Abstract
Understanding resistance in V600E BRAF advanced colon cancer treated with BRAF inhibitors plus anti-EGFR antibodies +/- MEK inhibitors: The URBAN study.
Author
person
Francesca Bergamo
Medical Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy, Italy
info_outline
Francesca Bergamo, Giada Munari, Krisida Cerma, Carlotta Ceccon, Rossana Intini, Chiara Borga, Riccardo Cerantola, Vittoria Matilde Piva, Valentina Angerilli, Alessandra Anna Anna Prete, Aldo Montagna, Mario Domenico Rizzato, Marianna Sabbadin, Giulia Barsotti, Chiara De Toni, Letizia Procaccio, Caterina Soldà, Angelo Paolo Dei Tos, Sara Lonardi, Matteo Fassan
Full text
Authors
person
Francesca Bergamo
Medical Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy, Italy
info_outline
Francesca Bergamo, Giada Munari, Krisida Cerma, Carlotta Ceccon, Rossana Intini, Chiara Borga, Riccardo Cerantola, Vittoria Matilde Piva, Valentina Angerilli, Alessandra Anna Anna Prete, Aldo Montagna, Mario Domenico Rizzato, Marianna Sabbadin, Giulia Barsotti, Chiara De Toni, Letizia Procaccio, Caterina Soldà, Angelo Paolo Dei Tos, Sara Lonardi, Matteo Fassan
Organizations
Medical Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy, Italy, Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy, Medical Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy, Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy, Italy, Department of Surgery, Oncology and Gastroenterology, University of Padua and Medical Oncology 1, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy, Medical Oncology 3, Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy
Abstract Disclosures
Research Funding
Institutional Funding
Partially funded by the Italian Ministry of Health grant “Ricerca Finalizzata Giovani Ricercatori” [grant number GR2019-12368903]
Background:
The combination of BRAF inhibitors (BRAFi) plus anti-EGFR antibodies is a new standard of care in
V600E BRAF
mutated (mut) metastatic colorectal cancer (mCRC). Nevertheless, resistance develops during the target therapy (TT). We designed the URBAN study, a translational prospective project, in order to identify possible primary and acquired resistance mechanisms.
Methods:
Patients (pts) with
V600E BRAF
mut mCRC treated with BRAFi + anti-EGFR +/- MEK inhibitors at Veneto Institute of Oncology were enrolled. Clinical data and liquid biopsy at baseline and progression were collected. The ctDNA derived from plasma was analyzed by the AVENIO expanded kit, a hybridization capture sequencing-based 77 genes pan-cancer assay contained in NCCN Guidelines. Survival outcomes were calculated using Kaplan–Meier curves, log-rank tests and univariate Cox regression models were also performed. The study is exploratory and no formal hypothesis has been postulated.
Results:
Forty consecutive
V600E BRAF
mut mCRC pts were enrolled. Median age was 63 years (42-77), 47.5% of pts were males. Right CRC were 65% and 20% were MSI-H. Only 5% of pts received TT after second line; doublet regimen was administered in 60% of pts while triplet in 40%. According to the mPFS of doublet arm in the BEACON trial (4.2 months, mo), our population was divided in responder (R), 24 (60%), and non-responder (NR), 16 (40%). In R vs NR group, mPFS was 9 vs 3.2 mo while mOS was 21.6 vs 10.7 mo, respectively. The
V600E BRAF
mut was detected in 85% of the pre-treatment plasma samples without statistically significant differences in the genomic alterations between R and NR groups, but there was a higher frequency of
MET
and
EGFR
amplification in NR group. At progression, the mutation of
BRAF
was lost in 2 cases in R group. After receiving TT, the most common acquired mutations involved
RAS
genes: 16 pts (40%) acquired at least one activating mutation in
KRAS
and/or
NRAS
. Among these, 9 pts showed multiple mutations of the same
RAS
gene probably due to both intra- and inter-lesional heterogeneities; none of these pts had MSI-H mCRC. We found a higher number of
RAS
and
MAP2K1
acquired mutations in NR and a trend to acquire
EGFR
amplification in R group. Inactivating mutations in
RFN43
gene was observed in 2 cases in R group. These data did not reach statistical significance, probably due to the low number of cases. Interestingly, 37% of NR pts acquired three or more molecular alterations vs 13% in R group. Furthermore, a higher number of genetic alterations was acquired in pts treated with doublet vs triplet regimen.
Conclusions:
This prospective, observational molecular profiling study provided further evidences to support the use of ctDNA in capturing the dynamic somatic mutational spectrum in
V600E BRAF
mut mCRC and to identify potential mechanisms of resistance to TT. An expansion of study population is ongoing.
9 organizations
3 drugs
9 targets
Organization
Department of Oncology and Haematology, Division of Oncology, University Hospital of Modena, Modena, ItalyOrganization
Veneto Institute of Oncology IOV–IRCCSOrganization
Padua, ItalyOrganization
Department of Medicine (DIMED) University of Padua and Veneto Institute of Oncology (IOV-IRCCS )Organization
Surgical Pathology & Cytopathology UnitOrganization
University of Padua School of MedicineOrganization
Medical Oncology 3Drug
BRAF inhibitorsDrug
MEK inhibitorsTarget
NRASTarget
KRAS G12CTarget
BRAFTarget
MAP2K1Target
RFN43Target
RAS/BRAFTarget
MEK1Target
metastatic breast cancer