2018年
No.22
Medical Abstracts
Keyword: lung cancer
1. N Engl J Med. 2018 Nov 22;379(21):2027-2039. doi: 10.1056/NEJMoa1810171. Epub
2018 Sep 25.
Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer.
Camidge DR(1), Kim HR(1), Ahn MJ(1), Yang JC(1), Han JY(1), Lee JS(1), Hochmair
MJ(1), Li JY(1), Chang GC(1), Lee KH(1), Gridelli C(1), Delmonte A(1), Garcia
Campelo R(1), Kim DW(1), Bearz A(1), Griesinger F(1), Morabito A(1), Felip E(1),
Califano R(1), Ghosh S(1), Spira A(1), Gettinger SN(1), Tiseo M(1), Gupta N(1),
Haney J(1), Kerstein D(1), Popat S(1).
Author information:
(1)From the University of Colorado Cancer Center, Aurora (D.R.C.); Division of
Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei
University College of Medicine (H.R.K.), Samsung Medical Center (M.-J.A.), and
Seoul National University Hospital (D.-W.K.), Seoul, National Cancer Center,
Goyang (J.-Y.H.), Seoul National University Bundang Hospital, Seongnam (J.-S.L.),
and Chungbuk National University Hospital, Chungbuk National University College
of Medicine, Cheongju (K.H.L.) - all in South Korea; National Taiwan University
Hospital (J.C.-H.Y.) and the Faculty of Medicine, School of Medicine, National
Yang-Ming University (G.-C.C.), …
BACKGROUND: Brigatinib, a next-generation anaplastic lymphoma kinase (ALK)
inhibitor, has robust efficacy in patients with ALK-positive non-small-cell lung
cancer (NSCLC) that is refractory to crizotinib. The efficacy of brigatinib, as
compared with crizotinib, in patients with advanced ALK-positive NSCLC who have
not previously received an ALK inhibitor is unclear.
METHODS: In an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio,
patients with advanced ALK-positive NSCLC who had not previously received ALK
inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7-day
lead-in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The
primary end point was progression-free survival as assessed by blinded
independent central review. Secondary end points included the objective response
rate and intracranial response. The first interim analysis was planned when
approximately 50% of 198 expected events of disease progression or death had
occurred.
RESULTS: A total of 275 patients underwent randomization; 137 were assigned to
brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the
median follow-up was 11.0 months in the brigatinib group and 9.3 months in the
crizotinib group. The rate of progression-free survival was higher with
brigatinib than with crizotinib (estimated 12-month progression-free survival,
67% [95% confidence interval {CI}, 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard
ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by
the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to
78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed
rate of intracranial response among patients with measurable lesions was 78% (95%
CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns
were noted.
CONCLUSIONS: Among patients with ALK-positive NSCLC who had not previously
received an ALK inhibitor, progression-free survival was significantly longer
among patients who received brigatinib than among those who received crizotinib.
(Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501
.).
DOI: 10.1056/NEJMoa1810171
PMID: 30280657 [Indexed for MEDLINE]
2. N Engl J Med. 2018 Nov 22;379(21):2040-2051. doi: 10.1056/NEJMoa1810865. Epub
2018 Sep 25.
Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer.
Paz-Ares L(1), Luft A(1), Vicente D(1), Tafreshi A(1), Gümü? M(1), Mazières J(1),
Hermes B(1), Çay ?enler F(1), Cs?szi T(1), Fülöp A(1), Rodríguez-Cid J(1), Wilson
J(1), Sugawara S(1), Kato T(1), Lee KH(1), Cheng Y(1), Novello S(1), Halmos B(1),
Li X(1), Lubiniecki GM(1), Piperdi B(1), Kowalski DM(1); KEYNOTE-407
Investigators.
Author information:
(1)From Hospital Universitario 12 de Octubre, Spanish National Cancer Research
Center, Universidad Complutense and Ciberonc, Madrid (L.P.-A.), and Hospital
Universitario Virgen Macarena, Seville (D.V.) - both in Spain; Leningrad Regional
Clinical Hospital, St. Petersburg, Russia (A.L.); Wollongong Oncology and
Wollongong Private Hospital, Wollongong, NSW, Australia (A.T.); Istanbul
Medeniyet University Hospital, Istanbul (M.G.), and Ankara University, Ankara
(F.Ç.?.) - both in Turkey; Centre Hospitalier Universitaire de Toulouse,
Université Paul Sabatier, Toulouse, France (J.M.); …
BACKGROUND: Standard first-line therapy for metastatic, squamous non-small-cell
lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients
with programmed death ligand 1 [PD-L1] expression on ≥50% of tumor cells). More
recently, pembrolizumab plus chemotherapy was shown to significantly prolong
overall survival among patients with nonsquamous NSCLC.
METHODS: In this double-blind, phase 3 trial, we randomly assigned, in a 1:1
ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg
of pembrolizumab or saline placebo for up to 35 cycles; all the patients also
received carboplatin and either paclitaxel or nanoparticle albumin-bound
[nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival
and progression-free survival.
RESULTS: After a median follow-up of 7.8 months, the median overall survival was
15.9 months (95% confidence interval [CI], 13.2 to not reached) in the
pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the
placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85;
P<0.001). The overall survival benefit was consistent regardless of the level of
PD-L1 expression. The median progression-free survival was 6.4 months (95% CI,
6.2 to 8.3) in the pembrolizumab-combination group and 4.8 months (95% CI, 4.3 to
5.7) in the placebo-combination group (hazard ratio for disease progression or
death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher
occurred in 69.8% of the patients in the pembrolizumab-combination group and in
68.2% of the patients in the placebo-combination group. Discontinuation of
treatment because of adverse events was more frequent in the
pembrolizumab-combination group than in the placebo-combination group (13.3% vs.
6.4%).
CONCLUSIONS: In patients with previously untreated metastatic, squamous NSCLC,
the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or
nab-paclitaxel resulted in significantly longer overall survival and
progression-free survival than chemotherapy alone. (Funded by Merck Sharp &
Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435 .).
DOI: 10.1056/NEJMoa1810865
PMID: 30280635 [Indexed for MEDLINE]
3. Nat Med. 2019 Jan;25(1):111-118. doi: 10.1038/s41591-018-0264-7. Epub 2018 Nov
26.
Aurora kinase A drives the evolution of resistance to third-generation EGFR
inhibitors in lung cancer.
Shah KN(1)(2), Bhatt R(1)(2), Rotow J(2)(3), Rohrberg J(2)(3), Olivas V(2)(3),
Wang VE(2), Hemmati G(2)(3), Martins MM(2)(3), Maynard A(2)(3), Kuhn J(4), Galeas
J(2), Donnella HJ(1)(2), Kaushik S(1)(2), Ku A(1)(2), Dumont S(4), Krings G(5),
Haringsma HJ(6), Robillard L(6), Simmons AD(6), Harding TC(6), McCormick F(2),
Goga A(2)(4), Blakely CM(2)(3), Bivona TG(2)(3), Bandyopadhyay S(7)(8).
Author information:
(1)Department of Bioengineering and Therapeutic Sciences, University of
California, San Francisco, San Francisco, CA, USA.
(2)Helen Diller Family Comprehensive Cancer Center, University of California, San
Francisco, San Francisco, CA, USA.
(3)Department of Medicine, University of California, San Francisco, San
Francisco, CA, USA.
(4)Department of Cell and Tissue Biology, University of California, San
Francisco, San Francisco, CA, USA.
…
Although targeted therapies often elicit profound initial patient responses,
these effects are transient due to residual disease leading to acquired
resistance. How tumors transition between drug responsiveness, tolerance and
resistance, especially in the absence of preexisting subclones, remains unclear.
In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we
demonstrate that residual disease and acquired resistance in response to EGFR
inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance
through the activation of AURKA by its coactivator TPX2 emerges in response to
chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase
inhibitors suppress this adaptive survival program, increasing the magnitude and
duration of EGFR inhibitor response in preclinical models. Treatment-induced
activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in
vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings
delineate a molecular path whereby drug resistance emerges from drug-tolerant
cells and unveils a synthetic lethal strategy for enhancing responses to EGFR
inhibitors by suppressing AURKA-driven residual disease and acquired resistance.
DOI: 10.1038/s41591-018-0264-7
PMCID: PMC6324945 [Available on 2019-05-26]
PMID: 30478424
4. Lancet Oncol. 2018 Dec;19(12):1654-1667. doi: 10.1016/S1470-2045(18)30649-1. Epub 2018 Nov 6.
Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from
a global phase 2 study.
Solomon BJ(1), Besse B(2), Bauer TM(3), Felip E(4), Soo RA(5), Camidge DR(6),
Chiari R(7), Bearz A(8), Lin CC(9), Gadgeel SM(10), Riely GJ(11), Tan EH(12),
Seto T(13), James LP(14), Clancy JS(15), Abbattista A(16), Martini JF(17), Chen
J(14), Peltz G(18), Thurm H(17), Ou SI(19), Shaw AT(20).
Author information:
(1)Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Electronic address:
ben.solomon@petermac.org.
(2)Gustave Roussy Cancer Campus, Villejuif, France; Department of Cancer
Medicine, Paris-Sud University, Orsay, France.
(3)Sarah Cannon Cancer Research Institute/Tennessee Oncology, PLLC, Nashville,
TN, USA.
…
Erratum in
Lancet Oncol. 2019 Jan;20(1):e10.
BACKGROUND: Lorlatinib is a potent, brain-penetrant, third-generation inhibitor
of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase
1 study, activity was seen in patients with ALK-positive non-small-cell lung
cancer, most of whom had CNS metastases and progression after ALK-directed
therapy. We aimed to analyse the overall and intracranial antitumour activity of
lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer.
METHODS: In this phase 2 study, patients with histologically or cytologically
ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or
without CNS metastases, with an Eastern Cooperative Oncology Group performance
status of 0, 1, or 2, and adequate end-organ function were eligible. Patients
were enrolled into six different expansion cohorts (EXP1-6) on the basis of ALK
and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally
once daily continuously in 21-day cycles. The primary endpoint was overall and
intracranial tumour response by independent central review, assessed in pooled
subgroups of ALK-positive patients. Analyses of activity and safety were based on
the safety analysis set (ie, all patients who received at least one dose of
lorlatinib) as assessed by independent central review. Patients with measurable
CNS metastases at baseline by independent central review were included in the
intracranial activity analyses. In this report, we present lorlatinib activity
data for the ALK-positive patients (EXP1-5 only), and safety data for all treated
patients (EXP1-6). This study is ongoing and is registered with
ClinicalTrials.gov, number NCT01970865.
FINDINGS: Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30
who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and
received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous
chemotherapy; 28 who were ALK positive and received one previous non-crizotinib
ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who were
ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine
kinase inhibitors with or without chemotherapy; and 47 who were ROS1 positive
with any previous treatment (EXP6). One patient in EXP4 died before receiving
lorlatinib and was excluded from the safety analysis set. In treatment-naive
patients (EXP1), an objective response was achieved in 27 (90·0%; 95% CI
73·5-97·9) of 30 patients. Three patients in EXP1 had measurable baseline CNS
lesions per independent central review, and objective intracranial responses were
observed in two (66·7%; 95% CI 9·4-99·2). In ALK-positive patients with at least
one previous ALK tyrosine kinase inhibitor (EXP2-5), objective responses were
achieved in 93 (47·0%; 39·9-54·2) of 198 patients and objective intracranial
response in those with measurable baseline CNS lesions in 51 (63·0%; 51·5-73·4)
of 81 patients. Objective response was achieved in 41 (69·5%; 95% CI 56·1-80·8)
of 59 patients who had only received previous crizotinib (EXP2-3A), nine (32·1%;
15·9-52·4) of 28 patients with one previous non-crizotinib ALK tyrosine kinase
inhibitor (EXP3B), and 43 (38·7%; 29·6-48·5) of 111 patients with two or more
previous ALK tyrosine kinase inhibitors (EXP4-5). Objective intracranial response
was achieved in 20 (87·0%; 95% CI 66·4-97·2) of 23 patients with measurable
baseline CNS lesions in EXP2-3A, five (55·6%; 21·2-86·3) of nine patients in
EXP3B, and 26 (53·1%; 38·3-67·5) of 49 patients in EXP4-5. The most common
treatment-related adverse events across all patients were hypercholesterolaemia
(224 [81%] of 275 patients overall and 43 [16%] grade 3-4) and
hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 3-4). Serious
treatment-related adverse events occurred in 19 (7%) of 275 patients and seven
patients (3%) permanently discontinued treatment because of treatment-related
adverse events. No treatment-related deaths were reported.
INTERPRETATION: Consistent with its broad ALK mutational coverage and CNS
penetration, lorlatinib showed substantial overall and intracranial activity both
in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in
those who had progressed on crizotinib, second-generation ALK tyrosine kinase
inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus,
lorlatinib could represent an effective treatment option for patients with
ALK-positive non-small-cell lung cancer in first-line or subsequent therapy.
FUNDING: Pfizer.
Copyright © 2018 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(18)30649-1
PMID: 30413378
5. Nat Med. 2018 Dec;24(12):1845-1851. doi: 10.1038/s41591-018-0232-2. Epub 2018 Nov 5.
Radiotherapy induces responses of lung cancer to CTLA-4 blockade.
Formenti SC(1), Rudqvist NP(2), Golden E(2)(3), Cooper B(4), Wennerberg E(2),
Lhuillier C(2), Vanpouille-Box C(2), Friedman K(5), Ferrari de Andrade L(6)(7),
Wucherpfennig KW(6)(7), Heguy A(8)(9), Imai N(10), Gnjatic S(10), Emerson RO(11),
Zhou XK(12), Zhang T(13), Chachoua A(14), Demaria S(15)(16).
Author information:
(1)Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA.
formenti@med.cornell.edu.
(2)Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA.
(3)Department of Radiation Oncology, University of California, San Francisco, CA,
USA.
…
Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in
preclinical studies and in some patients with melanoma1-3, but its efficacy in
inducing systemic responses (abscopal responses) against tumors unresponsive to
CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of
anti-tumor T cells, an effect dependent on type I interferon induction in the
irradiated tumor4-6. The latter is essential for achieving abscopal responses in
murine cancers6. The mechanisms underlying abscopal responses in patients treated
with radiation therapy and CTLA-4 blockade remain unclear. Here we report that
radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in
chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4
antibodies had failed to demonstrate significant efficacy alone or in combination
with chemotherapy7,8. Objective responses were observed in 18% of enrolled
patients, and 31% had disease control. Increased serum interferon-β after
radiation and early dynamic changes of blood T cell clones were the strongest
response predictors, confirming preclinical mechanistic data. Functional analysis
in one responding patient showed the rapid in vivo expansion of CD8 T cells
recognizing a neoantigen encoded in a gene upregulated by radiation, supporting
the hypothesis that one explanation for the abscopal response is
radiation-induced exposure of immunogenic mutations to the immune system.
DOI: 10.1038/s41591-018-0232-2
PMCID: PMC6286242 [Available on 2019-05-05]
PMID: 30397353
6. Lancet Oncol. 2018 Nov;19(11):1468-1479. doi: 10.1016/S1470-2045(18)30673-9. Epub 2018 Sep 24.
Avelumab versus docetaxel in patients with platinum-treated advanced
non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3
study.
Barlesi F(1), Vansteenkiste J(2), Spigel D(3), Ishii H(4), Garassino M(5), de
Marinis F(6), Özgüro?lu M(7), Szczesna A(8), Polychronis A(9), Uslu R(10),
Krzakowski M(11), Lee JS(12), Calabrò L(13), Arén Frontera O(14), Ellers-Lenz
B(15), Bajars M(16), Ruisi M(16), Park K(17).
Author information:
(1)Aix Marseille University, Assistance Publique Hôpitaux de Marseille,
Marseille, France.
(2)Department of Respiratory Oncology, University Hospital KU Leuven, Leuven,
Belgium.
(3)Sarah Cannon Research Institute, Nashville, TN, USA.
…
Erratum in
Lancet Oncol. 2018 Nov;19(11):e581.
BACKGROUND: Antibodies targeting the immune checkpoint molecules PD-1 or PD-L1
have demonstrated clinical efficacy in patients with metastatic non-small-cell
lung cancer (NSCLC). In this trial we investigated the efficacy and safety of
avelumab, an anti-PD-L1 antibody, in patients with NSCLC who had already received
platinum-based therapy.
METHODS: JAVELIN Lung 200 was a multicentre, open-label, randomised, phase 3
trial at 173 hospitals and cancer treatment centres in 31 countries. Eligible
patients were aged 18 years or older and had stage IIIB or IV or recurrent NSCLC
and disease progression after treatment with a platinum-containing doublet, an
Eastern Cooperative Oncology Group performance status score of 0 or 1, an
estimated life expectancy of more than 12 weeks, and adequate haematological,
renal, and hepatic function. Participants were randomly assigned (1:1), via an
interactive voice-response system with a stratified permuted block method with
variable block length, to receive either avelumab 10 mg/kg every 2 weeks or
docetaxel 75 mg/m2 every 3 weeks. Randomisation was stratified by PD-L1
expression (≥1% vs <1% of tumour cells), which was measured with the 73-10 assay,
and histology (squamous vs non-squamous). The primary endpoint was overall
survival, analysed when roughly 337 events (deaths) had occurred in the
PD-L1-positive population. Efficacy was analysed in all PD-L1-positive patients
(ie, PD-L1 expression in ≥1% of tumour cells) randomly assigned to study
treatment (the primary analysis population) and then in all randomly assigned
patients through a hierarchical testing procedure. Safety was analysed in all
patients who received at least one dose of study treatment. This trial is
registered with ClinicalTrials.gov, number NCT02395172. Enrolment is complete,
but the trial is ongoing.
FINDINGS: Between March 24, 2015, and Jan 23, 2017, 792 patients were enrolled
and randomly assigned to receive avelumab (n=396) or docetaxel (n=396). 264
participants in the avelumab group and 265 in the docetaxel group had
PD-L1-positive tumours. In patients with PD-L1-positive tumours, median overall
survival did not differ significantly between the avelumab and docetaxel groups
(11·4 months [95% CI 9·4-13·9] vs 10·3 months [8·5-13·0]; hazard ratio 0·90 [96%
CI 0·72-1·12]; one-sided p=0·16). Treatment-related adverse events occurred in
251 (64%) of 393 avelumab-treated patients and 313 (86%) of 365 docetaxel-treated
patients, including grade 3-5 events in 39 (10%) and 180 (49%) patients,
respectively. The most common grade 3-5 treatment-related adverse events were
infusion-related reaction (six patients [2%]) and increased lipase (four [1%]) in
the avelumab group and neutropenia (51 [14%]), febrile neutropenia (37 [10%]),
and decreased neutrophil counts (36 [10%]) in the docetaxel group. Serious
treatment-related adverse events occurred in 34 (9%) patients in the avelumab
group and 75 (21%) in the docetaxel group. Treatment-related deaths occurred in
four (1%) participants in the avelumab group, two due to interstitial lung
disease, one due to acute kidney injury, and one due to a combination of
autoimmune myocarditis, acute cardiac failure, and respiratory failure.
Treatment-related deaths occurred in 14 (4%) patients in the docetaxel group,
three due to pneumonia, and one each due to febrile neutropenia, septic shock,
febrile neutropenia with septic shock, acute respiratory failure, cardiovascular
insufficiency, renal impairment, leucopenia with mucosal inflammation and
pyrexia, infection, neutropenic infection, dehydration, and unknown causes.
INTERPRETATION: Compared with docetaxel, avelumab did not improve overall
survival in patients with platinum-treated PD-L1-positive NSCLC, but had a
favourable safety profile.
FUNDING: Merck and Pfizer.
Copyright © 2018 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(18)30673-9
PMID: 30262187
7. J Clin Oncol. 2019 Jan 10;37(2):97-104. doi: 10.1200/JCO.18.00131. Epub 2018 Nov
16.
SELECT: A Phase II Trial of Adjuvant Erlotinib in Patients With Resected
Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer.
Pennell NA(1), Neal JW(2), Chaft JE(3), Azzoli CG(4), Jänne PA(5), Govindan R(6),
Evans TL(7), Costa DB(8), Wakelee HA(2), Heist RS(4), Shapiro MA(1), Muzikansky
A(4), Murthy S(1), Lanuti M(4), Rusch VW(3), Kris MG(3), Sequist LV(4).
Author information:
(1)1 Cleveland Clinic Taussig Cancer Institute, Cleveland, OH.
(2)2 Stanford Cancer Institute and Stanford School of Medicine, Stanford, CA.
(3)3 Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College,
New York, NY.
(4)4 Massachusetts General Hospital, Boston, MA.
…
PURPOSE: Given the pivotal role of epidermal growth factor receptor (EGFR)
inhibitors in advanced EGFR-mutant non-small-cell lung cancer (NSCLC), we tested
adjuvant erlotinib in patients with EGFR-mutant early-stage NSCLC.
MATERIALS AND METHODS: In this open-label phase II trial, patients with resected
stage IA to IIIA (7th edition of the American Joint Committee on Cancer staging
system) EGFR-mutant NSCLC were treated with erlotinib 150 mg per day for 2 years
after standard adjuvant chemotherapy with or without radiotherapy. The study was
designed for 100 patients and powered to demonstrate a primary end point of
2-year disease-free survival (DFS) greater than 85%, improving on historic data
of 76%.
RESULTS: Patients (N = 100) were enrolled at seven sites from January 2008 to May
2012; 13% had stage IA disease, 32% had stage IB disease, 11% had stage IIA
disease, 16% had stage IIB disease, and 28% had stage IIIA disease. Toxicities
were typical of erlotinib; there were no grade 4 or 5 adverse events. Forty
percent of patients required erlotinib dose reduction to 100 mg per day and 16%
to 50 mg per day. The intended 2-year course was achieved in 69% of patients. The
median follow-up was 5.2 years, and 2-year DFS was 88% (96% stage I, 78% stage
II, 91% stage III). Median DFS and overall survival have not been reached; 5-year
DFS was 56% (95% CI, 45% to 66%), 5-year overall survival was 86% (95% CI, 77% to
92%). Disease recurred in 40 patients, with only four recurrences during
erlotinib treatment. The median time to recurrence was 25 months after stopping
erlotinib. Of patients with recurrence who underwent rebiopsy (n = 24; 60%), only
one had T790M mutation detected. The majority of patients with recurrence were
retreated with erlotinib (n = 26; 65%) for a median duration of 13 months.
CONCLUSION: Patients with EGFR-mutant NSCLC treated with adjuvant erlotinib had
an improved 2-year DFS compared with historic genotype-matched controls.
Recurrences were rare for patients receiving adjuvant erlotinib, and patients
rechallenged with erlotinib after recurrence experienced durable benefit.
DOI: 10.1200/JCO.18.00131
PMID: 30444685
8. J Natl Cancer Inst. 2018 Nov 13. doi: 10.1093/jnci/djy166. [Epub ahead of print]
Role of INSL4 Signaling in Sustaining the Growth and Viability of
LKB1-Inactivated Lung Cancer.
Yang R(1)(2), Li SW(1)(2)(3), Chen Z(1)(2), Zhou X(1)(2), Ni W(1)(4), Fu DA(5),
Lu J(1)(2)(6), Kaye FJ(2)(3), Wu L(1)(2)(4).
Author information:
(1)Department of Molecular Genetics and Microbiology.
(2)UF Health Cancer Center.
(3)Department of Medicine.
(4)UF Genetics Institute.
(5)Department of Pathology, Immunology and Laboratory Medicine.
(6)Department of Biochemistry and Molecular Biology, College of Medicine,
University of Florida, Gainesville, FL.
Background: The LKB1 tumor suppressor gene is commonly inactivated in non-small
cell lung carcinomas (NSCLC), a major form of lung cancer. Targeted therapies for
LKB1-inactivated lung cancer are currently unavailable. Identification of
critical signaling components downstream of LKB1 inactivation has the potential
to uncover rational therapeutic targets. Here we investigated the role of INSL4,
a member of the insulin/IGF/relaxin superfamily, in LKB1-inactivated NSCLCs.
Methods: INSL4 expression was analyzed using global transcriptome profiling,
quantitative reverse transcription PCR, western blotting, enzyme-linked
immunosorbent assay, and RNA in situ hybridization in human NSCLC cell lines and
tumor specimens. INSL4 gene expression and clinical data from The Cancer Genome
Atlas lung adenocarcinomas (n = 515) were analyzed using log-rank and Fisher
exact tests. INSL4 functions were studied using short hairpin RNA (shRNA)
knockdown, overexpression, transcriptome profiling, cell growth, and survival
assays in vitro and in vivo. All statistical tests were two-sided.
Results: INSL4 was identified as a novel downstream target of LKB1 deficiency and
its expression was induced through aberrant CRTC-CREB activation. INSL4 was
highly induced in LKB1-deficient NSCLC cells (up to 543-fold) and 9 of 41 primary
tumors, although undetectable in all normal tissues except the placenta. Lung
adenocarcinomas from The Cancer Genome Atlas with high and low INSL4 expression
(with the top 10th percentile as cutoff) showed statistically significant
differences for advanced tumor stage (P < .001), lymph node metastasis
(P = .001), and tumor size (P = .01). The INSL4-high group showed worse survival
than the INSL4-low group (P < .001). Sustained INSL4 expression was required for
the growth and viability of LKB1-inactivated NSCLC cells in vitro and in a mouse
xenograft model (n = 5 mice per group). Expression profiling revealed INSL4 as a
critical regulator of cell cycle, growth, and survival.
Conclusions: LKB1 deficiency induces an autocrine INSL4 signaling that critically
supports the growth and survival of lung cancer cells. Therefore, aberrant INSL4
signaling is a promising therapeutic target for LKB1-deficient lung cancers.
DOI: 10.1093/jnci/djy166
PMID: 30423141
9. PLoS Med. 2018 Nov 30;15(11):e1002711. doi: 10.1371/journal.pmed.1002711.
eCollection 2018 Nov.
Deep learning for lung cancer prognostication: A retrospective multi-cohort
radiomics study.
Hosny A(1), Parmar C(1), Coroller TP(1), Grossmann P(1), Zeleznik R(1), Kumar
A(1), Bussink J(2), Gillies RJ(3), Mak RH(4), Aerts HJWL(1)(4).
Author information:
(1)Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and
Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of
America.
(2)Department of Radiation Oncology, Radboud University Medical Center, Nijmegen,
The Netherlands.
(3)Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research
Institute, Tampa, Florida, United States of America.
(4)Department of Radiology, Brigham and Women's Hospital, Harvard Medical School,
Boston, Massachusetts, United States of America.
BACKGROUND: Non-small-cell lung cancer (NSCLC) patients often demonstrate varying
clinical courses and outcomes, even within the same tumor stage. This study
explores deep learning applications in medical imaging allowing for the automated
quantification of radiographic characteristics and potentially improving patient
stratification.
METHODS AND FINDINGS: We performed an integrative analysis on 7 independent
datasets across 5 institutions totaling 1,194 NSCLC patients (age median = 68.3
years [range 32.5-93.3], survival median = 1.7 years [range 0.0-11.7]). Using
external validation in computed tomography (CT) data, we identified prognostic
signatures using a 3D convolutional neural network (CNN) for patients treated
with radiotherapy (n = 771, age median = 68.0 years [range 32.5-93.3], survival
median = 1.3 years [range 0.0-11.7]). We then employed a transfer learning
approach to achieve the same for surgery patients (n = 391, age median = 69.1
years [range 37.2-88.0], survival median = 3.1 years [range 0.0-8.8]). We found
that the CNN predictions were significantly associated with 2-year overall
survival from the start of respective treatment for radiotherapy (area under the
receiver operating characteristic curve [AUC] = 0.70 [95% CI 0.63-0.78], p <
0.001) and surgery (AUC = 0.71 [95% CI 0.60-0.82], p < 0.001) patients. The CNN
was also able to significantly stratify patients into low and high mortality risk
groups in both the radiotherapy (p < 0.001) and surgery (p = 0.03) datasets.
Additionally, the CNN was found to significantly outperform random forest models
built on clinical parameters-including age, sex, and tumor node metastasis
stage-as well as demonstrate high robustness against test-retest (intraclass
correlation coefficient = 0.91) and inter-reader (Spearman's rank-order
correlation = 0.88) variations. To gain a better understanding of the
characteristics captured by the CNN, we identified regions with the most
contribution towards predictions and highlighted the importance of
tumor-surrounding tissue in patient stratification. We also present preliminary
findings on the biological basis of the captured phenotypes as being linked to
cell cycle and transcriptional processes. Limitations include the retrospective
nature of this study as well as the opaque black box nature of deep learning
networks.
CONCLUSIONS: Our results provide evidence that deep learning networks may be used
for mortality risk stratification based on standard-of-care CT images from NSCLC
patients. This evidence motivates future research into better deciphering the
clinical and biological basis of deep learning networks as well as validation in
prospective data.
DOI: 10.1371/journal.pmed.1002711
PMCID: PMC6269088
PMID: 30500819
10. Nat Commun. 2018 Nov 19;9(1):4559. doi: 10.1038/s41467-018-07077-1.
H3K9 methyltransferases and demethylases control lung tumor-propagating cells and
lung cancer progression.
Rowbotham SP(1)(2), Li F(3), Dost AFM(1)(2), Louie SM(1)(2), Marsh BP(1)(2),
Pessina P(1)(2), Anbarasu CR(1)(2), Brainson CF(4), Tuminello SJ(5), Lieberman
A(6), Ryeom S(6), Schlaeger TM(1), Aronow BJ(7), Watanabe H(5), Wong KK(3), Kim
CF(8)(9)(10).
Author information:
(1)Stem Cell Program, Division of Hematology/Oncology and Pulmonary and
Respiratory Diseases, Children's Hospital Boston, Boston, MA, 02115, USA.
(2)Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
(3)Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical
Center, New York, NY, 10016, USA.
(4)Department of Toxicology and Cancer Biology, University of Kentucky,
Lexington, KY, 40536, USA.
…
Epigenetic regulators are attractive anticancer targets, but the promise of
therapeutic strategies inhibiting some of these factors has not been proven in
vivo or taken into account tumor cell heterogeneity. Here we show that the
histone methyltransferase G9a, reported to be a therapeutic target in many
cancers, is a suppressor of aggressive lung tumor-propagating cells (TPCs).
Inhibition of G9a drives lung adenocarcinoma cells towards the TPC phenotype by
de-repressing genes which regulate the extracellular matrix. Depletion of G9a
during tumorigenesis enriches tumors in TPCs and accelerates disease progression
metastasis. Depleting histone demethylases represses G9a-regulated genes and TPC
phenotypes. Demethylase inhibition impairs lung adenocarcinoma progression in
vivo. Therefore, inhibition of G9a is dangerous in certain cancer contexts, and
targeting the histone demethylases is a more suitable approach for lung cancer
treatment. Understanding cellular context and specific tumor populations is
critical when targeting epigenetic regulators in cancer for future therapeutic
development.
DOI: 10.1038/s41467-018-07077-1
PMCID: PMC6242814
PMID: 30455465
11. Cell Metab. 2018 Nov 5. pii: S1550-4131(18)30637-5. doi:
10.1016/j.cmet.2018.10.005. [Epub ahead of print]
Genetic Analysis Reveals AMPK Is Required to Support Tumor Growth in Murine
Kras-Dependent Lung Cancer Models.
Eichner LJ(1), Brun SN(1), Herzig S(1), Young NP(1), Curtis SD(1), Shackelford
DB(1), Shokhirev MN(2), Leblanc M(1), Vera LI(1), Hutchins A(1), Ross DS(1), Shaw
RJ(3), Svensson RU(4).
Author information:
(1)Molecular and Cell Biology Laboratories, The Salk Institute for Biological
Studies, La Jolla, San Diego, CA, USA.
(2)Integrative Genomics and Bioinformatics Core, The Salk Institute for
Biological Studies, La Jolla, San Diego, CA, USA.
(3)Molecular and Cell Biology Laboratories, The Salk Institute for Biological
Studies, La Jolla, San Diego, CA, USA. Electronic address: shaw@salk.edu.
(4)Molecular and Cell Biology Laboratories, The Salk Institute for Biological
Studies, La Jolla, San Diego, CA, USA. Electronic address: rsvensson@salk.edu.
AMPK, a conserved sensor of low cellular energy, can either repress or promote
tumor growth depending on the context. However, no studies have examined AMPK
function in autochthonous genetic mouse models of epithelial cancer. Here, we
examine the role of AMPK in murine KrasG12D-mediated non-small-cell lung cancer
(NSCLC), a cancer type in humans that harbors frequent inactivating mutations in
the LKB1 tumor suppressor-the predominant upstream activating kinase of AMPK and
12 related kinases. Unlike LKB1 deletion, AMPK deletion in KrasG12D lung tumors
did not accelerate lung tumor growth. Moreover, deletion of AMPK in KrasG12D
p53f/f tumors reduced lung tumor burden. We identified a critical role for AMPK
in regulating lysosomal gene expression through the Tfe3 transcription factor,
which was required to support NSCLC growth. Thus, AMPK supports the growth of
KrasG12D-dependent lung cancer through the induction of lysosomes, highlighting
an unrecognized liability of NSCLC.
Copyright © 2018 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cmet.2018.10.005
PMID: 30415923
12. Cancer Discov. 2018 Nov;8(11):1422-1437. doi: 10.1158/2159-8290.CD-18-0385. Epub 2018 Sep 4.
Crebbp Loss Drives Small Cell Lung Cancer and Increases Sensitivity to HDAC
Inhibition.
Jia D(#)(1), Augert A(#)(1), Kim DW(#)(2), Eastwood E(1), Wu N(1), Ibrahim AH(1),
Kim KB(2), Dunn CT(2), Pillai SPS(3), Gazdar AF(4), Bolouri H(1), Park KS(5),
MacPherson D(6)(7).
Author information:
(1)Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle,
Washington.
(2)Department of Microbiology, Immunology, and Cancer Biology, University of
Virginia School of Medicine, Charlottesville, Virginia.
(3)Division of Comparative Medicine, Fred Hutchinson Cancer Research Center,
Seattle, Washington.
…
CREBBP, encoding an acetyltransferase, is among the most frequently mutated genes
in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report
acceleration of SCLC upon Crebbp inactivation in an autochthonous mouse model.
Extending these observations beyond the lung, broad Crebbp deletion in mouse
neuroendocrine cells cooperated with Rb1/Trp53 loss to promote neuroendocrine
thyroid and pituitary carcinomas. Gene expression analyses showed that Crebbp
loss results in reduced expression of tight junction and cell adhesion genes,
including Cdh1, across neuroendocrine tumor types, whereas suppression of Cdh1
promoted transformation in SCLC. CDH1 and other adhesion genes exhibited reduced
histone acetylation with Crebbp inactivation. Treatment with the histone
deacetylase (HDAC) inhibitor Pracinostat increased histone acetylation and
restored CDH1 expression. In addition, a subset of Rb1/Trp53/Crebbp-deficient
SCLC exhibited exceptional responses to Pracinostat in vivo Thus, CREBBP acts as
a potent tumor suppressor in SCLC, and inactivation of CREBBP enhances responses
to a targeted therapy.Significance: Our findings demonstrate that CREBBP loss in
SCLC reduces histone acetylation and transcription of cellular adhesion genes,
while driving tumorigenesis. These effects can be partially restored by HDAC
inhibition, which exhibited enhanced effectiveness in Crebbp-deleted tumors.
These data provide a rationale for selectively treating CREBBP-mutant SCLC with
HDAC inhibitors. Cancer Discov; 8(11); 1422-37. ©2018 AACR. This article is
highlighted in the In This Issue feature, p. 1333.
©2018 American Association for Cancer Research.
DOI: 10.1158/2159-8290.CD-18-0385
PMCID: PMC6294438 [Available on 2019-11-01]
PMID: 30181244
13. J Clin Oncol. 2018 Nov 1;36(31):3101-3109. doi: 10.1200/JCO.2018.77.7326. Epub
2018 Aug 29.
Phase Ib/II Study of Capmatinib (INC280) Plus Gefitinib After Failure of
Epidermal Growth Factor Receptor (EGFR) Inhibitor Therapy in Patients With
EGFR-Mutated, MET Factor-Dysregulated Non-Small-Cell Lung Cancer.
Wu YL(1), Zhang L(1), Kim DW(1), Liu X(1), Lee DH(1), Yang JC(1), Ahn MJ(1),
Vansteenkiste JF(1), Su WC(1), Felip E(1), Chia V(1), Glaser S(1), Pultar P(1),
Zhao S(1), Peng B(1), Akimov M(1), Tan DSW(1).
Author information:
(1)Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical
Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing
Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences,
Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research,
Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University
Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn,
Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National
Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University
Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven,
Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona,
Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover,
NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and
Daniel S.W. Tan, National Cancer Centre Singapore, Singapore.
PURPOSE: MET dysregulation occurs in up to 26% of non-small-cell lung cancers
(NSCLCs) after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor
(TKI) treatment. Capmatinib (INC280) is a potent and selective MET inhibitor with
preclinical activity in combination with gefitinib in EGFR-mutant,
MET-amplified/overexpressing models of acquired EGFR-TKI resistance. This phase
Ib/II study investigated the safety and efficacy of capmatinib plus gefitinib in
patients with EGFR-mutated, MET-dysregulated (amplified/overexpressing) NSCLC who
experienced disease progression while receiving EGFR-TKI treatment.
METHODS: Patients in phase Ib received capmatinib 100- to 800-mg capsules once
per day or 200- to 600-mg capsules or tablets twice per day, plus gefitinib 250
mg once per day. Patients in phase II received the recommended phase II dose. The
primary end point was the overall response rate (ORR) per Response Evaluation
Criteria in Solid Tumors (RECIST) version 1.1.
RESULTS: Sixty-one patients were treated in phase Ib, and 100 were treated in
phase II. The recommended phase II dose was capmatinib 400 mg twice per day plus
gefitinib 250 mg once per day. Preliminary clinical activity was observed, with
an ORR across phase Ib/II of 27%. Increased activity was seen in patients with
high MET-amplified tumors, with a phase II ORR of 47% in patients with a MET gene
copy number ≥ 6. Across phases Ib and II, the most common drug-related adverse
events were nausea (28%), peripheral edema (22%), decreased appetite (21%), and
rash (20%); the most common drug-related grade 3/4 adverse events were increased
amylase and lipase levels (both 6%). No significant drug-drug interactions
between capmatinib and gefitinib were evident.
CONCLUSION: This study, focused on a predominant EGFR-TKI resistance mechanism in
patients with EGFR-mutated NSCLC, shows that the combination of capmatinib with
gefitinib is a promising treatment for patients with EGFR-mutated,
MET-dysregulated NSCLC, particularly MET-amplified disease.
DOI: 10.1200/JCO.2018.77.7326
PMID: 30156984
14. Am J Respir Crit Care Med. 2018 Nov 1;198(9):1188-1198. doi:
10.1164/rccm.201710-2118OC.
Airway Microbiota Is Associated with Upregulation of the PI3K Pathway in Lung
Cancer.
Tsay JJ(1), Wu BG(1), Badri MH(2), Clemente JC(3), Shen N(3), Meyn P(4), Li Y(1),
Yie TA(1), Lhakhang T(4), Olsen E(1), Murthy V(1), Michaud G(1), Sulaiman I(1),
Tsirigos A(4), Heguy A(4), Pass H(5), Weiden MD(1), Rom WN(1), Sterman DH(1),
Bonneau R(2)(6), Blaser MJ(7), Segal LN(1).
Author information:
(1)1 Division of Pulmonary and Critical Care Medicine.
(2)2 Flatiron Institute, Center for Computational Biology, Simons Foundation, New
York, New York.
(3)3 Department of Genetics and Genomic Sciences and Immunology Institute, Icahn
School of Medicine at Mount Sinai, New York, New York.
(4)4 New York University Genomic Technology Center, New York, New York; and.
(5)5 Department of Cardiothoracic Surgery, and.
(6)6 New York University Center for Data Science, New York, New York.
(7)7 Department of Medicine, New York University School of Medicine, New York,
New York.
RATIONALE: In lung cancer, upregulation of the PI3K (phosphoinositide 3-kinase)
pathway is an early event that contributes to cell proliferation, survival, and
tissue invasion. Upregulation of this pathway was recently described as
associated with enrichment of the lower airways with bacteria identified as oral
commensals.
OBJECTIVES: We hypothesize that host-microbe interactions in the lower airways of
subjects with lung cancer affect known cancer pathways.
METHODS: Airway brushings were collected prospectively from subjects with lung
nodules at time of diagnostic bronchoscopy, including 39 subjects with final lung
cancer diagnoses and 36 subjects with noncancer diagnoses. In addition, samples
from 10 healthy control subjects were included. 16S ribosomal RNA gene amplicon
sequencing and paired transcriptome sequencing were performed on all airway
samples. In addition, an in vitro model with airway epithelial cells exposed to
bacteria/bacterial products was performed.
MEASUREMENTS AND MAIN RESULTS: The composition of the lower airway transcriptome
in the patients with cancer was significantly different from the control
subjects, which included up-regulation of ERK (extracellular signal-regulated
kinase) and PI3K signaling pathways. The lower airways of patients with lung
cancer were enriched for oral taxa (Streptococcus and Veillonella), which was
associated with up-regulation of the ERK and PI3K signaling pathways. In vitro
exposure of airway epithelial cells to Veillonella, Prevotella, and Streptococcus
led to upregulation of these same signaling pathways.
CONCLUSIONS: The data presented here show that several transcriptomic signatures
previously identified as relevant to lung cancer pathogenesis are associated with
enrichment of the lower airway microbiota with oral commensals.
DOI: 10.1164/rccm.201710-2118OC
PMCID: PMC6221574 [Available on 2019-11-01]
PMID: 29864375
