Encorafenib and Cetuximab in Patients With Metastatic, BRAFV600E-mutated, Colorectal Carcinoma: a Multi-centric, Multi-national, Prospective, Longitudinal, Non-interventional Study in Germany, Austria and Switzerland
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 500
- 试验地点
- 8
- 主要终点
- Overall Survival
研究概览
简要总结
The presence of a BRAFV600E mutation is a marker of poor prognosis in patients with mCRC and associated with a median overall survival (mOS) of approximately 12 to 14 months compared to 20 to 25 months for patients with BRAF wild-type tumours. After 1st line therapy, treatment outcomes with standard therapy are poor in patients with BRAF-mutated mCRC, with response rates (ORR) of ≤ 11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months, and a mOS between 4.1 and 6.2 months. Failure to achieve adequate survival outcomes with standard treatment regimens in patients with BRAF-mutated mCRC has encouraged efforts to combine multiple targeted therapies: With 665 randomized patients, the BEACON CRC trial represents the largest trial and is currently the only phase III study in patients with BRAFV600E-mutant mCRC.
BERING CRC - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in BRAFV600E-mutant mCRC patients, who have received prior systemic therapy. Data from this study will contribute to a deeper understanding and characterization to the everyday use of encorafenib and cetuximab in a broader patient population in the German, Austrian, and Swiss routine setting.
详细描述
The presence of a BRAFV600E mutation is a marker of poor prognosis in patients with mCRC and associated with a median overall survival (mOS) of approximately 12 to 14 months compared to 20 to 25 months for pa-tients with BRAF wild-type tumors. After 1st line therapy, treatment out-comes with standard therapy are poor in patients with BRAF-mutated mCRC, with response rates (ORR) of ≤ 11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months, and a mOS between 4.1 and 6.2 months.
Failure to achieve adequate survival outcomes with standard treatment regimens in patients with BRAF-mutated mCRC has encouraged efforts to combine multiple targeted therapies: With 665 randomized patients, the BEACON CRC trial represents the largest trial and is currently the only phase III study in patients with BRAFV600E-mutant mCRC. After a safety lead in for dose confirmation of the triplet regimen, the phase III part was per-formed with a total of 665 patients, randomized 1:1:1 to either receive encorafenib plus binimetinib and cetuximab (triplet) or encorafenib plus cetuximab (doublet) or FOLFIRI / IRI plus cetuximab (control).
The BEACON CRC study met its primary endpoints Overall Response Rate (ORR) and Overall Survival (OS) comparing Encorafenib + Binimetinib + Cetuximab vs. Chemotherapy + Cetuximab (ORR: 26 vs. 2%, p<0.001; OS: median 9.0 vs. 5.4 months, HR 0.52, p<0.001). The BEACON CRC study was alpha-controlled also for the secondary endpoint comparing Encorafenib + Cetuximab vs. Chemotherapy + Cetuximab in terms of ORR and OS and showed a statistically significant advantage (ORR: 20 vs. 2%, p<0.001; OS: median 8.4 vs. 5.4 months, HR 0.60, p<0.001). In terms of safety, the overall frequency of adverse events grade 3/4 was 58% (En-corafenib + Binimetinib + Cetuximab) vs. 50% (Encorafenib + Cetuximab) vs. 61% (Chemotherapy + Cetuximab). Analysis of Quality of Life data resulted in a longer maintenance of Quality of Life in the Encorafenib + Binimetinib + Cetuximab arm and the Encorafenib + Cetuximab arm com-pared to Chemotherapy + Cetuximab. Between Encorafenib + Binimetinib + Cetuximab and Encorafenib + Cetuximab, no relevant differences were reported. With a longer Follow-Up (12.8 months) the updated OS data showed a median OS of 9.3 months in both the Encorafenib + Binimetinib + Cetuximab arm and the Encorafenib + Cetuximab arm compared to 5.9 months in the control arm. Updated ORR rates were 27% in the triplet arm (p<0.0001 vs. control), 20% in the doublet arm (p<0.0001 vs. control) and 2% in the control arm. The safety and tolerability were adequate, manage-able and consistent with the known profiles of BRAF-, MEK-, and EGFR-inhibitors. Regarding the triplet combination, the most common adverse events of any grade were diarrhea (triplet: 62%; control: 48%), dermatitis acneiform (triplet: 49%; control: 39%), nausea (triplet: 45%; control: 41%), and vomiting (triplet: 38%; control: 29%). Regarding the doublet combina-tion, the most common adverse events of any grade were nausea (34%), diarrhea (33%), fatigue (doublet 30%; triplet 33%; control 27%) and derma-titis acneiform (29%).
The most common updated grade ≥3 adverse events regarding the triplet combination were diarrhea (triplet: 11%; control: 10%), abdominal pain (triplet: 6%; control: 5%), nausea (triplet: 5%; control: 2%,vomiting (triplet: 5%; control: 3%) and intestinal obstruction (triplet 5%; control 3%). With the doublet regimen, the most common updated grade ≥3 adverse events were intestinal obstruction (doublet 5%), asthenia (doublet 4%; triplet 4%; control 5%), fatigue (doublet 4%; triplet 2%; control 5%), diarrhea (3%) and abdominal pain (3%).
Based on these data, it is expected that the European Medicines Agency (EMA) will approve encorafenib plus cetuximab for the treatment of adult patients with metastatic BRAFV600E-mutant CRC, who have received prior systemic therapy.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent of the patient with regard to the pseudonymized documentation of his/her data in the frame of this non-interventional study
- •Legally capable patient ≥ 18 years of age (no upper limit)
- •Metastatic colorectal carcinoma with BRAFV600E-mutation, pretreated with systemic therapy
- •Decision was taken to treat the patient with the doublet therapy (encorafenib and cetuximab) in accordance with the current SmPC and by prescription; this decision was taken prior to and independent from the inclusion into the study;
- •Treatment with the doublet therapy (encorafenib plus cetuximab) has been started ≤ 3 months prior to providing written informed consent for this study or is planned to be started in the near future.
排除标准
- •More than 2 prior systemic regimens in the metastatic setting (adjuvant systemic therapy with relapse ≤ 6 months will be counted as metastatic treatment line; maintenance treatment will not be counted as separate metastatic treatment line)
- •Prior treatment with any RAF-inhibitor or MEK-inhibitor.
- •Presence of any contraindication with regard to the doublet therapy (encorafenib plus cetuximab) as specified in the corresponding SmPCs
- •Current or upcoming participation in an interventional clinical trial
- •Current or upcoming systemic treatment of any other tumor than metastatic colorectal carcinoma
- •Prisoners or persons who are compulsorily detained (involuntarily incarcerated).
结局指标
主要结局
Overall Survival
时间窗: At 12 months after start of treatment
Overall Survival rate
次要结局
- Patient and disease profiles at start of treatment with encorafenib plus cetuximab(Baseline)
- Patient's treatment satisfaction - overall(Through encorafenib plus cetuximab treatment completion, an average of 9 months)
- Treatment dose intensity(Through encorafenib plus cetuximab treatment completion, an average of 9 months)
- Type and sequence of treatments before and after encorafenib plus cetuximab(Through study completion, an average of 17 months)
- Characteristics of treatment with encorafenib plus cetuximab(Through encorafenib plus cetuximab treatment completion, an average of 9 months)
- Patient reported outcomes during treatment with encorafenib plus cetuximab - evaluated with EORTC QLQ C-30(Through encorafenib plus cetuximab treatment completion, an average of 9 months)
- Physician's treatment satisfaction - differentiated by efficiency, safety and overall(Through encorafenib plus cetuximab treatment completion, an average of 9 months)
- Treatment duration(Through encorafenib plus cetuximab treatment completion, an average of 9 months)
- Number of treatment interruptions(Through encorafenib plus cetuximab treatment completion, an average of 9 months)
- BRAF-mutation assessment(Baseline)
- Effectiveness of treatment with encorafenib and cetuximab(Through encorafenib plus cetuximab treatment completion, an average of 9 months)
- Safety and tolerability of treatment with encorafenib and cetuximab - Adverse events and adverse reactions including time to onset and time to resolution(Through encorafenib plus cetuximab treatment completion, an average of 9 months)
- Duration of treatment interruptions(Through encorafenib plus cetuximab treatment completion, an average of 9 months)