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Report from the World Conference on Lung Cancer
Lung cancer
Results from The Lung Cancer Mutation Consortium (LCMC)
Dr. Grzegorz Korpanty, MD, PhD, MRCP Department of Medical Oncology, Princess Margaret Hospital
Trial summary: Matching therapies to oncogenic
drivers
Kris M, Johnson B, Berry L, et al. Treatment with therapies matched to
oncogenic drivers improves survival in patients with lung cancers:
results from the Lung Cancer Mutation Consortium (LCMC) J Thorac
Oncol 2013; 8 (suppl 2):S3 Abstract PL02.2.
Background
Detecting and targeting oncogenic drivers like EGFR gene
mutation and ALK translocation have transformed the care
of patients with lung adenocarcinoma. The Lung Cancer
Mutation Consortium (LCMC) tests tumours for alterations
in the 10 most commonly mutated genes in lung adenocarcinoma using multiplexed assays. The results are provided
to clinicians to enable selection of treatments and clinical
trials matched to the detected driver mutation(s).
Fourteen US LCMC sites enrolled patients (N=1007)
with metastatic lung adenocarcinoma and tested their
tumours for activating mutations in 10 oncogenic driver genes.
The majority of patients were women, never- or formersmokers, with ECOG performance status 0–1. Median age
was 63 years. Tumours were tested from the 1007 patients
for at least 1 gene and from 733 patients for all 10 genes.
Results of genotyping are presented in Table 1.
Table 1. Oncogenic drivers and matching therapies in lung cancers
tested by LCMC
Driver
Any genotyping
(n=1007)
Targeted therapy
(n=1007)
Any Driver
622 (63%)
279 (28%)
EGFR (sensitizing)
156 (16%)
129 (82%)
EGFR (other)
53 (5%)
40 (75%)
ALK
78 (8%)
51 (65%)
KRAS
244 (24%)
22 (9%)
HER2
19 (2%)
11 (58%)
BRAF
18 (2%) (14-V600E)
3 (17%)
PIK3CA
7 (1%)
0
MET amplification
6 (1%)
3 (50%)
NRAS
5 (1%)
0
MEK1
2
0
Two drivers
34 (3%)
20 (58%)
Table 2. Survival of patients with the most common drivers (N=526)
Findings
For cases with any genotyping, results guided selection of
targeted therapy or clinical trial in 275 (28%). Among 942
patients with available full followup data, the median survival was 3.5 years for the 264 patients with an oncogenic
driver treated with genotype-directed therapy, 2.4 years for
the 318 patients with an oncogenic driver who were not
treated with genotype-directed therapy, and 2.1 years for
the 360 patients with no driver identified (p<0.0001).
The authors concluded that lung cancer patients with
oncogenic drivers receiving a corresponding targeted agent
lived longer (see Table 2) than patients who did not
received targeted treatment. An actionable driver was
detected in 64% of tumours from patients with lung adenocarcinoma and guided treatment selection and targeted trial
enrolment in nearly 1/3 of patients. This paradigm of care
and research in lung cancer will further expand as genotyping
becomes more efficient with Next Generation Sequencing
(NGS) platforms that will help to identify additional oncogenic and targetable drivers (i.e. ROS1 and RET).
Commentary: In the past few years, the oncology
community has seen a paradigm shift in the molecular diagnosis and treatment of lung cancer thanks to the identification
of mutations within the EGFR gene that are sensitive to
EGFR tyrosine kinase inhibitors (TKIs; erlotinib, gefitinib,
afatinib), and ALK rearrangements (i.e. EML4-ALK) that
are sensitive to the anti-ALK drug, crizotinib.1-4 These
breakthrough discoveries provided the unique opportunity
for molecularly selected lung cancer patients to receive targeted, personalized treatment options that resulted in
Driver
N
Median survival in years
(95% CI)
EGFR (sensitizing)
140
4.0 (2.7–5.4)
EGFR (other)
50
3.3 (2.2–6.2)
ALK
73
4.3 (3.0–NA)
KRAS
231
2.4 (1.9–3.6)
Two drivers
32
2.0 (1.6–4.6)
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unprecedented response rates and significantly prolonged
PFS when compared with systemic chemotherapy.5-13
Molecular testing of tumour samples from patients with
non-small cell lung cancer (NSCLC) is now recommended
by oncology societies worldwide.19, 20 Several international
guidelines now recommend first-line treatment with EGFR
TKIs and crizotinib in patients with EGFR-mutated and
ALK-rearranged NSCLC, respectively.18 Rapid evolution
and advances in DNA-based high-throughput genomic
technologies enable faster, cheaper and more accurate gene
sequencing when compared with first-generation Sanger
sequencing techniques.15,16
To improve patient outcomes, we have to be able to offer
specific targeted therapy to those patients with actionable/
“drugable” driver mutations.17,18 So far, outside of clinical trials
we can offer these treatments to only 2 groups of patients:
those with EGFR mutation and ALK rearrangement, the
vast majority of whom have adenocarcinoma histology.
The LCMC trial is an exciting collaborative initiative
supported by the National Cancer Institute (NCI) to characterize molecular/genetic profiles of lung adenocarcinomas
based on analysis of 10 common genetic driver mutations,
and facilitate delivery of personalized/targeted treatments
to patients based on these molecular/genetic profiles
(Table 1). The updated results (including survival of patients)
of the LCMC for 1007 enrolled patients were presented at
the 15th World Conference on Lung Cancer this year.
The most common genetic mutations (see Table 1) are
KRAS (24%), followed by EGFR (21%) and ALK (8%).
More than 60% of patients were found to have 1 mutation
in a test panel of 10 genes and 3% had 2 separate mutations
present. In general, 28% of all 1007 patients were treated
with targeted therapy based on the presence of a specific
driver mutation. The majority of patients with EGFR and
ALK identified as an oncogenic driver were treated with
targeted therapies in this trial (see Table 1). Although
KRAS was the most common driver mutation identified in
this study, only 9% of these patients were treated with targeted therapy. This reflects the need for clinical trials with
targeted agents for this large group of molecularly defined
patients with metastatic lung adenocarcinoma.
Survival data were available for 942 patients. Patients
with identified driver mutations who were treated with targeted therapy (n=264) lived significantly longer (median
OS 3.5 years, 95% CI 3.2–4.6, p<0.0001) than patients
with identified driver mutations not treated with targeted
agents (n=318) (median OS 2.4 years, 95% CI 1.8–2.9)
and patients without driver mutations (n=360; median OS
2.1 years, 95% CI 1.8–2.5).
Patients with sensitizing EGFR mutations and those with
ALK rearrangements lived significantly longer OS (p=0.001)
when compared with patients with KRAS mutation and
patients with 2 drivers (Table 2).
Thanks to recent developments in cancer genome
sequencing, methods of drug development and growing
numbers of biomarker-driven clinical trials, we are able to
offer some patients more efficacious and less toxic treatments,
allowing greater longevity and better quality of life. However,
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VOL. 13, No. 1, february 2014
finding clinically relevant targets for personalized therapy
remains a major challenge for physicians treating the majority
of NSCLC patients. Much progress has been made, and we
look forward to the day when molecular testing is available
to every lung cancer patient and we are able to offer a personalised treatment for most of our patients with metastatic
lung cancer.
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