AACR: Blueprint wants to make resistance to AstraZeneca's Tagrisso futile in lung cancer

About seven out of 10 patients with EGFR-mutated lung cancer progress after taking AstraZeneca’s Tagrisso, and a third of those patients see their cancer spread to the brain. Blueprint wants to change that.

The biotech’s first proof-of-concept data for BLU-945 will be presented at the American Association for Cancer Research conference in New Orleans, which begins today and runs through April 13. BLU-945 is a precision medicine in development for advanced EGFR-mutant non-small cell lung cancer (NSCLC) to prevent or treat tumor resistance that occurs with Tagrisso. Blueprint is hoping that BLU-945 will prolong the patient benefit seen with the AstraZeneca med.

Tagrisso is the standard-of-care for patients with NSCLC whose tumors harbor mutations in the EGFR gene. But eventually, the cancer cells begin to resist the therapy and develop new mutations allowing the disease to evade treatment. Most of the patients in Blueprint's trial have received at least three lines of treatment already, including Tagrisso.

“With all the progress that was made with the third-generation EGFR … resistance continues to be a concern down the road. That’s the focus of what we are trying to do at Blueprint,” said Fouad Namouni, president of R&D at Blueprint, in an interview.

BLU-945 is designed to be highly selective and potent, without causing adverse events. While resistance has long been a known issue with EGFR treatments like Tagrisso, combination studies have been difficult because adding meds tends to create toxicity, Namouni explained. Blueprint therefore had to design a molecule that could fight back against resistance, while not touching the so-called wild-type version of the EGFR gene, which can lead to toxicity.

The early readout from the phase 1/2 Symphony trial shows the first safety and clinical activity data, a major milestone for the Massachusetts biotech. Namouni said BLU-945 seems to be doing what they designed it to do while patients receive standard-of-care.

Results from the higher dose group are hinting at tumor shrinkage too. One patient experienced a partial response as of the March 9 cut off date.

As for safety, common adverse events included nausea, headache, difficulty breathing and vomiting, among others. The company did observe one incident of dose-limiting toxicity in a patient who experienced high levels of an enzyme called transaminases that can point to problems with the liver. The dose was interrupted, and the patient improved. Blueprint said that there were no study discontinuations.

Namouni said the safety profile suggests that the adverse events are not tied to inhibition of the wild-type EGFR.

For now, Blueprint is working to get the dosing just right, which will eventually be used for the phase 2 arm of the study.

Moving forward, Blueprint will initiate an additional cohort in the Symphony trial combining BLU-945 with Tagrisso this quarter. The company announced today a clinical supply agreement with AstraZeneca for work on the study as well as the early-stage Harmony program for BLU-701.

“They have good expertise in the field of EGFR-mutated lung cancer,” Namouni said of AstraZeneca. He said Blueprint is happy to get to work with the experienced team at the U.K. pharma and share learnings in this difficult disease.

The ultimate goal is to prevent the resistance from happening in the first place, Namouni said. Blueprint hopes in the next year to move into testing BLU-945 in the firstline setting in combination with Tagrisso.

“We're trying to see how we can help prevent the resistance from occurring to start with, just put pressure very early on,” Namouni said. “We always think that your best shot—if not sometimes your most important shot—in cancer is to start treating as early as you can.”