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RAS precision medicine trans-atlantic partnership: multi-centre pooled analysis of RAS pathway mutations in advanced NSCLC
Adderley, Helen Aldea, M. Aredo, J. Carter, Mathew Church, Matt Blackhall, Fiona H Krebs, Matthew G Wakelee, H. A. Besse, B. Planchard, D.
Adderley, Helen
Aldea, M.
Aredo, J.
Carter, Mathew
Church, Matt
Blackhall, Fiona H
Krebs, Matthew G
Wakelee, H. A.
Besse, B.
Planchard, D.
Citations
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Abstract
Introduction: The most common histological subtype of non-small
cell lung cancer (NSCLC) is adenocarcinoma (50-55% of patients), of
which the most common oncogenic driver is KRAS mutation (w30%
internationally). Genetic data has altered the taxonomy of NSCLC
over the past 10 years, highlighting subgroups such as EGFR mutation,
which have improved prognosis and are susceptible to targeted
therapies. Despite its frequency, targeting RAS has historically
been limited by pre-clinical and clinical failures. Emerging preclinical/
clinical data suggests there is value looking beyond RAS mutation,
analysing subtypes- represented by a limited number of
variations in its mutational isoforms, codons and alleles. Through
international collaboration our partnership aims to extend existing
knowledge of RAS precision medicine in NSCLC, evaluating biological,
clinical and treatment effects at subtype level. Methods: For
this analysis, the first 309/384 patients with stage IIIb/IV RAS- and/
or NF1-mutant NSCLC were identified from the Christie NHS Foundation
Trust and the Gustave Roussy Cancer Centre between August
2008 and July 2020. DNA was extracted from archival FFPE samples,
plasma or both to identify mutations using targeted next generation
sequencing. Molecular, clinical, pathological and outcome data were
collected on all patients and Kaplan-Meier survival analysis was
performed to test for survival differences between subtypes based
on treatment arms. For clinical characteristics, Mann-Whitney and
Fisher’s exact tests were used for statistical comparisons in
continuous and dichotomous datasets, respectively. Results: Of 309
patients analysed, 151 patients were from the Christie NHS Foundation
Trust and 158 patients from the Gustave Roussy Cancer
Centre. Mean age was 63, range 19-92. 30 patients (10%) had stage
IIIb disease with the remainder stage IV, 292 patients (94.5%)
demonstrated non-squamous histology vs. 16 (5%) squamous vs 1
(0.5%) adenosquamous. Median PD-L1 status across the cohort
was 20%. 209 patients (68%) had a mutation identified by tissue
analysis, 38 patients (12%) by plasma and 62 (20%) by both. The
most common RAS mutation identified was KRAS in 259 patients
(84%), followed by NRAS in 13 patients (4%) and HRAS in 7 patients
(2%). Amongst the KRAS mutant population, 111 pts (43%)
harboured a mutation in G12C, followed by 52 (20%) G12D and 41
(16%) G12V. Codon 61 was most commonly mutated within this
subgroup 16/259 (6%). 40 patients (13%) were identified as
carrying a mutation in NF1; 35 non-squamous histology, 4 squamous
and 1 adenosquamous. Progression free survival following
first line chemotherapy plus immunotherapy or immunotherapy
alone was variable across KRAS-, NRAS- and NF1-mutant subgroups
(8.3 vs. 14.9 vs. 10.2 months; p¼0.86). Median PD-L1 status was
found to be 63% vs. 100% vs. 79% respectively. Analysis of RAS
codon and allelic subgroups, including their therapeutic vulnerabilities
beyond immunotherapy, will be presented following further
analysis. Conclusion: The RAS precision medicine Trans-Atlantic
partnership is designed to evaluate prognostic/predictive value of
RAS and NF1 mutations in advanced NSCLC, focusing specifically
on signal seeking for therapeutic vulnerabilities in mutant RAS
isoforms, codons, and allelic subtypes. Ongoing analysis is planned
to expand the dataset and inform the optimal sequence of
therapy for subtypes of RAS- and NF1-mutant patients.
Description
Date
2021
Publisher
Collections
Keywords
Type
Meetings and Proceedings
Citation
Adderley H, Aldea M, Aredo J, Carter M, Church M, Blackhall F, et al. P90.04 RAS Precision Medicine Trans-Atlantic Partnership: Multi-Centre Pooled Analysis of RAS Pathway Mutations in Advanced NSCLC. Journal of Thoracic Oncology. 2021 Mar;16(3):S696–7.