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Cobimetinib Plus Vemurafenib in Patients With Colorectal Cancer With BRAF Mutations: Results From the Targeted Agent
Kelsey A Klute1, Michael Rothe2, Elizabeth Garrett-Mayer2
1University of Nebraska Medical Center, Omaha, NE.
Purpose:
TAPUR is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. The results of a cohort of patients with colorectal cancer (CRC) with BRAF mutations treated with cobimetinib (C) plus vemurafenib (V) are reported.
Methods:
Eligible patients had advanced CRC, no standard treatment options, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, tumors with BRAF V600E/D/K/R mutations, and no MAP2K1/2, MEK1/2, or NRAS mutations. C was taken 60 mg orally once daily for 21 days followed by seven days off, and V was taken 960 mg orally twice daily. Simon's two-stage design was used with a primary study end point of objective response or stable disease of at least 16 weeks duration. Secondary end points were progression-free survival, overall survival, and safety.
Results:
Thirty patients were enrolled from August 2016 to August 2018; all had CRC with a BRAF V600E mutation except one patient with a BRAF K601E mutation. Three patients were not evaluable for efficacy. Eight patients with partial responses and six patients with stable disease of at least 16 weeks duration were observed for disease control and objective response rates of 52% (95% CI, 35 to 65) and 30% (95% CI, 14 to 50), respectively. The null hypothesis of 15% disease control rate was rejected (P < .0001). Thirteen patients had at least one grade 3 adverse event or serious adverse event at least possibly related to C + V: anemia, decreased lymphocytes, dyspnea, diarrhea, elevated liver enzymes, fatigue, hypercalcemia, hypophosphatemia, rash, photosensitivity, and upper gastrointestinal hemorrhage.
Conclusion:
The combination of C + V has antitumor activity in heavily pretreated patients with CRC with BRAF mutations.
Insights
Cobimetinib plus vemurafenib showed significant antitumor activity in patients with advanced colorectal cancer and BRAF mutations. This combination therapy achieved a 52% disease control rate, offering a new treatment option for heavily pretreated patients.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Colorectal cancer (CRC) with BRAF mutations presents a therapeutic challenge.
- Targeted therapies are crucial for advanced cancers with specific genomic alterations.
Purpose of the Study:
- To evaluate the antitumor activity of cobimetinib (C) plus vemurafenib (V) in patients with advanced colorectal cancer (CRC) harboring BRAF mutations.
- To assess the objective response and disease control rates of this combination therapy.
Main Methods:
- A cohort of 30 patients with advanced CRC and BRAF mutations were enrolled in a phase II basket trial.
- Patients received cobimetinib (60 mg daily for 21 days on, 7 days off) plus vemurafenib (960 mg twice daily).
- Primary endpoint was objective response or stable disease of at least 16 weeks; secondary endpoints included survival and safety.
Main Results:
- A disease control rate of 52% (partial responses + stable disease ≥16 weeks) was observed, significantly above the 15% null hypothesis (P < .0001).
- Objective response rate was 30%.
- Common grade 3 adverse events included anemia, decreased lymphocytes, dyspnea, diarrhea, elevated liver enzymes, fatigue, hypercalcemia, hypophosphatemia, rash, photosensitivity, and upper gastrointestinal hemorrhage.
Conclusions:
- The combination of cobimetinib and vemurafenib demonstrates significant antitumor activity in heavily pretreated patients with BRAF-mutated CRC.
- This regimen offers a viable treatment option for this specific patient population.
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