EORTC-NCI-AACR 2016: ‘Remarkable Antitumor Activity’ in Phase I Studies of PDGFRα and KIT Mutation Inhibitors
Two studies at the 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Munich, Germany focused on the inhibition of mutations in the KIT and PDGFRα oncogenes. These genes provide instructions for making proteins that are part of a family of proteins called receptor tyrosine kinases, which are involved in cell signaling. When the genes are mutated, signaling malfunctions, leading to cell proliferation and cancer.
One trial focused on BLU-285, a treatment for gastrointestinal stromal tumors (GIST), and the second trial focused on DCC-2618, which also targets these mutations in GIST, but a broader range of alterations in these genes. DCC-2618 showed activity not only in GIST, but also in glioblastoma multiforme.
BLU-285
More than 85% of gastrointestinal stromal tumors are driven by specific mutations in KIT and PDGFRα. There is no effective treatment for GIST at present and although imatinib, a tyrosine kinase inhibitor, can provide some benefit initially, most patients will eventually experience disease progression, often driven by genetic changes known as secondary activation loop mutations. These activation loop mutations are often resistant to all approved kinase inhibitors.
In an ongoing phase I trial presented at the Symposium (Abstract 6LBA), 36 patients (as of November 1, 2016) with advanced GIST with mutations in either KIT or PDGFRα, some of whom had cancer that had continued to advance despite at least two previous treatments with tyrosine kinase inhibitors such as imatinib, were given BLU-285 once a day on a continuous schedule at doses ranging from 30 to 400 mg/d. BLU-285 is the first drug to selectively target activation loop mutations. It is an oral, investigational drug being studied for safety and clinical activity in patients with metastatic and treatment-resistant GIST.
Michael Heinrich, MD, of the Oregon Health & Science University, told the Symposium, “Although we are still increasing the doses in the phase I trial to establish the recommended dose, BLU-285 has shown remarkable antitumor activity, with a response seen at the lowest dose level. Computed tomography and magnetic resonance imaging scans showed that tumors shrank in 14 out of 15 evaluable PDGFRα patients, and 5 out of 13 evaluable KIT patients. In addition, there was a more than ten-fold reduction in levels of PDGFRα-mutated DNA circulating in the blood, and we saw this even before the imaging scans confirmed that tumors were shrinking. The treatment was well-tolerated to date, and 27 patients continue to be treated in the study, while nine discontinued treatment due to their disease progressing.”
Kapil Dhingra, MBBS, MD, PhD, a member of the executive committee for the Symposium, said, “The data from this study to date show that GISTs with PDGFRα and KIT mutations, including activation loop mutations, are sensitive to BLU-285, a potent and highly selective tyrosine kinase inhibitor. Preliminary clinical efficacy has been seen, even at very low doses, and it is active in patients with advanced disease, many of whom had disease that had progressed on previous treatments. Liquid biopsies showed a large reduction in circulating tumor DNA within 2 weeks of starting treatment.”
DCC-2618
A new drug called DCC-2618 targets the same oncogenes in GIST as BLU-285, but a broader range of alterations in these genes. It is being tested in a phase I trial in patients with advanced GIST and other advanced cancers, including one patient with glioblastoma multiforme. The results of the phase I trial were presented at the Symposium (Abstract 7LBA).
Patients with molecular alterations in KIT or PDGFRα genes were prioritized for enrollment in the trial. So far, 25 patients have been enrolled, but the researchers are hoping to recruit more, including patients with cancers other than GIST that have alterations in KIT or PDGFRα genes.
Filip Janku, MD, PhD, Assistant Professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, told the Symposium, “While it is early, we observed signs of benefit in the GIST patients treated whose disease had progressed despite multiple previous treatments. Early partial metabolic responses, a sign of reduced tumor metabolic activity, were observed in 14 of the 15 patients evaluated with KIT-mutant GIST.”
“In addition to GIST, we sought to evaluate patients with other genetically defined cancers that might also benefit from treatment with DCC-2618. For example, the first patient enrolled in the trial had glioblastoma multiforme with simultaneous alterations in KIT and PDGFRα genes. This patient began to demonstrate improvements relatively early in treatment as the tumor shrank slowly but steadily, and today, more than 12 months later, the patient is continuing to do well. We are very excited to see the response in this patient, as it is a very hard cancer to treat.”
“DCC-2618 is well tolerated by patients and the antitumor activity observed to date suggest that it is effectively inhibiting the tyrosine kinases that we are targeting. The findings are very encouraging in that they support a shift in oncology drug development toward targeted therapies, such as DCC-2618, in genetically-defined patient populations beginning as early as phase I clinical trials. This is important as it provides information early in the clinical development process to help define patient populations that might potentially benefit.”
“In this study, we also employed a novel next-generation sequencing technology to identify and dynamically track molecular alterations in tumor-derived circulating cell-free DNA isolated from blood of treated patients in order to understand the molecular basis of response, and intrinsic or adaptive resistance to DCC-2618.”
“DCC 2618 is one of the most active compounds I have ever seen in the phase I setting in my career.”
Dr. Dhingra added, “Even though the phase I dose escalation is ongoing, impressive early results have been seen, including in the difficult-to-treat site of the brain. Liquid biopsies have revealed in real or near-real time the presence of multiple mutations, reflecting a diversity in the genetic make-up of the tumors that might have been missed even if an invasive tissue biopsy had been done, which is traditionally considered to be the ‘gold standard’.”
The researchers are testing dose levels ranging from 20 mg to 150 mg in patients (taken orally twice a day over a 28-day cycle). Once the maximum tolerated dose has been identified, they plan to recruit groups of patients with a range of other cancers that have the KIT or PDGFRα mutations identified in this phase of the trial.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
