BRAF Inhibitor Encorafenib And Cetuximab Real Life Investigation of Next Generation CRC Treatment (BERING-CRC)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Colorectal Carcinoma
• Intervention / Treatment: Drug: Encorafenib; Drug: Cetuximab

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.

• Study Type: Observational
• Enrollment (Anticipated): 500

Contacts and Locations

• Study Contact: Name: Marion Schmoll; Phone Number: +4976115242627; Email: marion.schmoll@iomedico.com
• Study Contact Backup: Name: Frank Reichenbach, Dr. rer. nat; Phone Number: +4976145261846; Email: frank.reichenbach@pierre-fabre.com

Study Locations

• Austria
  • Wien, Austria, 1090
    • Recruiting
    • Clinic
  • Oberösterreich
    • Braunau Am Inn, Oberösterreich, Austria, 5280
      • Recruiting
      • Clinic
    • Linz, Oberösterreich, Austria, 4010
      • Recruiting
      • Clinic
  • Voralberg
    • Feldkirch, Voralberg, Austria, 6807
      • Recruiting
      • Clinic
• Germany
  • Aschaffenburg, Germany
    • Recruiting
    • Hospital
  • Berlin, Germany, 10407
    • Recruiting
    • Medical Care Centre
  • Berlin, Germany, 10707
    • Recruiting
    • Practice
  • Berlin, Germany, 10715
    • Recruiting
    • Practice
  • Berlin, Germany, 12559
    • Recruiting
    • Clinic
  • Berlin, Germany
    • Recruiting
    • Private Practice
  • Dresden, Germany
    • Recruiting
    • Private Practice
  • Esslingen, Germany
    • Recruiting
    • Hospital
  • Hamburg, Germany, 10259
    • Recruiting
    • Practice
  • Hamburg, Germany, 20259
    • Recruiting
    • Practice
  • Heidelberg, Germany
    • Recruiting
    • Private Practice
  • Leer, Germany
    • Recruiting
    • Private Practice
  • Lübeck, Germany
    • Recruiting
    • Private Practice
  • Naunhof, Germany
    • Recruiting
    • Private Practice
  • Offenburg, Germany
    • Recruiting
    • Private Practice
  • Oldenburg In Holstein, Germany
    • Recruiting
    • Private Practice
  • Schorndorf, Germany
    • Recruiting
    • Private Practice
  • Würzburg, Germany
    • Recruiting
    • Private Practice
  • Baden-Württemberg
    • Offenburg, Baden-Württemberg, Germany, 77654
      • Recruiting
      • Practice
    • Ulm, Baden-Württemberg, Germany, 89073
      • Recruiting
      • Medical Care Centre
    • Ulm, Baden-Württemberg, Germany, 89081
      • Recruiting
      • Clinic
  • Bayer
    • Aschaffenburg, Bayer, Germany, 63739
      • Recruiting
      • Medical Car Centre
  • Bayern
    • Augsburg, Bayern, Germany, 86150
      • Recruiting
      • Practice
    • Donauwörth, Bayern, Germany, 86609
      • Recruiting
      • Practice
    • Erlangen, Bayern, Germany, 91054
      • Recruiting
      • Clinic
    • München, Bayern, Germany, 81241
      • Recruiting
      • Practice
    • Würzburg, Bayern, Germany, 97080
      • Recruiting
      • Practice
  • Brandenburg
    • Potsdam, Brandenburg, Germany, 14467
      • Recruiting
      • Medical Care Centre
  • Mecklenburg Vorpommern
    • Rostock, Mecklenburg Vorpommern, Germany, 18057
      • Recruiting
      • Practice
    • Rostock, Mecklenburg Vorpommern, Germany, 18107
      • Recruiting
      • Practice
  • Mecklenburg-Vorpommern
    • Rostock, Mecklenburg-Vorpommern, Germany, 18057
      • Recruiting
      • Practice
    • Rostock, Mecklenburg-Vorpommern, Germany, 18107
      • Recruiting
      • Practice
  • Melcklenburg-Vorpommern
    • Rostock, Melcklenburg-Vorpommern, Germany, 18059
      • Recruiting
      • Clinic
  • Niedersachsen
    • Celle, Niedersachsen, Germany, 29221
      • Recruiting
      • Practice
    • Goslar, Niedersachsen, Germany, 38642
      • Recruiting
      • Medical Care Centre
    • Göttingen, Niedersachsen, Germany, 37073
      • Recruiting
      • Practice
    • Hannover, Niedersachsen, Germany, 30161
      • Recruiting
      • Medical Practice
    • Hannover, Niedersachsen, Germany, 30161
      • Recruiting
      • Practice
    • Leer, Niedersachsen, Germany, 26789
      • Recruiting
      • Practice
    • Weißenfels, Niedersachsen, Germany, 26121
      • Recruiting
      • Clinic
    • Wilhelmshaven, Niedersachsen, Germany, 26389
      • Recruiting
      • Medical Practice
  • Nordrhein Westfalen
    • Aachen, Nordrhein Westfalen, Germany, 52074
      • Recruiting
      • Clinic
    • Bottrop, Nordrhein Westfalen, Germany, 46236
      • Recruiting
      • Practice
    • Essen, Nordrhein Westfalen, Germany, 45147
      • Recruiting
      • Clinic
    • Moers, Nordrhein Westfalen, Germany, 47441
      • Recruiting
      • Practice
    • Mönchengladbach, Nordrhein Westfalen, Germany, 41239
      • Recruiting
      • Medical Care Centre
    • Mülheim an der Ruhr, Nordrhein Westfalen, Germany, 45468
      • Recruiting
      • Medical Care Centre
    • Paderborn, Nordrhein Westfalen, Germany, 33098
      • Recruiting
      • Clinic
  • Nordrhein-Westfalen
    • Aachen, Nordrhein-Westfalen, Germany, 52074
      • Recruiting
      • Clinic
    • Bochum, Nordrhein-Westfalen, Germany, 44791
      • Recruiting
      • Clinic
    • Bonn, Nordrhein-Westfalen, Germany, 53123
      • Recruiting
      • Practice
    • Bonn, Nordrhein-Westfalen, Germany, 53127
      • Recruiting
      • Clinic
    • Mönchengladbach, Nordrhein-Westfalen, Germany, 41239
      • Recruiting
      • Medical Care Centre
    • Neuss, Nordrhein-Westfalen, Germany, 41462
      • Recruiting
      • Medical Care Centre
    • Paderborn, Nordrhein-Westfalen, Germany, 33098
      • Recruiting
      • Clinic
    • Porta Westfalica, Nordrhein-Westfalen, Germany, 32457
      • Recruiting
      • Medical Care Centre
    • Stolberg, Nordrhein-Westfalen, Germany, 52222
      • Recruiting
      • Practice
    • Troisdorf, Nordrhein-Westfalen, Germany, 53840
      • Recruiting
      • Practice
    • Wuppertal, Nordrhein-Westfalen, Germany, 42283
      • Recruiting
      • Clinic
  • Nordrhein-westfalen
    • Moers, Nordrhein-westfalen, Germany, 47441
      • Recruiting
      • Practice
  • Rheinland Pfalz
    • Bad Kreuznach, Rheinland Pfalz, Germany, 55543
      • Recruiting
      • Practice
    • Kaiserslautern, Rheinland Pfalz, Germany, 67655
      • Recruiting
      • Practice
    • Worms, Rheinland Pfalz, Germany, 67547
      • Recruiting
      • Practice
  • Saarland
    • Saarbrücken, Saarland, Germany, 66113
      • Recruiting
      • Clinic
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • Recruiting
      • Practice
    • Naunhof, Sachsen, Germany, 04683
      • Recruiting
      • Prctice
    • Torgau, Sachsen, Germany, 04860
      • Recruiting
      • Clinic
  • Sachsen-Anhalt
    • Halle, Sachsen-Anhalt, Germany, 06110
      • Recruiting
      • Practice
    • Köthen, Sachsen-Anhalt, Germany, 06366
      • Recruiting
      • Clinic
    • Köthen, Sachsen-Anhalt, Germany, 06366
      • Recruiting
      • Practice
  • Schleswig-Holstein
    • Flensburg, Schleswig-Holstein, Germany, 24939
      • Recruiting
      • Clinic
  • Thüringen
    • Eisenach, Thüringen, Germany, 99817
      • Recruiting
      • Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Adult patients with metastatic, BRAFV600E-mutant, colorectal carcinoma, who have received prior systemic therapy, with the decision to receive the doublet therapy encorafenib plus cetuximab according to the current SmPC.

Description

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).

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

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

Collaborators and Investigators

• Sponsor: Pierre Fabre Pharma GmbH
• Collaborators: iOMEDICO AG; Pierre Fabre Pharma Austria; Pierre Fabre Pharma AG

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2020
• Primary Completion (Anticipated): September 1, 2026
• Study Completion (Anticipated): January 1, 2027

Study Registration Dates

• First Submitted: October 8, 2020
• First Submitted That Met QC Criteria: December 13, 2020
• First Posted (Actual): December 17, 2020

Study Record Updates

• Last Update Posted (Actual): September 29, 2022
• Last Update Submitted That Met QC Criteria: September 27, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: BRAFV600E mutation
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Carcinoma; Colorectal Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Cetuximab
• Other Study ID Numbers: NIS-PFO-2020-3101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No