Interim results from a phase 1/2 study have demonstrated encouraging activity and a favorable safety profile for the next-generation BRAF inhibitor PLX8394 among patients with refractory solid tumors with BRAF mutations. 

The investigators noted that ongoing research will further explore the recommended phase-2 dose of the novel agent with a modified tablet formulation, which may reduce dose burden and improve dose linearity.

In a presentation at the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (abstract 5LBA), the multicenter team of investigators behind the trial explained that BRAFV600 inhibition with first-generation BRAF inhibitors has offered marked clinical benefit in several types of tumor. Yet despite these advances, paradoxical re-activation of the mitogen-activated protein kinase (MAPK) pathway contributes to therapeutic resistance. 

“PLX8394 is a next-generation, orally available small-molecule BRAF inhibitor that does not induce MAPK paradoxical activation,” the authors wrote, “and blocks signaling from both monomeric BRAFV600 and dimeric BRAFnon-V600 mutated protein.”

A total of 75 patients were enrolled into the trial (NCT02428712) through July 31, 2020. The participants had either BRAFV600 tumors (n=49), BRAFnon-V600 tumors (n=17), or non-BRAF mutated tumors (n=9). Fifty-six patients were treated only with PLX8394, at doses of 450 mg BID, 450 mg TID, or 900 mg BID. The remaining 19 were treated with PLX8394 plus cobicistat (Tybost; Gilead). 

Of the original cohort, 45 patients with BRAF-mutations were evaluable. These individuals received a median of three prior therapies, including 12 who received prior MAPK-pathway targeted therapies. In total, 10 patients (22%) achieved confirmed and mostly durable partial responses, including three patients with gliomas, two with ovarian cancer, and one each for papillary thyroid cancer, small bowel, colorectal carcinoma, anaplastic thyroid carcinoma, and melanoma. 

At the time of the interim analysis, 10 patients had remained in the trial for at least 24 months (range 24-59 months), which the researchers said offered ‘encouraging’ long-term safety data, including a lack of secondary skin lesions commonly observed with Class 1 BRAF inhibitors.

The only observed disease-limiting toxicities were grade 3 elevations in aspartate aminotransferase (AST) and blood bilirubin. Other toxicities of at least grade 3 observed in at least two patients were increased alanine aminotransferase (ALT) and increased blood bilirubin in four patients each, increased AST in three patients, and diarrhea in two patients.

Interestingly, the use of cobicistat resulted in 2-3-fold increase of PLX8394 exposure, which demonstrated a non-saturating, dose-proportional increase in exposure. The 900 mg BID dose of PLX8394 plus cobicistat was declared the recommended phase-2 dose. 

Lead author Filip Janku, MD, PhD was encouraged by the findings. “Although we already have some BRAF inhibitor drugs, unfortunately they do not work for all patients with BRAF mutated cancers,” he said in a statement. “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,” added Dr. Janku, Associate Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston, Texas. “These results suggest that the combination of drugs we tested is relatively safe and may be effective for some patients.”

According to William R. Sellers, MD, co-chair of the EORTC-NCI-AACR symposium, BRAF is an important therapeutic target in cancer 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,” the Professor of Medicine at Harvard Medical School said in a statement.