The Use of Regorafenib in Patients with BRAF-Mutant Solid Tumors: A Summary of Results from the TAPUR Study

Background Introduction

The BRAF gene belongs to the cytoplasmic serine/threonine kinase family and regulates cell proliferation and survival by activating the mitogen-activated protein kinase signaling pathway (MAPK). BRAF mutations can lead to its abnormal activation and promote tumor formation. BRAF mutations are divided into three types: Class I mutations occur at the V600 site and activate monomers independent of Ras; Class II mutations activate dimers independent of Ras; Class III mutations are kinase-impaired, promoting the activation of CRAF. BRAF mutations are common in melanomas (about 40%), thyroid cancer, colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and cholangiocarcinoma.

Regorafenib is a small molecule multi-target tyrosine kinase inhibitor that targets proteins such as ABL, DDR2, EGFR, EPHA2, FGFR, KIT, PDGFR, PTK5, RAF, RET, SAPK2, TIE2, TRKA, and VEGFR, acting on angiogenesis, tumor occurrence, and cell proliferation. It has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic CRC, gastrointestinal stromal tumors (GIST), and hepatocellular carcinoma (HCC).

Source of Research

This research was jointly completed by Vaibhav Sahai, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Vijay Suhag, Elie G. Dib, and others from the University of Michigan Rogel Cancer Center and the American Society of Clinical Oncology (ASCO), among others. The study was published in the “JCO Precision Oncology” journal on February 21, 2024, with the DOI: https://doi.org/10.1200/po.23.00527.

Research Objectives and Methodology

Study Objectives

This study aims to evaluate the antitumor activity of the commercial targeted drug Regorafenib in patients with BRAF gene variant-carrying advanced cancers. The study analyzed the effects of Regorafenib treatment in a cohort of solid tumor patients carrying BRAF gene variations.

Research Methods

The TAPUR study is an open-label, non-randomized Phase II basket trial intended to evaluate the effectiveness of FDA-approved targeted drugs used for other indications in patients with specific genetic mutations in advanced cancer.

Research Process

1. Subject Selection and Grouping: Patients with Measurable Disease (as per RECIST v.1.1), an Eastern Cooperative Oncology Group performance status score (ECOG PS) of 0-1, appropriate organ function, and no other standard treatment options were included. The primary endpoint of the study was the disease control rate (DC) of stable disease lasting over 16 weeks (SD161).

2. Genetic Testing and Treatment Regimen: Clinical Laboratory Improvement Amendments (CLIA)-certified genetic tests were required to meet the inclusion criteria for subjects. All patients received a daily oral dose of 160mg Regorafenib, with a treatment cycle of 21 days of treatment every 28 days.

3. Data Analysis: A one-sided exact binomial test was used to evaluate outcomes, with a one-sided 90% confidence interval (CI) provided for the primary endpoint. Secondary endpoints included objective response rate (OR), progression-free survival (PFS), overall survival (OS), duration of response, duration of stable disease, and safety.

Data Collection and Evaluation

From June 2016 to June 2021, a total of 28 patients were recruited, carrying BRAF mutations and having 12 different types of tumors. All patients met the criteria for efficacy evaluation. The DC rate was evaluated using an exact one-sided binomial test, and secondary endpoints used Kaplan-Meier curves to estimate PFS and OS distributions.

Main Research Findings

Disease Control and Response Rates

• Disease Control Rate (DC): The DC rate was 21% (90% CI, 12 to 100).
• Objective Response Rate (OR): The OR was 7% (95% CI, 1 to 24).

Did not Meet Predefined Clinical Activity Standards: For the null hypothesis of a 15% DC rate, the P-value was 0.24, failing to reject the null hypothesis.

Adverse Reactions

• There were eight patients who experienced Grade 3 adverse reactions or serious adverse reactions related to Regorafenib, including hypertension, fatigue, hyponatremia, anemia, constipation, etc.

Survival and Disease Course

• Median Progression-Free Survival (PFS): 8 weeks (95% CI, 8 to 15).
• Median Overall Survival (OS): 28 weeks (95% CI, 17 to 41).

Conclusion and Discussion

This study indicates that Regorafenib did not meet the predefined clinical activity criteria. However, disease control responses were observed in some patients, particularly those carrying Class II and Class III BRAF mutations, suggesting the need for further investigation of this drug, especially since existing FDA-approved BRAF inhibitors are only effective for Class I BRAF mutations (specifically at the V600E site).

Research Highlights and Significance

• Research Highlights: This study systematically evaluated the efficacy of Regorafenib in patients with various BRAF mutation-solid tumors based on large-scale genetic testing for the first time.
• Scientific and Practical Value: The research provides important guidance for subsequent exploration of Regorafenib and its combination therapies in patients with specific types of BRAF mutation tumors.

Limitations and Suggestions

The sample size of this study is small, there is no control group, and the diversity of patient tumor types makes it difficult to draw conclusions about the efficacy for specific tumors. Furthermore, Regorafenib, as a multi-target inhibitor, may lead to low specificity; hence, further exploration of its combination with other signaling pathway inhibitors is required.

Although Regorafenib did not meet the pre-set efficacy standards, this study provides important reference for further research and optimization of treatments for tumors with Class II and Class III BRAF mutations.