Lung Cancer 159 (2021) 1–9

Contents lists available at ScienceDirect

Lung Cancer
journal homepage: www.elsevier.com/locate/lungcan

A retrospective observational study of the natural history of advanced

non–small-cell lung cancer in patients with KRAS p.G12C mutated or
wild-type disease
Alexander I. Spira a, b, c, Huakang Tu d, Shivani Aggarwal d, Hil Hsu d, Gillis Carrigan d,
Xuena Wang e, Gataree Ngarmchamnanrith f, Victoria Chia d, Jhanelle E. Gray g, *
a
Virginia Cancer Specialists, 8503 Arlington Blvd Suite 400, Fairfax, VA, 22031, USA
b
US Oncology Research, The Woodlands, TX, USA
c
Johns Hopkins School of Medicine, Baltimore, MD, USA
d
Center for Observational Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
e
Global Biostatistical Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320-1799, USA
f
Clinical Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320-1799, USA
g
Department of Thoracic Oncology, Moffitt Cancer Center, 12902 Magnolia Dr, Tampa, FL, 33612, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Introduction: The KRAS p.G12C mutation, prevalent in non–small-cell lung cancer (NSCLC), has only recently
Non–small-cell lung cancer become a viable target. Here we present results of the largest retrospective observational study analyzing KRAS
KRAS p.G12C p.G12C in patients with advanced NSCLC.
Retrospective
Materials and Methods: Adults with advanced NSCLC (All Advanced NSCLC cohort) and subcohorts with different
mutation profiles (KRAS p.G12C [G12C] and KRAS/EGFR/ALK wild type [Triple WT]) diagnosed January 2011
to March 2019 were selected from a US clinico-genomic database; treatment-related characteristics, molecular
profiles, real-world overall (rwOS) and progression-free survival (rwPFS) were analyzed.
Results: Demographics were similar across cohorts, with more smokers and nonsquamous cell carcinoma his­
tology in the G12C cohort. KRAS p.G12C was nearly mutually exclusive (≤1.2 %) with known actionable driver
mutations, but non-driver co-mutations were common (STK11, 21.5 %; KEAP1, 7.0 %; TP53, 48.0 %). Among
G12C patients, 20 % had no documentation of receiving systemic therapy. Across treated G12C patients, 67 %
received immune checkpoint inhibitors; first-line usage increased from 0% (2014) to 81 % (2019). Among G12C
patients, median (95 % CI) rwOS was 12.0 (9.6–15.3), 9.5 (8.1–13.1), and 6.7 (5.9–10.7) months after first,
second, and third line of therapy, respectively; median (95 % CI) rwPFS was 5.0 (4.4–5.8), 4.0 (2.8–5.3), and 3.1
(2.4–4.3) months. Outcomes for the G12C subcohort were similar to those for all patients (All Advanced NSCLC
cohort). Mutations in STK11/KEAP1 were associated with poorer survival across all cohorts.
Conclusion: The poor outcomes associated with KRAS p.G12C mutated advanced NSCLC indicate an unmet need
for more effective novel treatments.

Abbreviations: ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene; CGDB, clinico-genomic database; CGP, comprehensive genomic profiling; EGFR,
epidermal growth factor receptor; EHR, electronic health records; FH-FMI, Flatiron Health-Foundation Medicine; G12C, patients with KRAS p.G12C mutated NSCLC
included in study; KEAP1, Kelch-like ECH-associated protein 1 oncogene; KRAS, Kirsten rat sarcoma viral oncogene homolog; KRAS p.G12C, codon 12 glycine-to-
cysteine substitution of KRAS; MET, mesenchymal-epithelial transition; NGS, next-generation sequencing; NSCLC, non‒small-cell lung cancer; NTRK1‒3, neuro­
trophic tyrosine kinases 1–3 gene; PD-1, programmed death 1; PD-L1, programmed death ligand 1; RAS, rat sarcoma viral oncogene homolog; RECIST, Response
Evaluation Criteria in Solid Tumors; RET, rearranged-during-transfection gene; ROS1, ROS proto-oncogene 1; rwOS, real-world overall survival; rwPFS, real-world
progression-free survival; STK11/LKB1, serine/threonine kinase 11, liver kinase B1; TP53, tumor protein p53; Triple WT, KRAS/EGFR/ALK wild-type; VEGF, vascular
endothelial growth factor.
* Corresponding author.
E-mail addresses: Alexander.Spira@USOncology.com (A.I. Spira), htu01@amgen.com (H. Tu), shivania@amgen.com (S. Aggarwal), hhsu02@amgen.com
(H. Hsu), gcarriga@amgen.com (G. Carrigan), xuenaw@amgen.com (X. Wang), gatareen@amgen.com (G. Ngarmchamnanrith), vchia@amgen.com (V. Chia),
Jhanelle.gray@moffitt.org (J.E. Gray).

https://doi.org/10.1016/j.lungcan.2021.05.026
Received 15 April 2021; Received in revised form 18 May 2021; Accepted 22 May 2021
Available online 25 May 2021
0169-5002/© 2021 Published by Elsevier B.V.
A.I. Spira et al.
1. Introduction
Lung cancer is the second most common cancer in both men and
women, as well as the leading cause of cancer death worldwide [1].
Non–small-cell lung cancer (NSCLC) comprises about 84 % of lung
cancer cases [1]. The majority of US patients with NSCLC are diagnosed
with advanced disease and have a poor prognosis [2]. For patients with
advanced NSCLC and targetable driver mutations, targeted therapies
significantly improve treatment outcomes [3] and are the recommended
first-line therapies [4]; indeed, the benefit of targeted therapies in
earlier stage disease has also been demonstrated [5]. For patients with
advanced NSCLC without targetable driver mutations, immune check­
point inhibitors for programmed cell death-1 (PD-1) or programmed
death ligand-1 (PD-L1), used as a monotherapy or in combination with
chemotherapy, are recommended as first-line treatment [4,6].
Mutations in the rat sarcoma viral oncogene homolog (RAS) family of
proto-oncogenes are highly prevalent in NSCLC, with the Kirsten RAS
(KRAS) homolog being the most frequently mutated isoform [7].
Approximately 90 % of KRAS mutations in NSCLC occur in codon 12 [8].
The most common codon 12 mutation is a single guanine-to-thymine
substitution resulting in a glycine-to-cysteine substitution (KRAS p.
G12C) [7]. KRAS p.G12C occurs in approximately 13 % of NSCLC
adenocarcinoma cases and 41 % of KRAS mutated disease [9] and has
been identified as a putative oncogenic driver in several types of solid
tumors including NSCLC [10]. With the recent development of KRAS p.
G12C inhibitors such as sotorasib [11,12] and adagrasib [13,14], the
KRAS p.G12C mutation is emerging as the next targetable driver mu­
tation in NSCLC [15,16].
There is a lack of robust characterization of patients with KRAS p.
G12C mutated advanced NSCLC; few studies have described outcomes in
KRAS mutated NSCLC, and results have been inconsistent [17–20]. This
is partly due to sparse information on large cohorts of patients with
NSCLC with comprehensive clinical and genomic alteration data and
partly due to the effect of co-mutations such as serine/threonine kinase
11 (STK11/LKB1) and Kelch-like ECH-associated protein 1 oncogene
(KEAP1) [15]. The purpose of this study was to provide real-world ev­
idence on clinico-pathologic and molecular characteristics, treatment
patterns, and outcomes in patients with KRAS p.G12C mutated
advanced NSCLC (G12C cohort), as well as for patients with KRAS
wild-type, epidermal growth factor receptor (EGFR) wild-type, and
anaplastic lymphoma kinase (ALK) wild-type advanced NSCLC (here­
after referred to as Triple WT), and the overall cohort of patients with
advanced NSCLC (hereafter referred to as All Advanced NSCLC cohort)
using a de-identified nationwide (US-based) NSCLC clinico-genomic
database (CGDB).
2. Materials and methods
2.1. Study design
An observational retrospective cohort study of patients with
advanced NSCLC diagnosed between January 1, 2011, and March 31,
2019, was undertaken to characterize the natural history of patients
with advanced NSCLC. To ensure at least 6 months of follow-up for
outcomes, data were collected through September 30, 2019.
2.2. Data source
This study used the nationwide (US-based) de-identified Flatiron
Health-Foundation Medicine NSCLC CGDB (FH-FMI CGDB). The de-
identified data originated from approximately 280 US cancer clinics
(~800 sites of care) and excluded patients involved in clinical trials. The
FH-FMI CGDB integrates FMI’s comprehensive genomic profiling (CGP)
results with de-identified patient-level structured and unstructured data
derived from electronic health records (EHR) by de-identified deter­
ministic matching [21,22]. Genomic alterations were identified via
2
Lung Cancer 159 (2021) 1–9
comprehensive CGP of >300 cancer-related genes on FMI’s
next-generation sequencing (NGS) based FoundationOne® panel [23,
24]. As of June 2020, over 400,000 samples had been sequenced from
patients across the United States. A recent study using data from the
NSCLC cohort of the FH-FMI CGDB demonstrated that using a CGDB
derived from routine clinical care can be representative of the real-world
patient population [25]. Furthermore, well-established genomic
markers in the CGDB correlate with clinical outcomes [25].
2.3. Patients
Patients were included in the study if they were diagnosed with
advanced NSCLC and were ≥18 years old at the time of diagnosis
(N = 7069). Advanced NSCLC was defined as an initial diagnosis of
locally advanced (stage IIIB/IIIC) or metastatic (stage IV) disease, or an
initial diagnosis of early-stage disease with subsequent recurrence or
progressive disease. Demographic and clinical characteristics including
age, race, Eastern Cooperative Oncology Group performance status,
disease stage at initial diagnosis, metastatic sites, treatment patterns,
and mutation profiles were collected from all patients in the database
meeting the inclusion criteria.
2.4. Molecular characteristics
Mutation profiles were detected via FoundationOne tumor DNA
sequencing (Foundation Medicine, Cambridge, MA, USA) as part of
routine, real-world care. The FoundationOne platform is used to detect
short-variant mutations, rearrangements, and copy number alterations
from cancer specimens and has been shown to have >95 % sensitivity
and >99 % positive predictive value [23]. Variants of known or likely
significance were considered to be positive.
2.5. Treatment-related characteristics
Several treatment-related characteristics were collected, including
information related to treatment patterns and lines of therapy. Available
treatment history, including chemotherapies, targeted therapies, im­
munotherapies, and other therapies, was collected from the EHRs of the
study center. Detailed information on start and end dates for each line of
therapy was collected, as were details of each drug regimen. The first
line of therapy was defined from the start of the first systemic therapy
drug to the last administration of that systemic course of therapy or
death. All subsequent lines of therapy were defined in a similar fashion.
2.6. Outcomes
The endpoints of the study were real-world overall survival (rwOS)
and real-world progression-free survival (rwPFS) by line of therapy. For
patients who received systemic treatment, rwOS was defined as time
from start of treatment to death; rwPFS was defined as time from start of
treatment to progression or death, whichever occurred first. For patients
without any documentation of receiving systemic treatment, rwOS was
defined as time from advanced NSCLC diagnosis to death. The date of
death was computed using a composite real-world mortality endpoint
derived from EHR [26]. Patients who were lost to follow-up or followed
up to the end of study period without an outcome were censored. Date of
death or progression was extracted from real-world data collected in the
EHR as part of routine clinical care, with the information about each
progression event being retrospectively captured. Real-world disease
progression was identified from clinic notes from visits during which a
patient was evaluated for progression by the treating clinician and has
been shown to correlate with overall survival [27]. This approach is
conceptually different from prospective collection of progression data
within the context of a clinical study, commonly assessed using
Response Evaluation Criteria in Solid Tumors (RECIST) [28].
A.I. Spira et al. Lung Cancer 159 (2021) 1–9

2.7. Statistical analyses
All analyses were descriptive in nature, with no formal hypothesis
testing. Descriptive statistics (mean, median, standard deviation [SD],
range) were presented for continuous variables (eg, age). For categorical
variables (eg, race, disease stage), the number and percentage of pa­
tients in each group were reported. rwOS and rwPFS and corresponding
95 % confidence intervals (CI) were calculated using Kaplan-Meier es­
timates. In real-world settings, patients may have NGS undertaken at the
time of their advanced NSCLC diagnosis and before starting initial
therapy, or after receiving their initial therapy, resulting in an immortal
time period (ie, time from the start of the line of therapy to the NGS test
where the patient would have been alive and not eligible for an
outcome). Immortal time bias was accounted for via cohort restriction
by selecting patients whose NGS reporting date was before or up to 21
days after the start of line of therapy for outcome analyses by line of
therapy. For those who did not have any documentation of receiving
systemic treatment, rwOS and rwPFS were measured from advanced
NSCLC diagnosis date, and a delayed entry model was used to account
for immortal time bias.
3. Results
3.1. Patient population
There were 7069 patients who were diagnosed with advanced-stage
NSCLC and had received molecular testing through the FMI NGS testing
panel within the study time frame of January 1, 2011, to March 31, 2019
(All Advanced NSCLC cohort). Among these patients, 743 (10.5 %) were
positive for the KRAS p.G12C mutation and included in the G12C cohort,
and 3957 (56.0 %) were KRAS/EGFR/ALK wild type and included in the
Triple WT cohort.
Median age at advanced diagnosis was 68 years for the G12C cohort,
69 years for the Triple WT cohort, and 68 years for the All Advanced
NSCLC cohort. Female patients accounted for 61.1 % (n = 454/743) of
G12C patients, 42.1 % (n = 1665/3957) of Triple WT patients, and 50 %
(n = 3532/7069) of patients in the All Advanced NSCLC cohort. Overall,
~82 % of patients were current or former smokers, with the percentage
being higher in the G12C cohort (96.8 % [n = 719/743]). Furthermore,
most tumors were nonsquamous (76.1 % [n = 5382/7069] overall),
with a higher percentage of nonsquamous histology in the G12C cohort
(90.8 % [n = 675/743]). In addition, 86.1 % (n = 640/743) of the G12C
cohort, 80.6 % (n = 3191/3957) of the Triple WT cohort, and 84.0 %
(n = 5937/7069) of the All Advanced NSCLC cohort had evidence of
stage IV disease at the time of their advanced NSCLC diagnosis (Table 1).
The pattern of distant metastases was generally consistent across all
cohorts; however, a slightly higher percentage of patients with brain
metastasis was found in the G12C cohort. Baseline characteristics for all
cohorts are summarized in Table 1; baseline characteristics for the
cohort of patients with a KRAS mutation that was not a KRAS p.G12C
mutation are summarized in Supplementary Table 1.
KRAS p.G12C was nearly mutually exclusive (≤1.2 %) with all
actionable driver mutations with likely or known significance in NSCLC,
such as ALK rearrangements, EGFR mutations, ROS proto-oncogene 1
(ROS1) rearrangements, B-Raf proto-oncogene (BRAF) mutations, neu­
rotrophic tyrosine kinases 1–3 gene (NTRK1–3) rearrangements,
rearranged-during-transfection gene (RET) rearrangements, and
tyrosine-protein kinase gene mesenchymal-epithelial transition (MET)
short-variant alterations (Fig. 1; left). In comparison, the All Advanced
NSCLC cohort exhibited a high prevalence of EGFR mutations (13.6 %),

Table 1
Baseline characteristics.
Characteristic G12C (n = 743) Triple WT (n = 3957) All Advanced NSCLC (n = 7069)

Age at advanced diagnosis, years, median (range) 68 (29–85) 69 (26–85) 68 (24–85)

Female, n (%) 454 (61.1) 1665 (42.1) 3532 (50.0)
Race, n (%)
Asian 7 (0.9) 71 (1.8) 223 (3.2)
Black 38 (5.1) 258 (6.5) 401 (5.7)
Hispanic or Latino 2 (0.3) 2 (0.1) 4 (0.1)
White 550 (74.0) 2800 (70.8) 4951 (70.0)
Other 80 (10.8) 489 (12.4) 882 (12.5)
Not available 66 (8.9) 337 (8.5) 608 (8.6)
Current or former smoker, n (%) 719 (96.8) 3430 (86.7) 5786 (81.9)
Histology of NSCLC, n (%)
Nonsquamous 675 (90.8) 2506 (63.3) 5382 (76.1)
Squamous 31 (4.2) 1252 (31.6) 1387 (19.6)
Not otherwise specified 37 (5.0) 199 (5.0) 300 (4.2)
Stage at initial diagnosis, n (%)
Stage ≤ IIIA 213 (28.7) 1078 (27.2) 1825 (25.8)
Stage IIIB–IVB 513 (69.0) 2776 (70.2) 5079 (71.8)
Not reported 17 (2.3) 103 (2.6) 165 (2.3)
Stage IV disease at index date, n (%)
Any metastatic disease 640 (86.1) 3191 (80.6) 5937 (84.0)
Bone 231 (31.1) 1079 (27.3) 2132 (30.2)
Brain 174 (23.4) 577 (14.6) 1243 (17.6)
Distant lymph node 73 (9.8) 461 (11.7) 787 (11.1)
Lung 206 (27.7) 1091 (27.6) 2063 (29.2)
Advanced disease diagnosed in 2015 or later, n (%)* 611 (82.2) 3307 (83.6) 5810 (82.2)
Practice type, n (%)
Academic 46 (6.2) 245 (6.2) 537 (7.6)
Community 697 (93.8) 3712 (93.8) 6532 (92.4)
Number of total lines of therapy in advanced setting, n (%)
0 149 (20.1) 681 (17.2) 1206 (17.1)
1 293 (39.4) 1381 (34.9) 2479 (35.1)
2 150 (20.2) 1015 (25.7) 1755 (24.8)
3 83 (11.2) 491 (12.4) 871 (12.3)
≥4 68 (9.2) 389 (9.8) 758 (10.7)

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor oncogene; KRAS=Kirsten rat sarcoma viral oncogene homolog; NSCLC = non–small-cell
lung cancer; Triple WT=KRAS/EGFR/ALK wild type.
*
Checkpoint inhibitor therapy gained its first approval in NSCLC in March 2015.

3
A.I. Spira et al.
RET=rearranged-during-transfection gene; ROS1=ROS proto-oncogene 1; STK11=serine-threonine kinase 11 gene; TP53=tumor protein p53 gene; Triple
followed by BRAF mutations (4.2 %), ALK rearrangements (2.7 %), MET
short-variant alterations (2.0 %), and RET (0.9 %), ROS1 (0.7 %), and
NTRK rearrangements (0.2 %). For non-actionable drivers, patients with
the KRAS p.G12C mutation had a 21.5 % co-mutation rate of STK11
(also known as LKB1) versus only 10.7 % for the Triple WT cohort and
12.4 % for the All Advanced NSCLC cohort. KEAP1 mutations were also
prevalent in the G12C cohort (7.0 %) and occurred at a similar per­
centage in the other two cohorts (7.5 % for the Triple WT cohort, 6.4 %
for the All Advanced NSCLC cohort). Lastly, tumor protein p53 gene
(TP53) short-variant alterations were present in approximately half of
patients in the G12C cohort (48.0 %), 73.1 % of the Triple WT cohort,
and 63.2 % of the All Advanced NSCLC cohort (Fig. 1; right). Co-
mutation patterns for patients with KRAS mutations that were not
KRAS p.G12C are shown in Supplementary Fig. 1.
3.2. Treatment characteristics
A total of 594 (79.9 %) patients from the G12C cohort, 3276 (82.8 %)
patients from the Triple WT cohort, and 5863 (82.9 %) from the All
Advanced NSCLC cohort had documentation of having received sys­
temic treatment after diagnosis. The main therapies used were platinum-
based chemotherapy with or without a PD-1/PD-L1 inhibitor, PD-1/PD-
L1 monotherapy, and other therapies, including targeted therapies such
as combinations of immune checkpoint inhibitors, single-agent chemo­
therapies (eg, docetaxel, gemcitabine, pemetrexed), and vascular
endothelial growth factor (VEGF) and VEGF receptor inhibitors (eg,
bevacizumab and ramucirumab). Of all patients in the G12C cohort who
Fig. 2. Use of PD-1/PD-L1 inhibitors as a first-line therapy by year of first-line initiation in each cohort. ALK=anaplastic lymphoma kinase; EGFR=epidermal growth
factor receptor oncogene; KRAS=Kirsten rat sarcoma viral oncogene homolog; NSCLC = non–small-cell lung cancer; PD-1/L1=programmed cell death-1/
programmed death ligand-1; Triple WT=KRAS/EGFR/ALK wild type.
4
Lung Cancer 159 (2021) 1–9
Fig. 1. Co-mutation patterns in the three
advanced NSCLC cohorts.* Left: Mutually
exclusive co-mutations. Right: Frequent co-
mutations with KRAS mutations.
*Percentages based on the number of patients
tested for the co-mutation. ALK=anaplastic
lymphoma kinase; BRAF=B-Raf proto-
oncogene; EGFR=epidermal growth factor re­
ceptor oncogene; KEAP1=Kelch-like ECH-
associated protein 1 gene; KRAS=Kirsten rat
sarcoma viral oncogene homolog;
MET = mesenchymal-epithelial transition;
NSCLC = non–small-cell lung cancer;
NTRK=neurotrophic tyrosine kinase gene;
WT=KRAS/EGFR/ALK wild type.
received systemic treatment, 67 % (n = 396/594) received PD-1/PD-L1
inhibitors at some point in their treatment history. Year-on-year analysis
demonstrates a steady increase in the use of PD-1/PD-L1 inhibitors from
the time of first approval in 2014. None of the patients received first-line
PD1/PD-L1 inhibitors in 2014, and only 7.5 % (n = 3/40) of patients in
the G12C cohort, 7.9 % (n = 10/126) of patients in the Triple WT
cohort, and 6.2 % (n = 17/275) in the All Advanced NSCLC cohort
received first-line PD-1/PD-L1 inhibitors in 2015. In 2019, these
numbers increased to 81.0 % (n = 17/21) of patients in the G12C
cohort, 74.4 % (n = 96/129) in the Triple WT cohort, and 64.6 %
(n = 157/243) in the All Advanced NSCLC cohort (Fig. 2).
3.3. Outcomes
For the first line of therapy, median rwOS (95 % CI) was 12.0
(9.6–15.3) months for the G12C cohort, 10.8 (9.9–11.8) months for the
Triple WT cohort, and 12.9 (11.9–14.2) months for the All Advanced
NSCLC cohort (Fig. 3A). For the second line of therapy, median rwOS
(95 % CI) was 9.5 (8.1–13.1) months for the G12C cohort, 8.8 (7.8–9.8)
months for the Triple WT cohort, and 10.2 (9.5–11.3) months for the All
Advanced NSCLC cohort. Kaplan-Meier estimates for rwOS for the first
and second line of therapy showed a similar survival probability across
time for the three cohorts, with equally poor survival rates at the end of
database tracking (Fig. 4A, B). Similar patterns can be observed for the
third and fourth lines of therapy (Supplementary Fig. 2).
The median rwPFS in the G12C cohort was similar to that in the
Triple WT and All Advanced NSCLC cohorts across all lines of therapy
A.I. Spira et al.
Fig. 3. Median (95 % CI) (A) real-world overall survival (rwOS) and (B) real-world progression-free survival (rwPFS) for each line of treatment in each cohort.
ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor oncogene; KRAS=Kirsten rat sarcoma viral oncogene homolog; NSCLC = non–small-cell
lung cancer; Triple WT=KRAS/EGFR/ALK wild type.
(Fig. 3B). For the first line of therapy, median rwPFS (95 % CI) was 5.0
(4.4–5.8) months for the G12C cohort, 4.9 (4.5–5.2) months for the
Triple WT cohort, and 5.6 (5.3–5.8) months for the All Advanced NSCLC
cohort. For the second line, median rwPFS (95 % CI) was 4.0 (2.8–5.3)
months for the G12C cohort, 3.5 (3.2–4.1) months for the Triple WT
cohort, and 4.0 (3.7–4.4) months for the All Advanced NSCLC cohort.
Kaplan-Meier estimates for rwPFS for the first and second line of therapy
show a similar PFS probability across time for the three cohorts. In all
three cohorts, almost all patients show progression by the end of data­
base tracking (Fig. 4C, D). Findings were similar across cohorts for the
third and fourth lines of therapy (Supplementary Fig. 3). Median rwOS
and rwPFS and Kaplan-Meier estimates across lines of therapy for pa­
tients with KRAS mutations that were not KRAS p.G12C are shown in
Supplementary Figs. 1 and 4.
Due to the high co-occurrence of KRAS p.G12C with STK11 and/or
KEAP1 mutations (Fig. 1), outcomes for all cohorts were also stratified
by STK11/KEAP1 co-mutation status for the first and second lines of
therapy to assess for potential confounding (Fig. 5 and Supplementary
Fig. 5; outcomes for patients with KRAS mutations that were not KRAS p.
G12C stratified by STK11/KEAP1 co-mutation status are shown in
Supplementary Fig. 6). Overall, those wild type for both STK11 and
KEAP1 had numerically higher rwOS and rwPFS among all cohorts for
first line therapy (Fig. 5) than those with STK11 or KEAP1 mutations.
Although formal statistical comparisons were not undertaken, the
observed rwOS was slightly higher for patients in the G12C cohort
(n = 197, 15.2 [12.0–18.3] months) than for patients in the Triple WT
(n = 1023, 11.7 [10.6–12.9] months) and All Advanced NSCLC cohorts
(n = 1905, 14.8 [13.5–16.3] months) who were wild type for both
genes. For patients who were STK11 wild type and KEAP1 mutated,
median rwOS (95 % CI) was lower for patients in the G12C cohort
(n = 10, 4.5 [1.4–21.5] months) than for patients in the Triple WT
(n = 68, 7.2 [5.8–18.4] months) and the All Advanced NSCLC cohorts
(n = 93, 7.1 [5.8–12.7] months). In patients who were STK11 mutated
and KEAP1 wild type, median rwOS was similar among all cohorts
5
Lung Cancer 159 (2021) 1–9
(G12C cohort, n = 52, 9.0 [6.9–19.8] months; Triple WT, n = 114, 8.6
[5.2–10.0] months; All Advanced NSCLC, n = 252, 8.9 [7.3–10.2]
months; Fig. 5A). For the second line of therapy, one of the lowest rwOS
(95 % CI) was observed among patients in the G12C cohort who were
STK11 wild type and KEAP1 mutated (n = 5, 2.5 [1.0–14.9] months;
Supplementary Fig. 5A).
Median rwPFS (95 % CI) for the first line of therapy was slightly
higher for patients in the G12C cohort wild type for STK11 and KEAP1
(6.5 [5.1–8.4] months) than for patients in the Triple WT (5.1 [4.7–5.5]
months) and All Advanced NSCLC cohorts (6.1 [5.7–6.5] months) with
the same co-mutation status. Median rwPFS (95 % CI) was lower for
G12C patients in the STK11 wild type and KEAP1 mutated subcohort
(2.5 [1.1–5.7] months) than for patients in the Triple WT (4.4 [2.8–5.8]
months) and All Advanced NSCLC cohorts (4.3 [2.8–5.6] months) with
the same co-mutation status. In patients with STK11 mutated and KEAP1
wild type, median rwPFS was similar for patients in the G12C (4.1
[3.4–4.8] months), Triple WT (3.9 [2.8–5.0] months), and All Advanced
NSCLC cohorts (4.0 [3.5–4.6] months; Fig. 5B). Similar patterns were
observed for the second line of therapy (Supplementary Fig. 5B).
4. Discussion
To our knowledge, this study uses the largest dataset to date con­
taining information on outcomes and molecular characteristics of pa­
tients with advanced NSCLC harboring the KRAS p.G12C mutation. With
the possibility that the KRAS p.G12C mutation will become a targetable
driver mutation first in advanced NSCLC and then, if proven effective, in
earlier stage disease, we analyzed real-world evidence on clinical and
pathologic characteristics, treatment patterns, and outcomes in patients
with KRAS p.G12C mutation-positive advanced NSCLC (G12C cohort)
from a de-identified nationwide, US-based NSCLC CGDB. Additionally,
these characteristics were also described in patients without the three
main actionable drivers (Triple WT cohort) and the overall cohort of
patients with advanced NSCLC (All Advanced NSCLC cohort).
A.I. Spira et al. Lung Cancer 159 (2021) 1–9

Fig. 4. Kaplan-Meier analyses for real-world overall survival (rwOS) after (A) first and (B) second lines of therapy, and for real-world progression-free survival
(rwPFS) after (C) first and (D) second lines of therapy. ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor oncogene; KRAS=Kirsten rat
sarcoma viral oncogene homolog; NSCLC = non–small-cell lung cancer; Triple WT=KRAS/EGFR/ALK wild type.

Patients in the G12C cohort had demographic and clinical character­
istics similar to those in the overall group of patients with advanced
NSCLC; however, higher proportions of past or present smokers and
nonsquamous cell carcinoma histology were observed in the G12C cohort,
as has recently been reported based on data from the CRISP registry of
German patients [29]. These findings are consistent with earlier studies in
smaller populations showing that KRAS mutations, specifically the p.G12C
mutation, are highly prevalent among current or former smokers, and that
this mutation is associated with a high rate of brain metastases [18,20,30,
31]. Similarly, the KRAS p.G12C mutation was found to be higher in
current and former smokers in a large European data set in patients with
earlier stage disease (stage Ia to IIIb NSCLC) [32]. Other studies have also
demonstrated that nonsquamous cell carcinoma is the most common
histology type associated with KRAS mutations in general, as well as KRAS
p.G12C specifically [30,33]. Although KRAS mutations may be relatively
uncommon in some phenotypes, with a recent study finding a prevalence
of only 4.4 % in squamous cell carcinoma [33], KRAS p.G12C mutations
can be found across patient types (eg, in nonsmokers [34]); thus, broad
molecular testing is needed to identify KRAS p.G12C status in all patients
with NSCLC.
The KRAS p.G12C mutation was nearly mutually exclusive (≤1.2 %)
with all other actionable driver mutations (EGFR and BRAF mutations;
MET short-variant alterations; and ALK, ROS1, NTRK1–3, and RET
rearrangements). This is consistent with the current understanding that
KRAS p.G12C is mutually exclusive with other actionable mutations
[35–38]. Therefore, patients with NSCLC harboring a KRAS p.G12C
mutation are unlikely to be candidates for therapy targeted at these
actionable driver mutations. As such, there is a need for additional
novel, biomarker-driven, anticancer therapies with tolerable safety
profiles to address KRAS p.G12C mutated advanced NSCLC.
Furthermore, the KRAS p.G12C mutation was observed in the pres­
ence of high STK11 mutation levels in this study, as has recently been
reported by others in a single treatment center [39]. STK11 mutations
have been observed at a high rate in NSCLC and even higher in KRAS
mutated NSCLC; the KRAS p.G12C/STK11 co-mutation pattern has been
associated with lower overall survival and resistance to immune
checkpoint inhibitors [38,40–44]. KEAP1 mutations were prevalent in
the G12C cohort, as well as the other cohorts in this study; although
others have reported even higher levels of KEAP1 co-mutation [39].
Pathogenic KEAP1 mutations are associated with chemoresistance in

6
A.I. Spira et al.
preclinical models of NSCLC, and lower overall survival in NSCLC,
whereas patients with NSCLC harboring KEAP1 mutations are less sen­
sitive to platinum-based treatments [45–50]. In our study, rwOS and
rwPFS were generally longer for patients who had KRAS p.G12C
mutated advanced NSCLC that was wild type for both STK11 and KEAP1.
Therefore, the evidence points to a potential association of KRAS p.G12C
with other mutations that negatively affect survival outcomes in
advanced NSCLC and may lead to unresponsiveness to immune check­
point inhibitors [41].
Treatment patterns were generally similar among patients in the
G12C, Triple WT, and All Advanced NSCLC cohorts. The most common
regimens in the first and second lines of therapy after diagnosis of
advanced disease were platinum-based chemotherapy regimens and
regimens including immune checkpoint inhibitors; however, since their
approval in 2014, PD1/PD-L1 inhibitors are increasingly used, as has
been reported by others [29]. In our study, they were the most common
first-line treatment in the G12C, Triple WT, and All Advanced NSCLC
cohorts. For example, 81 % of patients in 2019 in the G12C cohort
received PD-1/PD-L1 inhibitors as part of their first-line therapy (Fig. 2).
Once patients, including those with KRAS p.G12C mutated NSCLC,
progressed on PD-1/PD-L1 inhibitors and first-line chemotherapy,
limited options are available [4].
In this study, the Triple WT cohort was included to illustrate out­
comes in patients for whom there are no or few approved targeted
therapies. In the real-world setting, patients in the G12C cohort were
found to have poor survival outcomes after different lines of therapy,
including immune checkpoint inhibitors; their prognosis was as poor as
that observed in patients in the Triple WT and All Advanced NSCLC
cohorts. This similarity in outcomes is consistent with other studies
showing that in Western populations, the KRAS p.G12C mutation is not
predictive of outcomes in patients with advanced NSCLC [17–20,39]. In
earlier stage NSCLC, KRAS p.G12C mutations were associated with a
trend toward shorter overall survival than those without KRAS muta­
tions [32]. Taken together, these findings reflect an unmet need for
7
Lung Cancer 159 (2021) 1–9
Fig. 5. Median (95 % CI) (A) real-world overall
survival (rwOS) and (B) real-world progression-
free survival (rwPFS) for the first line of therapy
in subcohorts of patients based on STK11 and
KEAP1 co-mutation patterns. ALK=anaplastic
lymphoma kinase; EGFR=epidermal growth
factor receptor oncogene; KEAP1=Kelch-like
ECH-associated protein 1 gene; KRAS=Kirsten
rat sarcoma viral oncogene homolog;
NSCLC = non–small-cell lung cancer;
STK11=serine-threonine kinase 11 gene; Triple
WT=KRAS/EGFR/ALK wild type.
effective treatments for patients with KRAS p.G12C mutation in both
early and advanced NSCLC. Furthermore, approximately 20 % of pa­
tients in the G12C cohort in our study did not have any record of
receiving any systemic therapies, further highlighting the need for
effective, safer, and more targeted therapies.
To our knowledge, this is the largest real-world dataset to compre­
hensively characterize the clinico-pathologic and molecular characteris­
tics, treatment patterns, and outcomes in patients with KRAS p.G12C
mutated advanced NSCLC, compared with patients with Triple WT
advanced NSCLC and All Advanced NSCLC cohorts. In addition, this study
included patients from a large number of community oncology practices
and academic centers across the United States, representing a true real-
world population. Furthermore, the mortality data in the CGDB is well
validated, with high sensitivity and specificity [26,51]. Finally, this study
included comprehensive genomic profiling results with de-identified
clinical data derived from EHR, including key variables such as histol­
ogy, dates of diagnosis, stage, treatment, and real-world progression.
This study has some limitations. First, the CGDB is limited to US pa­
tients, primarily those in community health centers, and those who
received molecular testing through the FMI NGS testing panel. Thus, re­
sults may not be generalizable to all patients with advanced NSCLC,
particularly those treated in academic centers or in other countries, or
patients who did not receive NGS testing as part of their care, or who were
identified using different testing methodologies, or those with earlier stage
disease. Nonetheless, it has been demonstrated that information obtained
from the database is reflective of the real-world patient population [25].
Second, the definition of rwPFS used in this study may lead to potential
misclassification of outcomes because the information about progression
is collected retrospectively rather than prospectively based on RECIST
criteria and relied on interpretation by individual physicians without
standardization. In addition, the subgroups analyzed in this study have
relatively small sample sizes, particularly subgroups with STK11 and/or
KEAP1 co-mutations; therefore, results should be interpreted with caution.
Finally, there are some limitations associated with most retrospective
A.I. Spira et al.
observational studies, such as the possibility of unmeasured confounding
or information bias [52] and potential missing data.
5. Conclusions
This analysis of clinico-pathologic and molecular characteristics,
treatment patterns, and outcomes of advanced NSCLC from a de-
identified nationwide (US-based) NSCLC CGDB helps increase under­
standing of KRAS p.G12C mutation-positive advanced NSCLC. A higher
percentage of patients with KRAS p.G12C mutation-positive advanced
NSCLC were current or former smokers and had nonsquamous histology.
The KRAS p.G12C mutation was virtually mutually exclusive with
actionable driver mutations; however, co-mutation with STK11 and
KEAP1 occurred in approximately 20 % and 7% patients with KRAS p.
G12C mutation-positive advanced NSCLC, respectively. Approximately
20 % of patients KRAS p.G12C mutation-positive advanced NSCLC had
no documented history of receiving systemic treatment; the majority of
those who received systemic treatment received PD-1/PD-L1 inhibitors.
The poor rwOS and rwPFS in patients with KRAS p.G12C mutation-
positive advanced NSCLC from a de-identified nationwide (US-based)
NSCLC CGDB are consistent with outcomes from other real-world evi­
dence studies and indicate an unmet need for more effective and safer
novel treatment options in patients with this type of advanced NSCLC.
Funding statement
This work was funded by Amgen Inc. Except for the role of Amgen
personnel as authors as identified or as outlined in the acknowledg­
ments, Amgen Inc. had no involvement in the study design, collection,
analysis and interpretation of data, the writing of this report, or the
decision to publish.
Disclosures
Alexander I. Spira reports grants from Amgen and personal fees from
AstraZeneca, Bristol Myers Squibb, Mirati, Novartis, and Sanofi. Hua­
kang Tu, Shivani Aggarwal, Gillis Carrigan, Xuena Wang, Gataree
Ngarmchamnanrith, and Victoria Chia report employment by and stock
ownership of Amgen Inc. Hil Hsu reports employment by Skye Biologics
and Amgen and stock ownership of Amgen Inc. Jhanelle E. Gray reports
personal fees from AstraZeneca, Blueprint Medicines, Bristol Myers
Squibb, EMD Serono – Merck KGaA, Inivata, Merck, Novartis, and
Janssen Scientific Affairs, LLC; research support from AstraZeneca,
Boehringer Ingelheim, Bristol Myers Squibb, Genentech, G 1 Thera­
peutics, Merck, Novartis, Pfizer, and Ludwig Institute of Cancer
Research; and unpaid consultancy for Daiichi Sankyo, Inc.
Data sharing
Qualified researchers may request data from Amgen clinical studies.
Complete details are available at the following: http://www.amgen.com
/datasharing.
Transparency document
The Transparency document associated with this article can be found
in the online version.
CRediT authorship contribution statement
Alexander I. Spira: Conceptualization, Data curation, Formal
analysis, Investigation, Methodology, Project administration, Re­
sources, Software, Supervision, Validation, Visualization, Writing -
original draft, Writing - review & editing. Huakang Tu: Conceptual­
ization, Data curation, Formal analysis, Funding acquisition, Investi­
gation, Methodology, Project administration, Resources, Software,
8
Lung Cancer 159 (2021) 1–9
Validation, Visualization, Writing - original draft, Writing - review &
editing. Shivani Aggarwal: Data curation, Formal analysis, Funding
acquisition, Investigation, Methodology, Software, Visualization,
Writing - review & editing. Hil Hsu: Data curation, Formal analysis,
Funding acquisition, Investigation, Methodology, Software, Visuali­
zation, Writing - review & editing. Gillis Carrigan: Data curation,
Formal analysis, Funding acquisition, Investigation, Methodology,
Software, Visualization, Writing - review & editing. Xuena Wang:
Data curation, Formal analysis, Funding acquisition, Investigation,
Methodology, Software, Visualization, Writing - review & editing.
Gataree Ngarmchamnanrith: Data curation, Formal analysis, Fund­
ing acquisition, Investigation, Methodology, Software, Visualization,
Writing - review & editing. Victoria Chia: Conceptualization, Data
curation, Formal analysis, Funding acquisition, Investigation, Meth­
odology, Resources, Software, Supervision, Validation, Visualization,
Writing - review & editing. Jhanelle E. Gray: Conceptualization, Data
curation, Formal analysis, Investigation, Methodology, Project
administration, Resources, Software, Supervision, Validation, Visual­
ization, Writing - original draft, Writing - review & editing.
Acknowledgments
The authors thank Yang Li, PhD (Amgen Inc., Thousand Oaks, CA)
and Vicky Kanta, PhD and Lee Hohaia, PharmD (ICON, North Wales,
PA), whose work was funded by Amgen Inc., for medical writing assis­
tance in the preparation of this manuscript.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.lungcan.2021.05.026.
References
[1] American Cancer Society, About Lung Cancer, 2020 (accessed October 20 2020),
https://www.cancer.org/cancer/lung-cancer/about.html.
[2] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2020, CA Cancer J. Clin. 70
(2020) 7–30.
[3] N. Duma, R. Santana-Davila, J.R. Molina, Non-small cell lung cancer:
epidemiology, screening, diagnosis, and treatment, Mayo Clin. Proc. 94 (2019)
1623–1640.
[4] National Comprehensive Cancer Network, Clinical Practice Guidelines in Oncology
(NCCN Guidelines): Non-Small Cell Lung Cancer (Version 8.2020), National
Comprehensive Cancer Network, 2020 (accessed February 17 2021), https://www.
nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professiona
ls/physician_gls/pdf/nscl.pdf.
[5] Y.L. Wu, M. Tsuboi, J. He, T. John, C. Grohe, M. Majem, et al., Osimertinib in
resected EGFR-Mutated non-small-Cell lung Cancer, N. Engl. J. Med. 383 (2020)
1711–1723.
[6] D. Planchard, S. Popat, K. Kerr, S. Novello, E.F. Smit, C. Faivre-Finn, et al.,
Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for
diagnosis, treatment and follow-up, Ann. Oncol. 29 (2018) iv192–iv237.
[7] I.A. Prior, P.D. Lewis, C. Mattos, A comprehensive survey of Ras mutations in
cancer, Cancer Res. 72 (2012) 2457–2467.
[8] R.P. Jones, P.A. Sutton, J.P. Evans, R. Clifford, A. McAvoy, J. Lewis, et al., Specific
mutations in KRAS codon 12 are associated with worse overall survival in patients
with advanced and recurrent colorectal cancer, Br. J. Cancer 116 (2017) 923–929.
[9] A. Biernacka, P.D. Tsongalis, J.D. Peterson, F.B. de Abreu, C.C. Black, E.
J. Gutmann, et al., The potential utility of re-mining results of somatic mutation
testing: KRAS status in lung adenocarcinoma, Cancer Genet. 209 (2016) 195–198.
[10] A. Fernández-Medarde, E. Santos, Ras in cancer and developmental diseases, Genes
Cancer 2 (2011) 344–358.
[11] J. Canon, K. Rex, A.Y. Saiki, C. Mohr, K. Cooke, D. Bagal, et al., The clinical KRAS
(G12C) inhibitor AMG 510 drives anti-tumour immunity, Nature 575 (2019)
217–223.
[12] D.S. Hong, M.G. Fakih, J.H. Strickler, J. Desai, G.A. Durm, G.I. Shapiro, et al.,
KRASG12C inhibition with sotorasib in advanced solid tumors, N. Engl. J. Med. 383
(2020) 1207–1217.
[13] J. Hallin, L.D. Engstrom, L. Hargis, A. Calinisan, R. Aranda, D.M. Briere, et al., The
KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of
KRAS-mutant cancers in mouse models and patients, Cancer Discov. 10 (2020)
54–71.
[14] Another KRAS inhibitor holds its own, Cancer Discov. 10 (2020), https://doi.org/
10.1158/2159-8290.Cd-nb2020-1098.
A.I. Spira et al.
[15] T.F. Burns, H. Borghaei, S.S. Ramalingam, T.S. Mok, S. Peters, Targeting KRAS-
mutant non-small-cell lung cancer: one mutation at a time, with a focus on KRAS
G12C mutations, J. Clin. Oncol. 38 (2020) 4208–4218.
[16] D. Kim, J.Y. Xue, P. Lito, Targeting KRAS(G12C): from inhibitory mechanism to
modulation of antitumor effects in patients, Cell 183 (2020) 850–859.
[17] W. Cui, F. Franchini, M. Alexander, A. Officer, H.L. Wong, M.J. IJzerman, et al.,
Assessing the significance of KRAS G12C mutation: clinicopathologic features,
treatments, and survival outcomes in a real-world KRAS mutant non-small cell lung
cancer cohort, J. Clin. Oncol. 38 (2020), https://doi.org/10.1200/
JCO.2020.1238.1215_suppl.e19324.
[18] W. Cui, F. Franchini, M. Alexander, A. Officer, H.L. Wong, I.J. M, et al., Real world
outcomes in KRAS G12C mutation positive non-small cell lung cancer, Lung Cancer
146 (2020) 310–317.
[19] F. Griesinger, W.E.E. Eberhardt, P. Hoffknecht, M. Metzenmacher, T. Wehler,
K. Kokowski, et al., 1364P Treatment and outcome of a real-world cohort of
patients with advanced, non-squamous NSCLC and KRAS mutations with a special
focus on KRAS G12C, Ann. Oncol. 31 (suppl 4) (2020) S872.
[20] K.C. Arbour, H. Rizvi, A.J. Plodkowski, D. Halpenny, M.D. Hellmann, G. Heller, et
al., Clinical characteristics and anti-PD-(L)1 treatment outcomes of KRAS-G12C
mutant lung cancer compared to other molecular subtypes of KRAS-mutant lung
cancer, J. Clin. Oncol. 38 (15 suppl) (2020), https://doi.org/10.1200/
JCO.2020.1238.1215_suppl.9596.
[21] B. Birnbaum, N. Nussbaum, K. Seidl-Rathkopf, M. Agrawal, M. Estevez, E. Estola, et
al., Model-assisted Cohort Selection With Bias Analysis for Generating Large-scale
Cohorts From the EHR for Oncology Research, 2020 (accessed February 18 2021),
https://arxiv.org/ftp/arxiv/papers/2001/2001.09765.pdf.
[22] X. Ma, L. Long, S. Moon, B.J.S. Adamson, S.S. Baxi, Comparison of population
characteristics in real-world clinical oncology databases in the US: flatiron Health,
SEER, and NPCR, medRxiv (2020), https://doi.org/10.1101/
2020.1103.1116.20037143.
[23] G.M. Frampton, A. Fichtenholtz, G.A. Otto, K. Wang, S.R. Downing, J. He, et al.,
Development and validation of a clinical cancer genomic profiling test based on
massively parallel DNA sequencing, Nat. Biotechnol. 31 (2013) 1023–1031.
[24] FoundationOne® CDx: Technical Information, Foundation Medicine, Inc.,
Cambridge, MA, 2020.
[25] G. Singal, P.G. Miller, V. Agarwala, G. Li, G. Kaushik, D. Backenroth, et al.,
Association of patient characteristics and tumor genomics with clinical outcomes
among patients with non-small cell lung cancer using a clinicogenomic database,
JAMA 321 (2019) 1391–1399.
[26] M.D. Curtis, S.D. Griffith, M. Tucker, M.D. Taylor, W.B. Capra, G. Carrigan, et al.,
Development and validation of a high-quality composite real-world mortality
endpoint, Health Serv. Res. 53 (2018) 4460–4476.
[27] S.D. Griffith, R.A. Miksad, G. Calkins, P. You, N.G. Lipitz, A.B. Bourla, et al.,
Characterizing the feasibility and performance of real-world tumor progression end
points and their association with overall survival in a large advanced non–small-
cell lung cancer data set, Jco Clin. Cancer Inform. (2019) 1–13.
[28] J.E. Dancey, L.E. Dodd, R. Ford, R. Kaplan, M. Mooney, L. Rubinstein, et al.,
Recommendations for the assessment of progression in randomised cancer
treatment trials, Eur. J. Cancer 45 (2009) 281–289.
[29] M. Sebastian, W.E.E. Eberhardt, P. Hoffknecht, M. Metzenmacher, T. Wehler,
K. Kokowski, et al., KRAS G12C-mutated advanced non-small cell lung cancer: a
real-world cohort from the German prospective, observational, nation-wide CRISP
Registry (AIO-TRK-0315), Lung Cancer (2021). In press.
[30] A. Ghimessy, P. Radeczky, V. Laszlo, B. Hegedus, F. Renyi-Vamos, J. Fillinger, et
al., Current therapy of KRAS-mutant lung cancer, Cancer Metastasis Rev. 39 (2020)
1159–1177.
[31] S. Dogan, R. Shen, D.C. Ang, M.L. Johnson, S.P. D’Angelo, P.K. Paik, et al.,
Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung
adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant
cancers, Clin. Cancer Res. 18 (2012) 6169–6177.
[32] S.P. Finn, A. Addeo, U. Dafni, E. Thunnissen, L. Bubendorf, L.B. Madsen, et al.,
Prognostic impact of KRAS G12C mutation in patients with NSCLC: results from the
European Thoracic Oncology Platform Lungscape Project, J. Thorac. Oncol.
(2021). February 26) [Epub ahead of print].
Lung Cancer 159 (2021) 1–9
[33] S.V. Liu, A.M. Vanderwalde, H. Mamdani, L.E. Raez, Y. Baca, J. Xiu, et al.,
Characterization of KRAS mutations (mt) in non-small cell lung cancer (NSCLC,
J. Clin. Oncol. 38 (2020), 9544-9544.
[34] M.L. Forsythe, A. Alwithenani, D. Bethune, M. Castonguay, A. Drucker,
G. Flowerdew, et al., Molecular profiling of non-small cell lung cancer, PLoS One
15 (2020), e0236580.
[35] R. Scharpf, G. Riely, M. Awad, M. Lenoue-Newton, B. Ricciuti, J. Rudolph, et al.,
Abstract 1095: comprehensive pan-cancer analyses of RAS genomic diversity,
Cancer Res. 80 (2020), 1095-1095.
[36] P. Martín Martorell, M. Huerta, A. Compañ Quilis, R. Abellán, E. Seda, S. Blesa, et
al., Coexistence of EGFR, KRAS, BRAF, and PIK3CA mutations and ALK
rearrangement in a comprehensive cohort of 326 consecutive Spanish
nonsquamous NSCLC patients, Clin. Lung Cancer 18 (2017) e395–e402.
[37] J.F. Gainor, A.M. Varghese, S.H. Ou, S. Kabraji, M.M. Awad, R. Katayama, et al.,
ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an
analysis of 1,683 patients with non-small cell lung cancer, Clin. Cancer Res. 19
(2013) 4273–4281.
[38] M. Scheffler, M.A. Ihle, R. Hein, S. Merkelbach-Bruse, A.H. Scheel, J. Siemanowski,
et al., K-ras mutation subtypes in NSCLC and associated co-occuring mutations in
other oncogenic pathways, J. Thorac. Oncol. 14 (2019) 606–616.
[39] K.C. Arbour, H. Rizvi, A.J. Plodkowski, M.D. Hellmann, A. Knezevic, G. Heller, et
al., Treatment outcomes and clinical characteristics of patients with KRAS-G12C
mutant non-small cell lung Cancer, Clin. Cancer Res. (2021).
[40] B. Ricciuti, K.C. Arbour, J.J. Lin, N. Vokes, A.V. Hoojghan, Y.Y. Li, et al., Effect of
STK11 mutations on efficacy of PD-1 inhibition in non-small cell lung cancer
(NSCLC) and dependence on KRAS mutation status, J. Clin. Oncol. 38 (2020)
e15113-e15113.
[41] A. Pavan, E. Zulato, L. Calvetti, A. Ferro, G. Nardo, A. Boscolo, et al., Plasma next-
generation sequencing (NGS) in advanced non-small cell lung cancer (aNSCLC)
patients (pts) treated with immune checkpoint inhibitors (ICIs): impact of STK11
and TP53 mutations on outcome, J. Clin. Oncol. 38 (2020), 3046-3046.
[42] Y. Tamiya, Y. Zenke, S. Matsumoto, N. Furuya, T. Sakamoto, T. Kato, et al.,
Therapeutic impact of mutation subtypes and concomitant STK11 mutations in
KRAS–mutated non-small cell lung cancer (NSCLC): a result of nationwide genomic
screening project (LC-SCRUM-Japan), J. Clin. Oncol. 38 (2020), 9589-9589.
[43] J. An, M. Yan, N. Yu, A. Chennamadhavuni, M. Furqan, T. Kruser, et al., Outcomes
of patients with stage III non-small cell lung cancer (NSCLC) that harbor a STK11
mutation, J. Clin. Oncol. 38 (2020), 9033-9033.
[44] R. Uba, L.E. Raez, K. Dumais, F. Gentile, H.W. Powery, G.C. Domingo, et al.,
Serine/threonine kinase 11 (STK11) mutations and immunotherapy resistance in
patients with non-small cell lung cancer, J. Clin. Oncol. 38 (2020) e15055-e15055.
[45] Y. Jeong, J.A. Hellyer, H. Stehr, N.T. Hoang, X. Niu, M. Das, et al., Role of KEAP1/
NFE2L2 mutations in the chemotherapeutic response of patients with non-small
cell lung cancer, Clin. Cancer Res. 26 (2020) 274–281.
[46] Y. Tian, K. Wu, Q. Liu, N. Han, L. Zhang, Q. Chu, et al., Modification of platinum
sensitivity by KEAP1/NRF2 signals in non-small cell lung cancer, J. Hematol.
Oncol. 9 (2016) 83.
[47] L.M. Solis, C. Behrens, W. Dong, M. Suraokar, N.C. Ozburn, C.A. Moran, et al., Nrf2
and KEAP1 abnormalities in non-small cell lung carcinoma and association with
clinicopathologic features, Clin. Cancer Res. 16 (2010) 3743–3753.
[48] K.C. Arbour, E. Jordan, H.R. Kim, J. Dienstag, H.A. Yu, F. Sanchez-Vega, et al.,
Effects of co-occurring genomic alterations on outcomes in patients with KRAS-
mutant non-small cell lung cancer, Clin. Cancer Res. 24 (2018) 334–340.
[49] F. Goeman, F. De Nicola, S. Scalera, F. Sperati, E. Gallo, L. Ciuffreda, et al.,
Mutations in the KEAP1-NFE2L2 pathway define a molecular subset of rapidly
progressing lung adenocarcinoma, J. Thorac. Oncol. 14 (2019) 1924–1934.
[50] C.A. Wohlhieter, A.L. Richards, F. Uddin, C.H. Hulton, À. Quintanal-Villalonga,
A. Martin, et al., Concurrent mutations in STK11 and KEAP1 promote ferroptosis
protection and SCD1 dependence in lung cancer, Cell Rep. 33 (2020), 108444.
[51] Q. Zhang, A. Gossai, S. Monroe, N.C. Nussbaum, C.M. Parrinello, Abstract 5772:
validation analysis of a composite real-world mortality endpoint for US cancer
patients, Cancer Res. 80 (2020), 5772-5772.
[52] E.J. Boyko, Observational research–opportunities and limitations, J. Diabetes
Complications 27 (2013) 642–648.