How to retarget cancers that have evaded targeted therapy

Targeted therapy drugs transformed the outlook for people with the rare cancers known as gastrointestinal stromal tumors, enabling some to survive a decade or longer. A fraction of GIST patients, however, never respond to treatment. And most of those who do respond eventually relapse because cancer cells evolve and become resistant to the drugs designed to stop them. It’s the big limitation of targeted therapies.

Photograph: Michael Heinrich, M.D., with patient Victoria Castle (OHSU/Kristyna Wentz-Graff)

But researchers now have found a way to retarget GISTs that have evaded targeted therapy. The new agent is being tested in a phase 1 clinical trial at OHSU and other medical centers, and the company developing it has announced plans to begin a phase 3 trial in the first half of 2018.

“We have seen many patients with a good response to treatment, even after many failed prior treatment attempts with conventional drugs,” said Michael Heinrich, M.D., an OHSU Knight Cancer Institute scientist and VA Portland Health System oncologist. “Some of the lesions disappear. It’s really quite dramatic.”

The first targeted therapies for GISTs were drugs designed to block signaling by a class of proteins called receptor tyrosine kinases. About 80 percent of GISTs have mutations in a receptor tyrosine kinase called KIT. The mutations alter the KIT protein so that it no longer works as a control signal. Instead, it remains stuck in an “on” configuration, thus driving a chain of events that result in tumor formation and growth. Drugs such as imatinib (Gleevec) bind with KIT to stop it from driving cancer growth.

Tumors rebound when additional mutations in the KIT protein prevent imatinib from binding effectively. A fraction of GIST patients never respond to imatinib or other approved targeted therapies because their tumors are driven by mutations in a different protein called PDGFRA.

Heinrich and others uncovered all of the ways that GISTs manage to evade targeted therapies, and that work caught the attention of Blueprint Medicines, a biotech startup in Cambridge, Massachusetts. (Blueprint’s scientific co-founders include Knight Cancer Institute Director Brian Druker, M.D., and Nick Lyden, Ph.D., the pharmaceutical industry biochemist who worked with Druker on the development of imatinib, which increased life expectancy for people with chronic myeloid leukemia to a level almost equal to that of the general population.)

The company made a drug, BLU-285, that is able to halt both KIT and PDGFRA mutant proteins that drive GISTs. All of the existing drugs used to treat GISTs bind to the inactive conformation of the KIT protein. Blueprint’s chemists developed a compound that would bind with the active conformation of KIT and PDGFRA, including mutant forms that are resistant to existing drugs. They described the details in a paper co-authored with Heinrich in the journal Science Translational Medicine.

blu-285 image
Illustrations of inhibitory activity (red circles) on the kinase family of proteins showing that BLU-285, a newly developed inhibitor for the treatment of GIST, has fewer off-target effects than existing drugs used to inhibit receptor tyrosine kinases. (E.K. Evans et al., Science Translational Medicine)

In the phase 1 trial, Heinrich and others have given the orally administered BLU-285 to more than 100 people with GIST cancers, most of whom previously received multiple rounds of treatment with imatinib and related drugs. As of mid-October, 30 patients with KIT-driven GIST and 31 patients with PDGFR-driven GIST had been evaluated for response.

Tumors shrank in 67 percent of the people with KIT-driven cancers, the company reported. The objective response rate (the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period) was 17 percent. Median progression-free survival (the length of time that people lived without tumors growing) was 11.5 months among those with KIT-driven cancers.

Among those with PDGFRA-driven GISTs, tumors shrank in all 31 of the subjects evaluated. The company reported an objective response rate of 71 percent, and estimated a 12-month progression-free survival of 78 percent. (Median progression free survival was not yet reached).

BLU-285 was well-tolerated, and most adverse events reported by investigators were grade 1 or 2. The most common included nausea, fatigue, edema, vomiting and diarrhea. Investigators reported more severe, grade 3 or higher, treatment-related adverse events in about a third of subjects, and six people (5 percent) discontinued treatment due to adverse events.

It remains to be seen to how readily GIST cancers will evolve  mutations to resist BLU-285. And Heinrich cautioned that not all driver mutations can be targeted. “There still are situations where we know what’s wrong but we don’t have anything to offer,” he said. But for now, he said, the data are looking “spectacularly better than what we had to offer before.”

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Citations

A precision therapy against cancers driven by KIT/PDGFRA mutations, Erica K. Evans, Alexandra K. Gardino, Joseph L. Kim, Brian L. Hodous, Adam Shutes, Alison Davis, Xing Julia Zhu, Oleg Schmidt-Kittler, Doug Wilson, Kevin Wilson, Lucian DiPietro, Yulian Zhang, Natasja Brooijmans, Timothy P. LaBranche, Agnieszka Wozniak, Yemarshet K. Gebreyohannes, Patrick Schöffski, Michael C. Heinrich, Daniel J. DeAngelo, Stephen Miller, Beni Wolf, Nancy Kohl, Timothy Guzi, Nicholas Lydon, Andy Boral and Christoph Lengauer. Science Translational Medicine (November 1, 2017)

Blueprint Medicines Announces New Data from Ongoing Phase 1 Clinical Trial of BLU-285 in Patients with Advanced Gastrointestinal Stromal Tumors Showing Strengthened Clinical Activity across Spectrum of KIT and PDGFRα Genotypes (November 10, 2017)

 

Disclosures: Heinrich is an investigator for Blueprint Medicines’ ongoing Phase 1 GIST study. He has served as a consultant for Blueprint Medicines, Novartis, MolecularMD. He has received research funding from Blueprint Medicines and has provided expert testimony for Novartis. Brian Druker, M.D., director of the OHSU Knight Cancer Institute is a scientific co-founder of Blueprint Medicines. He is not involved in the clinical trial of BLU-285.