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

Metastatic Colorectal Carcinoma Clinical Trial

— BERING-CRC  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04673955
• Other study ID #: NIS-PFO-2020-3101
• Status: Recruiting
• Start date: September 3, 2020
• Est. completion date: January 2027

Study information

• Verified date: September 2022
• Source: Pierre Fabre Pharma GmbH
• Contact: Marion Schmoll
• Phone: +4976115242627
• Email: marion.schmoll[@]iomedico.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: January 2027
• Est. primary completion date: September 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Carcinoma
• Colorectal Neoplasms
• Metastatic Colorectal Carcinoma

Intervention

Drug:
• Encorafenib
Observation of real-life treatment with encorafenib and cetuximab
• Cetuximab
Observation of real-life treatment with encorafenib and cetuximab

Locations

Country	Name	City	State
Austria	Clinic	Braunau Am Inn	Oberösterreich
Austria	Clinic	Feldkirch	Voralberg
Austria	Clinic	Linz	Oberösterreich
Austria	Clinic	Wien
Germany	Clinic	Aachen	Nordrhein Westfalen
Germany	Clinic	Aachen	Nordrhein-Westfalen
Germany	Hospital	Aschaffenburg
Germany	Medical Car Centre	Aschaffenburg	Bayer
Germany	Practice	Augsburg	Bayern
Germany	Practice	Bad Kreuznach	Rheinland Pfalz
Germany	Clinic	Berlin
Germany	Medical Care Centre	Berlin
Germany	Practice	Berlin
Germany	Practice	Berlin
Germany	Private Practice	Berlin
Germany	Clinic	Bochum	Nordrhein-Westfalen
Germany	Clinic	Bonn	Nordrhein-Westfalen
Germany	Practice	Bonn	Nordrhein-Westfalen
Germany	Practice	Bottrop	Nordrhein Westfalen
Germany	Practice	Celle	Niedersachsen
Germany	Practice	Donauwörth	Bayern
Germany	Practice	Dresden	Sachsen
Germany	Private Practice	Dresden
Germany	Clinic	Eisenach	Thüringen
Germany	Clinic	Erlangen	Bayern
Germany	Clinic	Essen	Nordrhein Westfalen
Germany	Hospital	Esslingen
Germany	Clinic	Flensburg	Schleswig-Holstein
Germany	Medical Care Centre	Goslar	Niedersachsen
Germany	Practice	Göttingen	Niedersachsen
Germany	Practice	Halle	Sachsen-Anhalt
Germany	Practice	Hamburg
Germany	Practice	Hamburg
Germany	Medical Practice	Hannover	Niedersachsen
Germany	Practice	Hannover	Niedersachsen
Germany	Private Practice	Heidelberg
Germany	Practice	Kaiserslautern	Rheinland Pfalz
Germany	Clinic	Köthen	Sachsen-Anhalt
Germany	Practice	Köthen	Sachsen-Anhalt
Germany	Practice	Leer	Niedersachsen
Germany	Private Practice	Leer
Germany	Private Practice	Lübeck
Germany	Practice	Moers	Nordrhein Westfalen
Germany	Practice	Moers	Nordrhein-westfalen
Germany	Medical Care Centre	Mönchengladbach	Nordrhein-Westfalen
Germany	Medical Care Centre	Mönchengladbach	Nordrhein Westfalen
Germany	Medical Care Centre	Mülheim an der Ruhr	Nordrhein Westfalen
Germany	Practice	München	Bayern
Germany	Prctice	Naunhof	Sachsen
Germany	Private Practice	Naunhof
Germany	Medical Care Centre	Neuss	Nordrhein-Westfalen
Germany	Practice	Offenburg	Baden-Württemberg
Germany	Private Practice	Offenburg
Germany	Private Practice	Oldenburg In Holstein
Germany	Clinic	Paderborn	Nordrhein Westfalen
Germany	Clinic	Paderborn	Nordrhein-Westfalen
Germany	Medical Care Centre	Porta Westfalica	Nordrhein-Westfalen
Germany	Medical Care Centre	Potsdam	Brandenburg
Germany	Clinic	Rostock	Melcklenburg-Vorpommern
Germany	Practice	Rostock	Mecklenburg Vorpommern
Germany	Practice	Rostock	Mecklenburg Vorpommern
Germany	Practice	Rostock	Mecklenburg-Vorpommern
Germany	Practice	Rostock	Mecklenburg-Vorpommern
Germany	Clinic	Saarbrücken	Saarland
Germany	Private Practice	Schorndorf
Germany	Practice	Stolberg	Nordrhein-Westfalen
Germany	Clinic	Torgau	Sachsen
Germany	Practice	Troisdorf	Nordrhein-Westfalen
Germany	Clinic	Ulm	Baden-Württemberg
Germany	Medical Care Centre	Ulm	Baden-Württemberg
Germany	Clinic	Weißenfels	Niedersachsen
Germany	Medical Practice	Wilhelmshaven	Niedersachsen
Germany	Practice	Worms	Rheinland Pfalz
Germany	Clinic	Wuppertal	Nordrhein-Westfalen
Germany	Practice	Würzburg	Bayern
Germany	Private Practice	Würzburg

Sponsors (4)

Lead Sponsor	Collaborator
Pierre Fabre Pharma GmbH	iOMEDICO AG, Pierre Fabre Pharma AG, Pierre Fabre Pharma Austria

Countries where clinical trial is conducted

Austria,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival	Overall Survival rate	At 12 months after start of treatment
Secondary	Patient and disease profiles at start of treatment with encorafenib plus cetuximab	Demographic and disease chracteristics	Baseline
Secondary	BRAF-mutation assessment	Date and type of BRAFV600E testing	Baseline
Secondary	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
Secondary	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
Secondary	Effectiveness of treatment with encorafenib and cetuximab	Further Overall Survival parameters	Through encorafenib plus cetuximab treatment completion, an average of 9 months
Secondary	Effectiveness of treatment with encorafenib and cetuximab	Best observed tumor response	Through encorafenib plus cetuximab treatment completion, an average of 9 months
Secondary	Effectiveness of treatment with encorafenib and cetuximab	Time to progression	Through encorafenib plus cetuximab treatment completion, an average of 9 months
Secondary	Effectiveness of treatment with encorafenib and cetuximab	Overall response rate	Through encorafenib plus cetuximab treatment completion, an average of 9 months
Secondary	Effectiveness of treatment with encorafenib and cetuximab	Duration of response	Through encorafenib plus cetuximab treatment completion, an average of 9 months
Secondary	Effectiveness of treatment with encorafenib and cetuximab	Progression-free-survival	Through encorafenib plus cetuximab treatment completion, an average of 9 months
Secondary	Effectiveness of treatment with encorafenib and cetuximab	Disease control rate	Through encorafenib plus cetuximab treatment completion, an average of 9 months
Secondary	Effectiveness of treatment with encorafenib and cetuximab	Duration of disease control	Through encorafenib plus cetuximab treatment completion, an average of 9 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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