Clinical trial NCT04673955: BRAF Inhibitor Encorafenib And Cetuximab Real Life Investigation of Next Generation CRC Treatment
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
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Metastatic Colorectal Carcinoma
Keywords: BRAFV600E mutation
Lead sponsor: Pierre Fabre Pharma GmbH
Sponsor class: INDUSTRY
Collaborators: name: iOMEDICO AG
name: Pierre Fabre Pharma AG
name: Pierre Fabre Pharma Austria
First posted: 2020-12-17
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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).

Primary outcomes:
measure: Overall Survival
timeFrame: At 12 months after start of treatment
Secondary outcomes:
measure: Patient and disease profiles at start of treatment with encorafenib plus cetuximab
timeFrame: Baseline
measure: BRAF-mutation assessment
timeFrame: Baseline
measure: Type and sequence of treatments before and after encorafenib plus cetuximab
timeFrame: Through study completion, an average of 17 months
measure: Characteristics of treatment with encorafenib plus cetuximab
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Effectiveness of treatment with encorafenib and cetuximab
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Effectiveness of treatment with encorafenib and cetuximab
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Effectiveness of treatment with encorafenib and cetuximab
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Effectiveness of treatment with encorafenib and cetuximab
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Effectiveness of treatment with encorafenib and cetuximab
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Effectiveness of treatment with encorafenib and cetuximab
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Effectiveness of treatment with encorafenib and cetuximab
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Effectiveness of treatment with encorafenib and cetuximab
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Patient reported outcomes during treatment with encorafenib plus cetuximab - evaluated with EORTC QLQ C-30
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Patient's treatment satisfaction - overall
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Physician's treatment satisfaction - differentiated by efficiency, safety and overall
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Safety and tolerability of treatment with encorafenib and cetuximab - Adverse events and adverse reactions including time to onset and time to resolution
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Treatment duration
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Treatment dose intensity
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Number of treatment interruptions
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
measure: Duration of treatment interruptions
timeFrame: Through encorafenib plus cetuximab treatment completion, an average of 9 months
Other outcomes:
Locations:
city: Braunau Am Inn
country: Austria
facility: Clinic
state: Oberösterreich
city: Linz
country: Austria
facility: Clinic
state: Oberösterreich
city: Feldkirch
country: Austria
facility: Clinic
state: Voralberg
city: Wien
country: Austria
facility: Clinic
city: Offenburg
country: Germany
facility: Practice
state: Baden-Württemberg
city: Ulm
country: Germany
facility: Medical Care Centre
state: Baden-Württemberg
city: Ulm
country: Germany
facility: Clinic
state: Baden-Württemberg
city: Augsburg
country: Germany
facility: Practice
state: Bayern
city: Donauwörth
country: Germany
facility: Practice
state: Bayern
city: Erlangen
country: Germany
facility: Clinic
state: Bayern
city: München
country: Germany
facility: Practice
state: Bayern
city: Würzburg
country: Germany
facility: Practice
state: Bayern
city: Aschaffenburg
country: Germany
facility: Medical Car Centre
state: Bayer
city: Potsdam
country: Germany
facility: Medical Care Centre
state: Brandenburg
city: Rostock
country: Germany
facility: Practice
state: Mecklenburg Vorpommern
city: Rostock
country: Germany
facility: Practice
state: Mecklenburg Vorpommern
city: Rostock
country: Germany
facility: Practice
state: Mecklenburg-Vorpommern
city: Rostock
country: Germany
facility: Practice
state: Mecklenburg-Vorpommern
city: Rostock
country: Germany
facility: Clinic
state: Melcklenburg-Vorpommern
city: Celle
country: Germany
facility: Practice
state: Niedersachsen
city: Goslar
country: Germany
facility: Medical Care Centre
state: Niedersachsen
city: Göttingen
country: Germany
facility: Practice
state: Niedersachsen
city: Hannover
country: Germany
facility: Medical Practice
state: Niedersachsen
city: Hannover
country: Germany
facility: Practice
state: Niedersachsen
city: Leer
country: Germany
facility: Practice
state: Niedersachsen
city: Weißenfels
country: Germany
facility: Clinic
state: Niedersachsen
city: Wilhelmshaven
country: Germany
facility: Medical Practice
state: Niedersachsen
city: Aachen
country: Germany
facility: Clinic
state: Nordrhein Westfalen
city: Bottrop
country: Germany
facility: Practice
state: Nordrhein Westfalen
city: Essen
country: Germany
facility: Clinic
state: Nordrhein Westfalen
city: Moers
country: Germany
facility: Practice
state: Nordrhein Westfalen
city: Mönchengladbach
country: Germany
facility: Medical Care Centre
state: Nordrhein Westfalen
city: Mülheim an der Ruhr
country: Germany
facility: Medical Care Centre
state: Nordrhein Westfalen
city: Paderborn
country: Germany
facility: Clinic
state: Nordrhein Westfalen
city: Aachen
country: Germany
facility: Clinic
state: Nordrhein-Westfalen
city: Bochum
country: Germany
facility: Clinic
state: Nordrhein-Westfalen
city: Bonn
country: Germany
facility: Practice
state: Nordrhein-Westfalen
city: Bonn
country: Germany
facility: Clinic
state: Nordrhein-Westfalen
city: Moers
country: Germany
facility: Practice
state: Nordrhein-westfalen
city: Mönchengladbach
country: Germany
facility: Medical Care Centre
state: Nordrhein-Westfalen
city: Neuss
country: Germany
facility: Medical Care Centre
state: Nordrhein-Westfalen
city: Paderborn
country: Germany
facility: Clinic
state: Nordrhein-Westfalen
city: Porta Westfalica
country: Germany
facility: Medical Care Centre
state: Nordrhein-Westfalen
city: Stolberg
country: Germany
facility: Practice
state: Nordrhein-Westfalen
city: Troisdorf
country: Germany
facility: Practice
state: Nordrhein-Westfalen
city: Wuppertal
country: Germany
facility: Clinic
state: Nordrhein-Westfalen
city: Bad Kreuznach
country: Germany
facility: Practice
state: Rheinland Pfalz
city: Kaiserslautern
country: Germany
facility: Practice
state: Rheinland Pfalz
city: Worms
country: Germany
facility: Practice
state: Rheinland Pfalz
city: Saarbrücken
country: Germany
facility: Clinic
state: Saarland
city: Halle
country: Germany
facility: Practice
state: Sachsen-Anhalt
city: Köthen
country: Germany
facility: Clinic
state: Sachsen-Anhalt
city: Köthen
country: Germany
facility: Practice
state: Sachsen-Anhalt
city: Dresden
country: Germany
facility: Practice
state: Sachsen
city: Naunhof
country: Germany
facility: Prctice
state: Sachsen
city: Torgau
country: Germany
facility: Clinic
state: Sachsen
city: Flensburg
country: Germany
facility: Clinic
state: Schleswig-Holstein
city: Eisenach
country: Germany
facility: Clinic
state: Thüringen
city: Aschaffenburg
country: Germany
facility: Hospital
city: Berlin
country: Germany
facility: Medical Care Centre
city: Berlin
country: Germany
facility: Practice
city: Berlin
country: Germany
facility: Practice
city: Berlin
country: Germany
facility: Clinic
city: Berlin
country: Germany
facility: Private Practice
city: Dresden
country: Germany
facility: Private Practice
city: Esslingen
country: Germany
facility: Hospital
city: Hamburg
country: Germany
facility: Practice
city: Hamburg
country: Germany
facility: Practice
city: Heidelberg
country: Germany
facility: Private Practice
city: Leer
country: Germany
facility: Private Practice
city: Lübeck
country: Germany
facility: Private Practice
city: Naunhof
country: Germany
facility: Private Practice
city: Offenburg
country: Germany
facility: Private Practice
city: Oldenburg In Holstein
country: Germany
facility: Private Practice
city: Schorndorf
country: Germany
facility: Private Practice
city: Würzburg
country: Germany
facility: Private Practice
Study officials:
References: