A next-generation BRAF inhibitor has shown promising early signs of safety and clinical efficacy in solid tumors whose treatment has been limited by resistance to approved first-generation BRAF inhibitors, according to a study presented at the 2020 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.
The new drug, PLX8394, is designed to avoid toxicity and other limitations experienced with first-generation inhibitors of the mutated BRAF gene that promotes the growth of several types of cancers of the bowel, brain, and skin-particularly melanoma, where the gene is mutated in about half of all patients.
In a Phase I/II clinical trial, the new drug-given with cobicistat to increase blood levels of PLX8394-was tested in patients with advanced or metastatic cancers to determine safety and early signals of clinical activity in patients with BRAF alterations.
"Although we already have some BRAF inhibitor drugs, unfortunately, they do not work for all patients with BRAF mutated cancers," said Filip Janku, MD, PhD, Associate Professor in the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center. "In some cases, even when these drugs do work at first, cancers develop resistance. First-generation BRAF inhibitors also can 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."
As outlined in his presentation, Janku explained that first-generation drugs targeting BRAF have proven effective in treating patients with BRAF mutations, but can also activate other cancer-related signaling pathways, including the mitogen-activate protein kinase (MAPK) pathway that promotes cell growth, proliferation, and survival. This is known as "paradoxical activation."
"Paradoxical activation of the MAPK pathway, a feedback mechanism overcoming BRAF inhibition, is often responsible for resistance to approved FDA first-generation BRAF inhibitors, which is often responsible for resistance," noted Janku.
In preclinical studies, PLX8394-an orally available small molecule BRAF inhibitor-was shown not to cause paradoxical activation, while broadly targeting multiple forms of mutant BRAF. Cobicistat was added to the clinical trial regimen to enhance the drug's blood concentration.
"Initially, we did not use cobicistat and we had a problem to achieve adequate levels of the drug in blood," Janku said in an interview. "Cobicistat, which slows down metabolism of PLX8394, helped to increase levels of PLX8934 in blood to increase efficacy. Additionally, cobicistat is thought to increase the ability of PLX8394 to get into the central nervous system, making it more active against brain tumors."
As of July 31, 2020, some 75 patients with solid tumors were given oral doses of PLX8934 at a level of either 450 mg twice daily, 450 mg three times per day, or 900 mg twice daily. Some 56 patients received cobicistat in combination with the new drug, while 18 others were treated with just PLX8394 without cobicistat. Patients who received the new drug plus cobicistat saw their blood levels of PLX8394 doubling or tripling.
Data on 45 of the 75 patients with BRAF alterations who received PLX8394 and cobicistat were available for researchers to evaluate. All patients had metastatic or advanced cancers; most already had received three different types of treatments before joining the trial.
The results showed that 10 of the 45 patients, or 22 percent, had a partial response to the new drug, meaning their tumors shrank by at least 30 percent. This included three people with glioma, two with ovarian cancer, and others with bowel cancer, thyroid cancer, or melanoma. Ten of the 45 patients remained on the regimen for at least 2 years (24-59 months) while the data was analyzed, providing encouraging long-term safety data.
"All 10 patients in the study for more than 2 years had an alteration in BRAF," said Janku. "Perhaps most interesting is that four patients with relapsed/refractory BRAF mutation glioma demonstrated shrinkage of their tumors, three of which were partial responses; and there was anti-tumor activity in some patients with Class 2 mutations and BRAF fusion for which first-generation BRAF inhibitors are not active."
About 4 percent of the patients experienced serious treatment-related side effects including Grade 3 levels of a liver enzyme aspartate aminotransferase and bilirubin. These levels decreased when PLX8394 treatment was interrupted and dose reduced. Some patients also experienced diarrhea.
Patients did not experience secondary skin lesions that typically have been associated with first-generation BRAF inhibitors.
Based on the data, the 900 mg twice daily dosage of PLX8934 plus cobicistat was established as the recommended Phase II dose.
William R. Sellers, MD, Professor of Medicine at the Dana-Farber Cancer Institute, Harvard Medical School, and Co-Chair of the EORTC-NCI-AACR symposium, shared his thoughts on the study: "Understanding which genes go wrong in cancer and how they are mutated is a crucial step towards finding treatments that are targeted to work effectively in individual patients.
"BRAF is mutated in approximately half of melanoma patients, as well as in small fractions of colorectal and lung cancer. It is therefore an important therapeutic target and, indeed, BRAF inhibitors have significant clinical benefit in such patients.
"This trial shows positive signs for using a next-generation BRAF inhibitor to treat patients with a variety of different cancer types and we look forward to hearing further results from the next stage of this research."
Warren Froelich is a contributing writer.