Blueprint Medicines presented data from two patients showing that a combination of its RET inhibitor BLU-667 and AstraZeneca’s tyrosine kinase inhibitor Tagrisso could potentially beat treatment resistance in patients with non-small cell lung cancer (NSCLC) who have a specific mutation.

The patients had advanced EGFR-mutant NSCLC which had worsened despite receiving standard targeted therapy. They also had RET fusions, a key driver in some cancers. After eight weeks of treatment with BLU-667 and Tagrisso, both patients had a partial response and a 78% reduction in target tumors as measured by Response Evaluation Criteria in Solid Tumors (RECIST). The data were presented Wednesday at the International Association for the Study of Lung Cancer’s World Conference on Lung Cancer and will be published online in Cancer Discovery.

Adverse events were low-grade, and both patients are still being treated with the combination. Based on these data, Blueprint is looking into testing the combination in more patients with the same treatment-resistant EGFR-mutant cancer and who also have an RET fusion.

"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, non-small cell lung cancer," said senior author Lecia Sequist, M.D., a medical oncologist at Massachusetts General Hospital Cancer Center and an associate professor of medicine at Harvard Medical School, in a release. "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 eight 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 one of four kinase inhibitors that Blueprint has in phase 1 development. At this year’s AACR meeting, the Cambridge, Massachusetts-based biotech reported early data from its ARROW trial, which is testing the drug in RET-altered solid tumors, including NSCLC and medullary thyroid cancer (MTC). The proof-of-concept data showed that tumors shrank in 84% of evaluable patients, who had advanced disease and many of whom had received prior treatments, including immunotherapy, multikinase therapy and chemotherapy.

The trial tested a daily dose of BLU-667 ranging from 30 mg to 600 mg. It will move forward with the optimized dose and increase enrollment to investigate the drug’s activity in different tumor types. RET mutations, which are found in 60% of patients with MTC and 1% to 2% of patients with NSCLC, are also implicated in breast and colon cancers, the company said.

"It’s important to remember that although RET is relatively rare in terms of cancer-causing mutations, it does affect 10,000 lung cancer patients worldwide every year," said Blueprint Chief Medical Officer Anthony Boral, M.D., Ph.D., at the time. "These patients are not yet benefiting from targeted cancer therapies that other patient populations are benefiting from."

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