BRAF Inhibitor Encorafenib And Cetuximab Real Life Investigation of Next Generation CRC Treatment

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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. Data from pivotal clinical trials are usually based on a selected patient population in order to provide standardized results in the given indication. However, after marketing authorization usage in a broader patient popula-tion is to be expected. Therefore, BERINGCRC - 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.

Official Title
-----------------
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

Conditions
-----------------
Metastatic Colorectal Carcinoma

Intervention / Treatment
-----------------
* Drug: Encorafenib
* Drug: Cetuximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. Exclusion Criteria: 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).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Encorafenib|Observation of real-life treatment with encorafenib and cetuximab|
|Drug: Cetuximab|Observation of real-life treatment with encorafenib and cetuximab|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall Survival rate | At 12 months after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient and disease profiles at start of treatment with encorafenib plus cetuximab | Demographic and disease chracteristics | Baseline | 
| BRAF-mutation assessment | Date and type of BRAFV600E testing | Baseline | 
| Type and sequence of treatments before and after encorafenib plus cetuximab | Treatment sequence prior to and after encorafenib plus cetuximab | Through study completion, an average of 17 months | 
| Characteristics of treatment with encorafenib plus cetuximab | Evaluation of reason for treatment selection (efficacy, safety profile, quality of life, patients preference, physician's preference, comorbidities, other) | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 
| Effectiveness of treatment with encorafenib and cetuximab | Further Overall Survival parameters | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 
| Effectiveness of treatment with encorafenib and cetuximab | Best observed tumor response | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 
| Effectiveness of treatment with encorafenib and cetuximab | Time to progression | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 
| Effectiveness of treatment with encorafenib and cetuximab | Overall response rate | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 
| Effectiveness of treatment with encorafenib and cetuximab | Duration of response | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 
| Effectiveness of treatment with encorafenib and cetuximab | Progression-free-survival | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 
| Effectiveness of treatment with encorafenib and cetuximab | Disease control rate | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 
| Effectiveness of treatment with encorafenib and cetuximab | Duration of disease control | 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 | EORTC QLQ C-30 questionnaires (European Organisation for Research and Treatment of Cancer Quality of Life C-30 questionnaires) to assess quality of life of cancer patients; comprises 30 items, 24 of which are aggregated into nine multi-item scales, that is, five functioning scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, pain and nausea/vomiting) and one global health status scale. The remaining six single-item (dyspnoea, appetite loss, sleep disturbance, constipation, diarrhoea and the financial impact) scales assess symptoms. Only in case of prospective inclusion. | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 
| Patient's treatment satisfaction - overall | 4-point scale: very satisfied, satisfied, dissatisfied, very dissatisfied | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 
| Physician's treatment satisfaction - differentiated by efficiency, safety and overall | 4-point scale: very satisfied, satisfied, dissatisfied, very dissatisfied | 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 | Number of patients with Adverse Events and maximum grade per patient, Adverse Drug Reactions, Adverse Drug Reactions grade 3/4, Serious Adverse Events, Serious Adverse Drug Reactions | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 
| Treatment duration | From date to first treatment until date of last treatment (single compounds and whole treatment) | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 
| Treatment dose intensity | From date to first treatment until date of last treatment (single compounds and whole treatment) | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 
| Number of treatment interruptions | From date to first treatment until date of last treatment (single compounds and whole treatment) | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 
| Duration of treatment interruptions | From date to first treatment until date of last treatment (single compounds and whole treatment) | Through encorafenib plus cetuximab treatment completion, an average of 9 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
BRAFV600E mutation