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Next-Generation BRAF Inhibitor Shows Activity in Phase I/II Trial


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A new drug designed to treat cancers in patients with an altered BRAF gene showed activity and had a favorable safety profile in an early-phase trial. These findings were presented by Janku et al at the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (Abstract LBA-05).

The BRAF gene is involved in telling healthy cells when to grow and form new cells, but it is also known to be mutated in several types of cancer, including forms of bowel, brain, and skin cancers. A few BRAF inhibitors have already proved effective in treating patients. However, these first-generation BRAF inhibitors do not work on all BRAF-mutated cancers; in other cases, cancers become resistant to the treatment.

PLX8394

The new drug, PLX8394, is a next-generation BRAF inhibitor, designed to avoid this resistance and work against cancers with a wider range of BRAF mutations.

“The next-generation BRAF inhibitor that we gave to patients in this trial was designed to avoid those problems. These results suggest that the combination of drugs we tested is relatively safe and may be effective for some patients.”
— Filip Janku, MD, PhD

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So far, 75 patients in the phase I/II trial have been treated with PLX8394, taken twice a day by mouth, with or without another drug called cobicistat. Data on 45 of these patients with BRAF alterations (who received PLX8394 and cobicistat) were available for researchers to evaluate. These patients had advanced disease, and most had already received three different types of treatments before joining the trial.

Findings

The researchers reported that the addition of cobicistat resulted in doubling to tripling the level of PLX8394 in the blood.

Of the 45 patients, 10 (22%) had a partial response to the new drug. This included three with glioma; two with ovarian cancer; and others with bowel cancer, thyroid cancer, or melanoma. In addition, 10 of the 45 patients had remained on the treatment for at least 2 years when the data were analyzed.

Serious side effects of the treatment experienced by some patients were increased alanine aminotransferase and blood bilirubin; these levels lowered when PLX-8394 was interrupted and the dose was reduced. Some patients also experienced diarrhea.

Study author Filip Janku, MD, PhD, Associate Professor for Investigational Cancer Therapeutics (Phase I Clinical Trials Program) and Center Medical Director for Clinical and Translational Research Center at The University of Texas MD Anderson Cancer Center, said, “Although we already have some BRAF inhibitor drugs, unfortunately, they do not work for all patients with BRAF-mutated cancers. In some cases, even when these drugs do work at first, cancers develop resistance. First-generation BRAF inhibitors can also cause unpleasant skin lesions and skin cancers in some patients.”

“The next-generation BRAF inhibitor that we gave to patients in this trial was designed to avoid those problems. These results suggest that the combination of drugs we tested is relatively safe and may be effective for some patients.”

Dr. Janku and his colleagues will continue to study the combination of PLX8394 and cobicistat for treating patients, particularly to discover the optimum dose of the drugs.

Disclosure: For full disclosures of the study authors, visit cm.eortc.org.

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®.
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