Κυριακή, 18 Δεκεμβρίου 2016

EFFECTIVE NEW TARGETED DRUGS FOR GIST

MUNICH — Two novel drugs that target mutations in oncogenes have shown clinically relevant activity against treatment-resistant advanced cancers, including some "remarkable activity" in gastrointestinal stromal tumors (GISTs), researchers report from early phase 1 dose-escalation studies.
The two novel drugs are BLU-285 (under development by Blueprint Inc), an oral agent that inhibits PDGFR-alpha D842V and KIT Exon 17 mutants, which play a key role in GIST, and DCC-2618 (under development by Deciphera Pharmaceuticals), which is described as a potent inhibitor of wild-type and mutant KIT, including refractory Exon 17 D816 KIT mutations.
New data on the two drugs were presented here at the 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.
More than 85% of GISTs are driven by mutations in the KIT and PDGFR-alpha oncogenes, which are involved in cell signaling via receptor tyrosine kinases, researchers here told the meeting attendees.
Because currently approved drugs for GIST do not effectively target primary and acquired mutations in the activation loop, the majority of patients experience disease progression, typically as a result of secondary activation of loop mutations that make the tumors resistant to approved kinase inhibitors.
The studies presented at the meeting showed that two novel compounds not only reduced levels of circulating DNA but also achieved partial responses in some patients.
Michael Heinrich, MD, from Knight Cancer Institute, Oregon Health and Science University, Portland, who is lead researcher of one of the trials, said in a press conference that the two studies "highlight the importance of knowledge, of knowing exactly what is the problem and taking a new approach to fixing it."
He continued by saying that the new data underline that fact "in a phase 1 study where, traditionally, we would not expect much in the way of results, we in fact see dramatic, impressive, and unprecedented results, even in the first-dose cohort at the lowest dose that was chosen only for safety, not because we had the expectation that it could possibly work.
"But because the biology and the chemistry were so perfectly married, we in fact do see those responses," he added.
Details of BLU-285 Activity
For the first study, Dr Heinrich and colleagues examined the safety, pharmacokinetics, and clinical activity of BLU-285, which is a potent, highly selective oral inhibitor that targets KIT Exon 17 and PDGFR-alpha D842 activation loop mutants.
They recruited adult patients with unresectable GIST who had been treated with two or more kinase inhibitors, including imatinib (Gleevec, Novartis) or who had a primary PDGFR-alpha D842 mutation. These patients received BLU-285 in a 3+3 dose escalation, followed by once-daily treatment in a 4-week cycle. Dose increases were permissible if deemed safe.
By September 23, 2016, 32 patients had been treated with BLU-285 at doses of 30 to 400 mg/day. These included 17 patients with a PDGFR-alpha D842 mutation and 15 with a KIT Exon 17 mutation. These patients had previously been treated with tyrosine kinase inhibitors and had taken a median of three prior drugS.
The novel drug was found to be rapidly absorbed, at a Tmax of 2-4 hours, and the half-life was over 24 hours, thus supporting once-daily dosing. The majority of adverse events were of grade 1 or 2; the most common were nausea (38%), fatigue (31%), and peripheral edema (31%). There were no grade 4 or 5 toxicities.
Eight patients discontinued treatment because of progressive disease; 24 patients remained in the study, with treatment durations of two to 12 cycles.
Although the patients were still in dose escalation, antitumor activity was seen at all dose levels, including a reduction in tumor burden on the RECIST 1.1 criteria in 11 of 12 PDGFR-alpha D842 mutation patients and 5 of 13 KIT Exon 17 mutation patients.
CT and MRI revealed notable reductions in nontarget lesions, including ascites and diffuse omental disease. There was a greater than 10-fold reduction in levels of circulating PDGFR-alpha D842-mutant DNA, which was observed before the radiographic response.
Dr Heinrich said: "Although we are still increasing the doses in the phase 1 trial to establish the recommended dose, BLU-285 has shown remarkable antitumor activity, with a response seen at the lowest dose level."
Jean-Charles Soria, MD, chair of the scientific committee for the EORTC-NCI-AACR Symposium and Director of the Site de Recherche Intégrée sur le Cancer (SIRIC) Socrate project at Gustave Roussy Cancer Campus, Paris, France, commented in a press conference that he found the results "very interesting."
He said: "Clinical efficacy is seen even at very low doses, and this clinical efficacy is very impressive.... This clinical efficacy, which is confirmed by radiological readouts, also translates in reduction in circulating tumor DNA that can be observed within 2 weeks, even before the first CT scan or X-rays show any level of tumor shrinkage."
Details of DCC-2618 Activity
In the second study, Filip Janku, MD, PhD, assistant professor in the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, and colleagues conducted a phase 1 dose escalation trial in which DCC-2618 was given to patients with advanced GIST and other tumors.
To date, 24 patients have been enrolled. They have received DCC-2618, a novel drug that was designed to inhibit a broad range of KIT and PDGFR kinase mutations. The drug was administered orally twice daily at five dose levels: 20 mg (n = 4), 30 mg (n = 4), 50 mg (n = 4), 100 mg (n = 6), and 150 mg (n = 6).
Fourteen patients currently remain in the study. The most common grade 3/4 adverse events have been fatigue, lipase elevation, dyspnea, anemia, and decreased appetite. There has been one case of a grade 3 dose-limiting elevation in lipase level with the 100-mg dose.
The active metabolite of the drug, DP-5349, was detected at a parent:metablite ratio of 0.56 with the 50-mg dose and 0.4 with the 100-mg dose. The maximum tolerated dose has not yet been reached.
Two patients have achieved a partial response on RECIST criteria. Partial metabolic responses, as defined by the EORTC criteria, were seen in all seven KIT-mutant GIST patients on retrospective review of their records.
To examine the molecular basis of the drug response, the team used a novel next-generation sequencing technology to identify and dynamically track molecular alterations in tumor-derived circulating cell-free DNA isolated from blood samples.
This showed that in all five GIST patients who were tested, drug treatment was associated with a reduction in the frequency of KIT cell-free DNA levels.
Dr Janku said in a release: "DCC 2618 is one of the most active compounds I have ever seen in the phase 1 setting in my career.
"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 1 clinical trials," he continued.
"This is important, as it provides information early in the clinical development process to help define patient populations that might potentially benefit," he added.
The team also enrolled a patient with the rare, aggressive glioblastoma multiforme. The patient had simultaneous KIT and PDGFA mutations.
Dr Janku said: "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 this is a very hard cancer to treat," he added.
Kapil Dhingra, MD, a member of the conference executive committee and managing member of KAPital Consulting LLC, New York City, commented: "Even though the phase 1 dose escalation is ongoing, impressive early results have been seen, including in the difficult-to-treat site of the brain."
The BLU-285 study was funded by Blueprint Medicines. The DCC-2618 study was funded by Deciphera Pharmaceuticals.
EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium. Abstracts 6LBA and 7LBA, presented December 1, 2016.

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