinib in additional patients with treatment-resistant, EGFR-mutant NSCLC harboring a RET fusion.

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RET-Altered Solid Tumors

RET-activating fusions and mutations are a key disease driver in many cancer types, including NSCLC and MTC. RET fusions are implicated in approximately 1-2 percent of patients with NSCLC, while RET mutations are implicated in approximately 60 percent of patients with MTC. In addition, oncogenic RET alterations are observed at low frequencies in colorectal, breast, pancreatic, and other cancers, and RET fusions have been observed in patients with treatment-resistant, EGFR-mutant NSCLC.

Currently, there are no approved therapies that selectively target RET-driven cancers, though there are several approved multi-kinase inhibitors with RET activity being evaluated in clinical trials. Thus far, clinical activity attributable to RET inhibition has been uncertain for these inhibitors, likely due to insufficient inhibition of RET and off-target toxicities. There is a need for precision therapies that provide durable clinical benefit by selectively targeting RET alterations and resistance mutations.

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More on BLU-667

BLU-667 is an investigational, once-daily oral precision therapy specifically designed for highly potent and selective targeting of oncogenic RET fusions, mutations, and resistance mutations. In preclinical studies, BLU-667 consistently demonstrated sub-nanomolar potency against the most common RET fusions, activating mutations, and resistance mutations.

In addition, BLU-667 demonstrated markedly improved selectivity for RET compared to approved multi-kinase inhibitors, including more than 80-fold improved potency for RET versus VEGFR2. By suppressing primary and secondary mutants, BLU-667 has the potential to overcome and prevent the emergence of clinical resistance. This approach is expected to enable durable clinical responses across the range of RET alterations, with a favorable safety profile.

In April 2018, researchers presented proof-of-concept data from its ongoing phase I ARROW clinical trial of BLU-667 in patients with RET-altered NSCLC, MTC, and other advanced solid tumors at the American Association for Cancer Research Annual Meeting. The data showed broad and robust clinical activity across multiple tumor types and RET genotypes, including in patients whose disease had progressed on prior multi-kinase therapy. Radiographic tumor reductions were observed in 84 percent of patients with RET-altered solid tumors and measurable target lesions. The data also showed that BLU-667 was generally well-tolerated, and most adverse events reported by investigators were grade 1. Global enrollment in the dose expansion portion of the phase I ARROW clinical trial is ongoing.

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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