RAF Inhibitor Plus Cobicistat Is Promising in BRAF+ Refractory Solid Tumors

PLX8394, a next-generation BRAF inhibitor, in combination with cobicistat (Tybost) was found to demonstrate encouraging clinical activity with an acceptable safety profile in patients with BRAF-mutated, refractory solid tumors, according to results from a phase 1/2 trial (NCT02428712) presented during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics.

PLX8394, a next-generation BRAF inhibitor, in combination with cobicistat (Tybost) was found to demonstrate encouraging clinical activity with an acceptable safety profile in patients with BRAF-mutated, refractory solid tumors, according to results from a phase 1/2 trial (NCT02428712) presented during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics.1

Results showed that among patients with BRAF-mutated solid tumors (n = 45) who had received a median of 3 previous lines of therapy, 22% (n = 10) had confirmed and mostly durable partial responses; this included 3 patients with gliomas, 2 with ovarian cancer, 1 with papillary thyroid cancer, 1 with small bowel disease, 1 with colorectal carcinoma, 1 with anaplastic thyroid carcinoma, and 1 with melanoma.

“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,” stated 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.2 “First-generation BRAF inhibitors can also cause unpleasant skin lesions and skin cancers in some patients.”

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

PLX8394, a next-generation, orally available, small-molecule BRAF inhibitor, does not encourage the paradoxical activation of the MAPK pathway and blocks signaling from monomeric BRAF V600 and dimeric BRAF non-V600—mutated protein.

In the dose-escalation portion of the trial, investigators set out to examine the safety, pharmacokinetics, and pharmacodynamics of the agent with or without the CYP3A4 inhibitor cobicistat in adult and pediatric patients with advanced BRAF-mutated tumors, in addition to determining the recommended phase 2 dose. In the dose-extension portion, investigators are evaluating objective tumor response with the BRAF inhibitor in adult and adolescent patients with advanced BRAF-mutated tumors.3

As of July 31, 2020, a total of 75 patients received treatment with PLX8394 at a dose of either 450 mg twice daily, 450 mg three times per day, and 900 mg twice daily. Fifty-six patients received PLX8394 with cobicistat, while 19 patients received the investigational agent as a monotherapy. The addition of cobicistat led to a 2- to 3-fold increase of PLX8394 exposure, showing a non-saturating dose proportional increase in exposure.

At the time of the analysis, a total of 10 participants were on the study for 24 months or longer. The only dose-limiting toxicities included grade 3 elevated aspartate aminotransferase (AST) and grade 3 blood bilirubin increase. Based on the data, the 900 mg twice daily dose of PLX8394 plus cobicistat was established as the recommended phase 2 dose.

With regard to safety, other grade 3 or higher adverse effects included increased alanine aminotransferase (n = 4), increased AST (n = 3), blood bilirubin increase (n = 4), and diarrhea (n = 2).

Additionally, PLX8394 was associated with a lack of secondary skin lesions that typically occurs with class 1 BRAF inhibitors.

“BRAF is a gene mutated in approximately half of [patients with] melanoma as well as in smaller fractions of colorectal and lung cancer. It is, therefore, an important therapeutic target and, indeed, BRAF inhibitors have significant clinical benefit in such patients,” William R. Sellers, MD, professor of medicine at the Dana-Farber Cancer Institute and Harvard Medical School, added.2 “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 research.”

References

1. Fanku J, Sharman E, Parikh AR, et al. Interim results from a phase 1/2 precision medicine study of PLX8394- a next generation BRAF inhibitor. Presented at: Presented at: 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics; October 24-25, 2020; Virtual. Abstract LBA-05. https://bit.ly/2HFJSmF.

2. Next generation BRAF inhibitor cancer drug shows promise in early patient trial. News release. EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. Accessed October 26, 2020. https://bit.ly/3juOtWb.

3. A study of PLX8394 as a single agent in patients with advanced unresectable solid tumors. ClinicalTrials.gov. Updated October 19, 2020. Accessed October 26, 2020. https://clinicaltrials.gov/ct2/show/NCT02428712.

This article was originally published on OncLive as, "Next-Generation BRAF Inhibitor Plus Cobicistat Elicits Encouraging Activity in BRAF+ Refractory Solid Tumors."