Clinical trial NCT04775095: BRAF V600-mutated Lung Carcinoma Treated With the Combination of Dabrafenib-trametinib: a Retrospective Evaluation
Official title: BRAF V600-mutated Lung Carcinoma Treated With the Combination of Dabrafenib-trametinib: a Retrospective Evaluation (Secondary Data Use Study of Dabrafenib-Trametinib in "Real Life" for Non-Small Cell Lung Cancer With a BRAF V600 Mutation)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Non Small Cell Lung Cancer
BRAF V600 Mutation
Keywords: Non-Small Cell Lung Cancer
BRAF V600 Mutation
Real-world study
IFCT
Lead sponsor: Intergroupe Francophone de Cancerologie Thoracique
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2021-03-01
Enrollment: 163
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All patients with histologically or cytologically confirmed extensive stage NSCLC with BRAF V600 (E or non E) mutation diagnosed on tumor sample and/or on liquid biopsy (co mutations allowed) between 01/01/2016 and 31/12/2019

Brief summary: BLaDE cohort will evaluate overall survival (OS), real world progression-free survival (PFS), best response and duration of treatment in patients with advanced, metastatic Non-Small Cell Lung Cancer (NSCLC) harboring BRAF V600E or non E mutation who received dabrafeninb-trametinib combination or not. Subsequent or previous treatments (treatments delivered after or before dabrafeninb-trametinib combination will be recorded). Those outcomes will be correlated to clinical, pathological, and radiological characteristics of patients.

Detailed description: The braf gene (V Raf murine sarcoma viral oncogene homolog, long arm of chromosome 7q3) codes for a protein (serine / threonine kinase) which regulates the signaling pathway RAS - RAF - MEK - ERK playing an important role in the proliferation processes, cell survival, angiogenesis, cell invasion and migration.

When activated by mutations, BRAF phosphorylates MEK to promote cell growth, proliferation and survival. In non-small cell lung cancer (NSCLC), BRAF mutations are found in 1-2% of cases. BRAF mutations are distinguished by kinase activity and their signaling via the mitogen-activated kinase (MAPK) pathway. BRAF V600 mutations, class I, signal as monomers with or without activated RAS. BRAF non-V600 are classified as either class II that signal as dimmers when RAS as activated or class III with impaired kinase activity but increased MAPK pathway signaling. The most frequent mutation in NSCLC (50% of cases) is the V600E mutation (glutamate / valine substitution, codon 600 of exon 15) which is activating (others mutations: G469A and D594G, respectively 39% and 11% of cases). One phase II trial demonstrated that the dabrafenib-trametinib combination had significant anti-tumor activity in terms of response rate, PFS in patients with a NSCLC with the BRAF V600E mutation, pretreated or not. In this multicentre non-randomized phase II open label study, a dabrafenib-trametinib combination was tested in 59 previously treated patients with metastatic stage IV BRAF V600E mutated NSCLC with documented progression after at least one prior platinum based chemotherapy. Overall response rate (ORR) was 63.2% (95% CI: 49.3 to 75.6%), median PFS was 9.7 months (95%CI 6.9-19.6). In the cohort of patients previously untreated (n=36) and treated with first line dabrafenib-trametinib combination, the investigator-assessed confirmed ORR was 64% (95% CI 46-79 %), the median investigator assessed PFS was 10.9 months (95CI:7-16.6) and the 6 month-PFS was 72% (53-84%) respectively.

At the last ASCO conference 2020, the data have been updated. In cohorts of untreated and previously treated patients, the ORR was 63.9% (95CI 46.2-79.2) and 68.4% (95CI 54.8, 80.1), median PFS 10.8 months (95CI 7.0-14.5) and 10.2 months (95CI: 6.9-16.7). Median OS was 17.3 months (95% CI: 12.3-40.2; 3 years OS: 40%) and 18.2 months (95% CI: 14.3-28.6; 3 years OS: 33%) with 14/36 and 11/57 patients alive in treatment naïve and pretreated patients respectively.

The dabrafenib-trametinib combination had European authorization since 2017. In January 2020, the French Transparency Committee validated its possible use in second line in current practice, after failure of a first therapeutic line (whatever its nature) but only for BRAF V600E mutations. Clinical outcomes data on BRAF-mutated V600 NSCLC patients treated in routine practice by dabrafenib-trametinib combination is limited with only retrospective studies including few patients.

The primary objective of this retrospective multicenter observational study is to describe, in real world, the characteristics and evolution of NSCLC patients with a BRAF V600 E mutation treated with the dabrafenib-trametinib combination regardless of the line of treatment. Also, this retrospective multicenter observational will describe in real world, the characteristics, treatment and evolution of NSCLC patients with a BRAF V600 non E mutation.

Eligibility criteria: Inclusion Criteria:

* Patients with histologically or cytologically confirmed extensive stage NSCLC
* Presence of BRAF V 600 E or non E mutation diagnosed on tumor sample and/or on liquid biopsy (co mutations allowed) between 01/01/2016 and 31/12/2019
* Patients who received at least one dose of treatment with dabrafenib-trametinib combination (whatever the treatment line)
* NSCLC BRAF V600 patients who have not received the dabrafenib-trametinib combination will be included for the collection of clinical and demographic data, treatments received and OS
* Patients who were informed about the study and do not refused for their data to be collected and used
* Age \> 18 years

Exclusion Criteria:

* Patients harboring a non V600 BRAF mutation
* Patients enrolled in a clinical trial assessing treatment with dabrafenib-trametinib combination
* Explicit refusal by the patient to collect his or her data
* Patients under curatorship or guardianship
* Unable to obtain data collection

Primary outcomes:
measure: Overall survival (OS) at 12 months in non-small cell lung cancer (NSCLC) BRAF V600E-mutated patients receiving the combination of dabrafenib-trametinib as second line or more treatment
timeFrame: 12 months
Secondary outcomes:
measure: OS at 18 and 24 months and median OS in NSCLC BRAF V600E-mutated patients receiving the combination of dabrafenib-trametinib as second line or more treatment
timeFrame: 18 and 24 months
measure: OS at 12, 18 and 24 months and median OS in NSCLC BRAF V600E-mutated patients receiving the combination of dabrafenib-trametinib as first-line treatment
timeFrame: at 12, 18 and 24 months
measure: OS at 12, 18 and 24 months and median OS in NSCLC BRAF V600E-mutated patients regardless of the treatment received
timeFrame: at 12, 18 and 24
measure: OS at 12, 18 and 24 months and median OS in NSCLC BRAF V600E-mutated patients not treated by the combination of dabrafenib-trametinib, according to the treatment and the line received
timeFrame: at 12, 18 and 24
measure: OS at 12 months and median OS in NSCLC BRAF V600 non E-mutated patients according to the treatment and the line received
timeFrame: at 12 months
Other outcomes:
Locations:
city: Créteil
country: France
facility: Créteil - CHI
city: Lyon
country: France
facility: Lyon - CRLCC
Study officials:
affiliation: Créteil -CHI
name: Jean-Bernard AULIAC, Dr
role: STUDY_CHAIR
affiliation: Lyon - CLCC
name: Aurélie SWALDUZ, Dr
role: STUDY_CHAIR
References: