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Regorafenib in Patients With Solid Tumors With BRAF Alterations: Results From the Targeted Agent and Profiling
Vaibhav Sahai1, Michael Rothe2, Pam K Mangat2
1University of Michigan Rogel Cancer Center, Ann Arbor, MI.
Purpose:
Targeted Agent and Profiling Utilization Registry is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer with genomic alterations known to be drug targets. Results of a cohort of patients with solid tumors with BRAF alterations treated with regorafenib are reported.
Methods:
Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-1, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as investigator assessment of patients with complete or partial response (PR) or stable disease of at least 16-weeks duration (SD16+). Low accruing histology-specific cohorts with BRAF alterations treated with regorafenib were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power, 0.84; α, .10). Secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of stable disease, and safety.
Results:
Twenty-eight patients with 12 tumor types with BRAF alterations were enrolled from June 2016 to June 2021. All patients were evaluable for efficacy. Two patients with PR and four with SD16+ were observed for DC and OR rates of 21% (90% CI, 12 to 100) and 7% (95% CI, 1 to 24), respectively. The null hypothesis of 15% DC rate was not rejected (P = .24). Eight patients had at least one grade 3 adverse event or serious adverse event at least possibly related to regorafenib.
Conclusion:
Regorafenib did not meet prespecified criteria to declare a signal of activity in patients with solid tumors with BRAF alterations.
Insights
Regorafenib did not show significant antitumor activity in advanced solid tumors with BRAF alterations. The drug failed to meet the prespecified criteria for disease control in this targeted therapy trial.
Area of Science:
- Oncology
- Genomics
- Clinical Trials
Background:
- Advanced cancers with specific genomic alterations present treatment challenges.
- Targeted therapies offer potential for personalized cancer treatment based on molecular profiling.
- The BRAF gene is a known target in various solid tumors.
Purpose of the Study:
- To evaluate the antitumor activity of regorafenib in patients with advanced solid tumors harboring BRAF alterations.
- To assess disease control rates as the primary endpoint in this phase II basket trial.
- To investigate secondary endpoints including objective response and survival outcomes.
Main Methods:
- A phase II basket trial enrolled 28 patients with 12 tumor types and BRAF alterations.
- Patients received regorafenib; efficacy was evaluated by investigator assessment of disease control (DC).
- The primary endpoint (DC rate) was compared against a null rate of 15% using a one-sided exact binomial test.
Main Results:
- The overall disease control rate was 21% (2 partial responses, 4 with stable disease ≥16 weeks).
- The objective response rate was 7%.
- Regorafenib showed a grade 3 adverse event rate of 29% in this cohort.
Conclusions:
- Regorafenib did not meet the prespecified criteria to demonstrate a signal of activity in patients with BRAF-altered solid tumors.
- Further investigation of regorafenib in this specific patient population is not supported by these findings.
- The study highlights the importance of rigorous endpoint evaluation in targeted therapy trials.
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