2019年
No.8
Medical Abstracts
Keyword: lung cancer
1. Lancet. 2019 May 4;393(10183):1819-1830. doi: 10.1016/S0140-6736(18)32409-7. Epub 2019 Apr 4.
Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing,
locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a
randomised, open-label, controlled, phase 3 trial.
Mok TSK(1), Wu YL(2), Kudaba I(3), Kowalski DM(4), Cho BC(5), Turna HZ(6), Castro
G Jr(7), Srimuninnimit V(8), Laktionov KK(9), Bondarenko I(10), Kubota K(11),
Lubiniecki GM(12), Zhang J(13), Kush D(12), Lopes G(14); KEYNOTE-042
Investigators.
Author information:
(1)Department of Clinical Oncology, State Key Laboratory of South China, Chinese
University of Hong Kong, Shatin, Hong Kong Special Administrative Region, China.
Electronic address: tony@clo.cuhk.edu.hk.
(2)Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong
General Hospital and Guangdong Academy of Medical Sciences, Guandong, China.
(3)Department of Internal Diseases, Riga East Clinical University-Latvian
Oncology Center, Riga, Latvia.
…
BACKGROUND: First-line pembrolizumab monotherapy improves overall and
progression-free survival in patients with untreated metastatic non-small-cell
lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score
(TPS) of 50% or greater. We investigated overall survival after treatment with
pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.
METHODS: This randomised, open-label, phase 3 study was done in 213 medical
centres in 32 countries. Eligible patients were adults (≥18 years) with
previously untreated locally advanced or metastatic non-small-cell lung cancer
without a sensitising EGFR mutation or ALK translocation and with an Eastern
Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life
expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation
was computer generated, accessed via an interactive voice-response and integrated
web-response system, and stratified by region of enrolment (east Asia vs rest of
world), ECOG performance status score (0 vs 1), histology (squamous vs
non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly
assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every
3 weeks for up to 35 cycles or the investigator's choice of platinum-based
chemotherapy for four to six cycles. Primary endpoints were overall survival in
patients with a TPS of 50% or greater, 20% or greater, and 1% or greater
(one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124,
respectively) in the intention-to-treat population, assessed sequentially if the
previous findings were significant. This study is registered at
ClinicalTrials.gov, number NCT02220894.
FINDINGS: From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women,
median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated
to pembrolizumab (n=637) or chemotherapy (n=637) and included in the
intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818
patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up
was 12·8 months. Overall survival was significantly longer in the pembrolizumab
group than in the chemotherapy group in all three TPS populations (≥50% hazard
ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively.
Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636
treated patients in the pembrolizumab group and in 252 (41%) of 615 in the
chemotherapy group and led to death in 13 (2%) and 14 (2%) patients,
respectively.
INTERPRETATION: The benefit-to-risk profile suggests that pembrolizumab
monotherapy can be extended as first-line therapy to patients with locally
advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK
alterations and with low PD-L1 TPS.
FUNDING: Merck Sharp & Dohme.
Copyright © 2019 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(18)32409-7
PMID: 30955977 [Indexed for MEDLINE]
2. Lancet Oncol. 2019 May;20(5):625-635. doi: 10.1016/S1470-2045(19)30035-X. Epub
2019 Apr 8.
Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive
advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an
open-label, randomised, multicentre, phase 3 trial.
Saito H(1), Fukuhara T(2), Furuya N(3), Watanabe K(2), Sugawara S(4), Iwasawa
S(5), Tsunezuka Y(6), Yamaguchi O(7), Okada M(8), Yoshimori K(9), Nakachi I(10),
Gemma A(11), Azuma K(12), Kurimoto F(13), Tsubata Y(14), Fujita Y(15), Nagashima
H(16), Asai G(17), Watanabe S(18), Miyazaki M(19), Hagiwara K(20), Nukiwa T(21),
Morita S(22), Kobayashi K(7), Maemondo M(23).
Author information:
(1)Kanagawa Cancer Center, Yokohama, Japan.
(2)Miyagi Cancer Center, Natori, Japan.
(3)St Marianna University School of Medicine, Kawasaki, Japan.
…
BACKGROUND: Resistance to first-generation or second-generation EGFR tyrosine
kinase inhibitor (TKI) monotherapy develops in almost half of patients with
EGFR-positive non-small-cell lung cancer (NSCLC) after 1 year of treatment. The
JO25567 phase 2 trial comparing erlotinib plus bevacizumab combination therapy
with erlotinib monotherapy established the activity and manageable toxicity of
erlotinib plus bevacizumab in patients with NSCLC. We did a phase 3 trial to
validate the results of the JO25567 study and report here the results from the
preplanned interim analysis.
METHODS: In this prespecified interim analysis of the randomised, open-label,
phase 3 NEJ026 trial, we recruited patients with stage IIIB-IV disease or
recurrent, cytologically or histologically confirmed non-squamous NSCLC with
activating EGFR genomic aberrations from 69 centres across Japan. Eligible
patients were at least 20 years old, and had an Eastern Cooperative Oncology
Group performance status of 2 or lower, no previous chemotherapy for advanced
disease, and one or more measurable lesions based on Response Evaluation Criteria
in Solid Tumours (1.1). Patients were randomly assigned (1:1) to receive oral
erlotinib 150 mg per day plus intravenous bevacizumab 15 mg/kg once every 21
days, or erlotinib 150 mg per day monotherapy. Randomisation was done by
minimisation, stratified by sex, smoking status, clinical stage, and EGFR
mutation subtype. The primary endpoint was progression-free survival. This study
is ongoing; the data cutoff for this prespecified interim analysis was Sept 21,
2017. Efficacy was analysed in the modified intention-to-treat population, which
included all randomly assigned patients who received at least one dose of
treatment and had at least one response evaluation. Safety was analysed in all
patients who received at least one dose of study drug. The trial is registered
with the University Hospital Medical Information Network Clinical Trials
Registry, number UMIN000017069.
FINDINGS: Between June 3, 2015, and Aug 31, 2016, 228 patients were randomly
assigned to receive erlotinib plus bevacizumab (n=114) or erlotinib alone
(n=114). 112 patients in each group were evaluable for efficacy, and safety was
evaluated in 112 patients in the combination therapy group and 114 in the
monotherapy group. Median follow-up was 12·4 months (IQR 7·0-15·7). At the time
of interim analysis, median progression-free survival for patients in the
erlotinib plus bevacizumab group was 16·9 months (95% CI 14·2-21·0) compared with
13·3 months (11·1-15·3) for patients in the erlotinib group (hazard ratio 0·605,
95% CI 0·417-0·877; p=0·016). 98 (88%) of 112 patients in the erlotinib plus
bevacizumab group and 53 (46%) of 114 patients in the erlotinib alone group had
grade 3 or worse adverse events. The most common grade 3-4 adverse event was rash
(23 [21%] of 112 patients in the erlotinib plus bevacizumab group vs 24 [21%] of
114 patients in the erlotinib alone group). Nine (8%) of 112 patients in the
erlotinib plus bevacizumab group and five (4%) of 114 patients in the erlotinib
alone group had serious adverse events. The most common serious adverse events
were grade 4 neutropenia (two [2%] of 112 patients in the erlotinib plus
bevacizumab group) and grade 4 hepatic dysfunction (one [1%] of 112 patients in
the erlotinib plus bevacizumab group and one [1%] of 114 patients in the
erlotinib alone group). No treatment-related deaths occurred.
INTERPRETATION: The results of this interim analysis showed that bevacizumab plus
erlotinib combination therapy improves progression-free survival compared with
erlotinib alone in patients with EGFR-positive NSCLC. Future studies with longer
follow-up, and overall survival and quality-of-life data will be required to
further assess the efficacy of this combination in this setting.
FUNDING: Chugai Pharmaceutical.
Copyright © 2019 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(19)30035-X
PMID: 30975627
3. JAMA. 2019 Apr 9;321(14):1391-1399. doi: 10.1001/jama.2019.3241.
Association of Patient Characteristics and Tumor Genomics With Clinical Outcomes
Among Patients With Non-Small Cell Lung Cancer Using a Clinicogenomic Database.
Singal G(1)(2), Miller PG(3), Agarwala V(4)(5), Li G(1), Kaushik G(1), Backenroth
D(4), Gossai A(4), Frampton GM(1), Torres AZ(4), Lehnert EM(1), Bourque D(1),
O'Connell C(4), Bowser B(4), Caron T(4), Baydur E(4), Seidl-Rathkopf K(4), Ivanov
I(4), Alpha-Cobb G(1), Guria A(1), He J(1), Frank S(4), Nunnally AC(6), Bailey
M(1), Jaskiw A(4), Feuchtbaum D(4), Nussbaum N(4)(7), Abernethy AP(4)(8), Miller
VA(1).
Author information:
(1)Foundation Medicine Inc, Cambridge, Massachusetts.
(2)Brigham and Women's Hospital, Boston, Massachusetts.
(3)Department of Medical Oncology, Dana Farber Cancer Institute, Boston,
Massachusetts.
…
Comment in
JAMA. 2019 Apr 9;321(14):1359-1360.
Importance: Data sets linking comprehensive genomic profiling (CGP) to clinical
outcomes may accelerate precision medicine.
Objective: To assess whether a database that combines EHR-derived clinical data
with CGP can identify and extend associations in non-small cell lung cancer
(NSCLC).
Design, Setting, and Participants: Clinical data from EHRs were linked with CGP
results for 28?998 patients from 275 US oncology practices. Among 4064 patients
with NSCLC, exploratory associations between tumor genomics and patient
characteristics with clinical outcomes were conducted, with data obtained between
January 1, 2011, and January 1, 2018.
Exposures: Tumor CGP, including presence of a driver alteration (a pathogenic or
likely pathogenic alteration in a gene shown to drive tumor growth); tumor
mutation burden (TMB), defined as the number of mutations per megabase; and
clinical characteristics gathered from EHRs.
Main Outcomes and Measures: Overall survival (OS), time receiving therapy,
maximal therapy response (as documented by the treating physician in the EHR),
and clinical benefit rate (fraction of patients with stable disease, partial
response, or complete response) to therapy.
Results: Among 4064 patients with NSCLC (median age, 66.0 years; 51.9% female),
3183 (78.3%) had a history of smoking, 3153 (77.6%) had nonsquamous cancer, and
871 (21.4%) had an alteration in EGFR, ALK, or ROS1 (701 [17.2%] with EGFR, 128
[3.1%] with ALK, and 42 [1.0%] with ROS1 alterations). There were 1946 deaths in
7 years. For patients with a driver alteration, improved OS was observed among
those treated with (n = 575) vs not treated with (n = 560) targeted therapies
(median, 18.6 months [95% CI, 15.2-21.7] vs 11.4 months [95% CI, 9.7-12.5] from
advanced diagnosis; P < .001). TMB (in mutations/Mb) was significantly higher
among smokers vs nonsmokers (8.7 [IQR, 4.4-14.8] vs 2.6 [IQR, 1.7-5.2]; P < .001)
and significantly lower among patients with vs without an alteration in EGFR (3.5
[IQR, 1.76-6.1] vs 7.8 [IQR, 3.5-13.9]; P < .001), ALK (2.1 [IQR, 0.9-4.0] vs 7.0
[IQR, 3.5-13.0]; P < .001), RET (4.6 [IQR, 1.7-8.7] vs 7.0 [IQR, 2.6-13.0];
P = .004), or ROS1 (4.0 [IQR, 1.2-9.6] vs 7.0 [IQR, 2.6-13.0]; P = .03). In
patients treated with anti-PD-1/PD-L1 therapies (n = 1290, 31.7%), TMB of 20 or
more was significantly associated with improved OS from therapy initiation (16.8
months [95% CI, 11.6-24.9] vs 8.5 months [95% CI, 7.6-9.7]; P < .001), longer
time receiving therapy (7.8 months [95% CI, 5.5-11.1] vs 3.3 months [95% CI,
2.8-3.7]; P < .001), and increased clinical benefit rate (80.7% vs 56.7%;
P < .001) vs TMB less than 20.
Conclusions and Relevance: Among patients with NSCLC included in a longitudinal
database of clinical data linked to CGP results from routine care, exploratory
analyses replicated previously described associations between clinical and
genomic characteristics, between driver mutations and response to targeted
therapy, and between TMB and response to immunotherapy. These findings
demonstrate the feasibility of creating a clinicogenomic database derived from
routine clinical experience and provide support for further research and
discovery evaluating this approach in oncology.
DOI: 10.1001/jama.2019.3241
PMCID: PMC6459115 [Available on 2019-10-09]
PMID: 30964529 [Indexed for MEDLINE]
4. Lancet Oncol. 2019 Apr;20(4):494-503. doi: 10.1016/S1470-2045(18)30896-9. Epub
2019 Feb 12.
Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1
non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised
controlled trial.
Ball D(1), Mai GT(2), Vinod S(3), Babington S(4), Ruben J(5), Kron T(6), Chesson
B(7), Herschtal A(8), Vanevski M(8), Rezo A(9), Elder C(10), Skala M(11), Wirth
A(7), Wheeler G(7), Lim A(12), Shaw M(7), Schofield P(13), Irving L(14), Solomon
B(6); TROG 09.02 CHISEL investigators.
Collaborators: Nedev N, Le H.
Author information:
(1)Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum
Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
Electronic address: david.ball@petermac.org.
(2)Princess Alexandra Hospital and University of Queensland, Brisbane, QLD,
Australia.
(3)Liverpool Hospital and University of New South Wales, Sydney, NSW, Australia.
…
BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is widely used to
treat inoperable stage 1 non-small-cell lung cancer (NSCLC), despite the absence
of prospective evidence that this type of treatment improves local control or
prolongs overall survival compared with standard radiotherapy. We aimed to
compare the two treatment techniques.
METHODS: We did this multicentre, phase 3, randomised, controlled trial in 11
hospitals in Australia and three hospitals in New Zealand. Patients were eligible
if they were aged 18 years or older, had biopsy-confirmed stage 1 (T1-T2aN0M0)
NSCLC diagnosed on the basis of 18F-fluorodeoxyglucose PET, and were medically
inoperable or had refused surgery. Patients had to have an Eastern Cooperative
Oncology Group performance status of 0 or 1, and the tumour had to be
peripherally located. Patients were randomly assigned after stratification for T
stage and operability in a 2:1 ratio to SABR (54 Gy in three 18 Gy fractions, or
48 Gy in four 12 Gy fractions if the tumour was <2 cm from the chest wall) or
standard radiotherapy (66 Gy in 33 daily 2 Gy fractions or 50 Gy in 20 daily 2·5
Gy fractions, depending on institutional preference) using minimisation, so no
sequence was pre-generated. Clinicians, patients, and data managers had no
previous knowledge of the treatment group to which patients would be assigned;
however, the treatment assignment was subsequently open label (because of the
nature of the interventions). The primary endpoint was time to local treatment
failure (assessed according to Response Evaluation Criteria in Solid Tumors
version 1.0), with the hypothesis that SABR would result in superior local
control compared with standard radiotherapy. All efficacy analyses were based on
the intention-to-treat analysis. Safety analyses were done on a per-protocol
basis, according to treatment that the patients actually received. The trial is
registered with ClinicalTrials.gov (NCT01014130) and the Australia and New
Zealand Clinical Trials Registry (ACTRN12610000479000). The trial is closed to
new participants.
FINDINGS: Between Dec 31, 2009, and June 22, 2015, 101 eligible patients were
enrolled and randomly assigned to receive SABR (n=66) or standard radiotherapy
(n=35). Five (7·6%) patients in the SABR group and two (6·5%) in the standard
radiotherapy group did not receive treatment, and a further four in each group
withdrew before study end. As of data cutoff (July 31, 2017), median follow-up
for local treatment failure was 2·1 years (IQR 1·2-3·6) for patients randomly
assigned to standard radiotherapy and 2·6 years (IQR 1·6-3·6) for patients
assigned to SABR. 20 (20%) of 101 patients had progressed locally: nine (14%) of
66 patients in the SABR group and 11 (31%) of 35 patients in the standard
radiotherapy group, and freedom from local treatment failure was improved in the
SABR group compared with the standard radiotherapy group (hazard ratio 0·32, 95%
CI 0·13-0·77, p=0·0077). Median time to local treatment failure was not reached
in either group. In patients treated with SABR, there was one grade 4 adverse
event (dyspnoea) and seven grade 3 adverse events (two cough, one hypoxia, one
lung infection, one weight loss, one dyspnoea, and one fatigue) related to
treatment compared with two grade 3 events (chest pain) in the standard treatment
group.
INTERPRETATION: In patients with inoperable peripherally located stage 1 NSCLC,
compared with standard radiotherapy, SABR resulted in superior local control of
the primary disease without an increase in major toxicity. The findings of this
trial suggest that SABR should be the treatment of choice for this patient group.
FUNDING: The Radiation and Optometry Section of the Australian Government
Department of Health with the assistance of Cancer Australia, and the Cancer
Society of New Zealand and the Cancer Research Trust New Zealand (formerly
Genesis Oncology Trust).
Copyright © 2019 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(18)30896-9
PMID: 30770291
5. J Clin Invest. 2019 Apr 29;130:2279-2292. doi: 10.1172/JCI121323. eCollection
2019 Apr 29.
Oncolytic virotherapy for small-cell lung cancer induces immune infiltration and
prolongs survival.
Kellish P(1), Shabashvili D(1), Rahman MM(2), Nawab A(1), Guijarro MV(1), Zhang
M(3), Cao C(3), Moussatche N(2), Boyle T(4), Antonia S(4), Reinhard M(5),
Hartzell C(1), Jantz M(3), Mehta HJ(3), McFadden G(2), Kaye FJ(3), Zajac-Kaye
M(1).
Author information:
(1)Department of Anatomy and Cell Biology.
(2)Department of Molecular Genetics and Microbiology.
(3)Department of Medicine, University of Florida, Gainesville, Florida, USA.
(4)Moffitt Cancer Center, Tampa, Florida, USA.
(5)Department of Veterinary Pathology, University of Florida, Gainesville,
Florida, USA.
Oncolytic virotherapy has been proposed as an ablative and immunostimulatory
treatment strategy for solid tumors that are resistant to immunotherapy alone;
however, there is a need to optimize host immune activation using preclinical
immunocompetent models in previously untested common adult tumors. We studied a
modified oncolytic myxoma virus (MYXV) that shows high efficiency for
tumor-specific cytotoxicity in small-cell lung cancer (SCLC), a neuroendocrine
carcinoma with high mortality and modest response rates to immune checkpoint
inhibitors. Using an immunocompetent SCLC mouse model, we demonstrated the safety
of intrapulmonary MYXV delivery with efficient tumor-specific viral replication
and cytotoxicity associated with induction of immune cell infiltration. We
observed increased SCLC survival following intrapulmonary MYXV that was enhanced
by combined low-dose cisplatin. We also tested intratumoral MYXV delivery and
observed immune cell infiltration associated with tumor necrosis and growth
inhibition in syngeneic murine allograft tumors. Freshly collected primary human
SCLC tumor cells were permissive to MYXV and intratumoral delivery into
patient-derived xenografts resulted in extensive tumor necrosis. We confirmed
MYXV cytotoxicity in classic and variant SCLC subtypes as well as
cisplatin-resistant cells. Data from 26 SCLC human patients showed negligible
immune cell infiltration, supporting testing MYXV as an ablative and
immune-enhancing therapy.
DOI: 10.1172/JCI121323
PMID: 31033480
6. J Exp Med. 2019 Jun 3;216(6):1377-1395. doi: 10.1084/jem.20181394. Epub 2019 Apr
23.
Lamin B1 loss promotes lung cancer development and metastasis by epigenetic
derepression of RET.
Jia Y(1)(2), Vong JS(1), Asafova A(1), Garvalov BK(3)(4), Caputo L(1), Cordero
J(1)(2), Singh A(1)(2), Boettger T(1), Günther S(1), Fink L(5), Acker T(4),
Barreto G(1), Seeger W(1)(6), Braun T(1), Savai R(1)(6), Dobreva G(7)(2)(8).
Author information:
(1)Max Planck Institute for Heart and Lung Research, Member of the German Center
for Lung Research, Bad Nauheim, Germany.
(2)Anatomy and Developmental Biology, Centre for Biomedicine and Medical
Technology Mannheim (CBTM) and European Center for Angioscience (ECAS), Medical
Faculty Mannheim, Heidelberg University, Mannheim, Germany.
(3)Microvascular Biology and Pathobiology, European Center for Angioscience
(ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
…
Although abnormal nuclear structure is an important criterion for cancer
diagnostics, remarkably little is known about its relationship to tumor
development. Here we report that loss of lamin B1, a determinant of nuclear
architecture, plays a key role in lung cancer. We found that lamin B1 levels were
reduced in lung cancer patients. Lamin B1 silencing in lung epithelial cells
promoted epithelial-mesenchymal transition, cell migration, tumor growth, and
metastasis. Mechanistically, we show that lamin B1 recruits the polycomb
repressive complex 2 (PRC2) to alter the H3K27me3 landscape and repress genes
involved in cell migration and signaling. In particular, epigenetic derepression
of the RET proto-oncogene by loss of PRC2 recruitment, and activation of the
RET/p38 signaling axis, play a crucial role in mediating the malignant phenotype
upon lamin B1 disruption. Importantly, loss of a single lamin B1 allele induced
spontaneous lung tumor formation and RET activation. Thus, lamin B1 acts as a
tumor suppressor in lung cancer, linking aberrant nuclear structure and
epigenetic patterning with malignancy.
© 2019 Jia et al.
DOI: 10.1084/jem.20181394
PMID: 31015297
7. Nat Commun. 2019 Apr 18;10(1):1812. doi: 10.1038/s41467-019-09734-5.
AURKB as a target in non-small cell lung cancer with acquired resistance to
anti-EGFR therapy.
Bertran-Alamillo J(1), Cattan V(2), Schoumacher M(2), Codony-Servat J(1),
Giménez-Capitán A(1), Cantero F(2), Burbridge M(2), Rodríguez S(1), Teixidó
C(1)(3), Roman R(1), Castellví J(1), García-Román S(1), Codony-Servat C(1),
Viteri S(4), Cardona AF(5)(6), Karachaliou N(4), Rosell R(1)(4)(7)(8),
Molina-Vila MA(9).
Author information:
(1)Laboratory of Oncology, Pangaea Oncology, Quiron Dexeus University Hospital,
08028, Barcelona, Spain.
(2)Institut de Recherches Internationales Servier, 92284, Suresnes, France.
(3)Servicio Anatomía Patológica, Hospital Clínic de Barcelona, Barcelona, 08036,
Spain.
…
Non-small cell lung cancer (NSCLC) tumors harboring mutations in EGFR ultimately
relapse to therapy with EGFR tyrosine kinase inhibitors (EGFR TKIs). Here, we
show that resistant cells without the p.T790M or other acquired mutations are
sensitive to the Aurora B (AURKB) inhibitors barasertib and S49076.
Phospho-histone H3 (pH3), a major product of AURKB, is increased in most
resistant cells and treatment with AURKB inhibitors reduces the levels of pH3,
triggering G1/S arrest and polyploidy. Senescence is subsequently induced in
cells with acquired mutations while, in their absence, polyploidy is followed by
cell death. Finally, in NSCLC patients, pH3 levels are increased after
progression on EGFR TKIs and high pH3 baseline correlates with shorter survival.
Our results reveal that AURKB activation is associated with acquired resistance
to EGFR TKIs, and that AURKB constitutes a potential target in NSCLC progressing
to anti-EGFR therapy and not carrying resistance mutations.
DOI: 10.1038/s41467-019-09734-5
PMCID: PMC6472415
PMID: 31000705 [Indexed for MEDLINE]
8. Nat Commun. 2019 Apr 16;10(1):1772. doi: 10.1038/s41467-019-09762-1.
Comprehensive genomic and immunological characterization of Chinese non-small
cell lung cancer patients.
Zhang XC(1), Wang J(2), Shao GG(3), Wang Q(4), Qu X(5), Wang B(5), Moy C(6), Fan
Y(5), Albertyn Z(7), Huang X(5), Zhang J(5), Qiu Y(5), Platero S(6), Lorenzi
MV(6), Zudaire E(6), Yang J(5), Cheng Y(8), Xu L(9), Wu YL(10).
Author information:
(1)Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and
Guangdong Academy of Medical Sciences, 510080, Guangzhou, China.
(2)Peking University People's Hospital, Beijing, 100044, China.
(3)Thoracic Surgery, 1st Hospital of Jilin University, 130021, Changchun, China.
…
Deep understanding of the genomic and immunological differences between Chinese
and Western lung cancer patients is of great importance for target therapy
selection and development for Chinese patients. Here we report an extensive
molecular and immune profiling study of 245 Chinese patients with non-small cell
lung cancer. Tumor-infiltrating lymphocyte estimated using immune cell signatures
is found to be significantly higher in adenocarcinoma (ADC, 72.5%) compared with
squamous cell carcinoma (SQCC, 54.4%). The correlation of genomic alterations
with immune signatures reveals that low immune infiltration was associated with
EGFR mutations in ADC samples, PI3K and/or WNT pathway activation in SQCC. While
KRAS mutations are found to be significantly associated with T cell infiltration
in ADC samples. The SQCC patients with high antigen presentation machinery and
cytotoxic T cell signature scores are found to have a prolonged overall survival
time.
DOI: 10.1038/s41467-019-09762-1
PMCID: PMC6467893
PMID: 30992440 [Indexed for MEDLINE]
9. J Natl Cancer Inst. 2019 Apr 12. pii: djz041. doi: 10.1093/jnci/djz041. [Epub
ahead of print]
Identification of candidates for longer lung cancer screening intervals following
a negative low-dose computed tomography result.
Robbins HA(1), Berg CD(2), Cheung LC(2), Chaturvedi AK(2), Katki HA(2).
Author information:
(1)Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health,
Baltimore, Maryland. Current affiliation: International Agency for Research on
Cancer, Lyon, France.
(2)Division of Cancer Epidemiology and Genetics, National Cancer Institute,
Rockville, Maryland.
Lengthening the annual low-dose computed tomography (CT) screening interval for
individuals at lowest risk of lung cancer could reduce harms and improve
efficiency. We analyzed 23,328 participants in the National Lung Screening Trial
who had a negative CT screen (no ≥ 4mm nodules) to develop an individualized
model for lung-cancer risk after a negative CT. The Lung Cancer Risk Assessment
Tool + CT (LCRAT+CT) updates "pre-screening risk" (calculated using traditional
risk factors) with selected CT features. At the next annual screen following a
negative CT, risk of cancer detection was reduced among the 70% of participants
with neither CT-detected emphysema nor consolidation (median-risk=0.2%,
IQR=0.1%-0.3%). However, risk increased for the 30% with CT-emphysema
(median-risk=0.5%, IQR=0.3%-0.8%) and the 0.6% with consolidation (median=1.6%,
IQR=1.0%-2.5%). As one example, a threshold of next-screen risk below 0.3% would
lengthen the interval for 57.8% of screen-negatives, thus averting 49.8% of
next-screen false-positives among screen-negatives but delaying diagnosis for
23.9% of cancers. Our results support that many, but not all, screen-negatives
might reasonably lengthen their CT screening interval.
© World Health Organization, 2019. All rights reserved. The World Health
Organization has granted the Publisher permission for the reproduction of this
article.
DOI: 10.1093/jnci/djz041
PMID: 30976808
10. Nat Commun. 2019 Apr 10;10(1):1665. doi: 10.1038/s41467-019-09295-7.
Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1
inhibition.
Gao L(1)(2), Hu Y(1), Tian Y(1), Fan Z(1)(3), Wang K(4), Li H(1), Zhou Q(1), Zeng
G(1), Hu X(5), Yu L(6), Zhou S(7)(8)(9), Tong X(7)(8)(9)(10), Huang H(7)(8)(9),
Chen H(11), Liu Q(12), Liu W(1), Zhang G(1), Zeng M(13), Zhou G(14), He Q(15), Ji
H(16)(17)(18)(19), Chen L(20).
Author information:
(1)Key Laboratory of Functional Protein Research of Guangdong Higher Education,
Institute of Life and Health Engineering, College of Life Science and Technology,
Jinan University, 510632, Guangzhou, China.
(2)College of Life Sciences, Beijing Normal University, 100875, Beijing, China.
(3)College of Biological Sciences, China Agricultural University, 100094,
Beijing, China.
…
Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor
suppressor genes remain to be systemically identified for lung cancer. Through
the genome-wide screening of tumor-suppressive transcription factors, we
demonstrate here that GATA4 functions as an essential tumor suppressor in lung
cancer in vitro and in vivo. Ectopic GATA4 expression results in lung cancer cell
senescence. Mechanistically, GATA4 upregulates multiple miRNAs targeting TGFB2
mRNA and causes ensuing WNT7B downregulation and eventually triggers cell
senescence. Decreased GATA4 level in clinical specimens negatively correlates
with WNT7B or TGF-β2 level and is significantly associated with poor prognosis.
TGFBR1 inhibitors show synergy with existing therapeutics in treating
GATA4-deficient lung cancers in genetically engineered mouse model as well as
patient-derived xenograft (PDX) mouse models. Collectively, our work demonstrates
that GATA4 functions as a tumor suppressor in lung cancer and targeting the TGF-β
signaling provides a potential way for the treatment of GATA4-deficient lung
cancer.
DOI: 10.1038/s41467-019-09295-7
PMCID: PMC6458308
PMID: 30971692 [Indexed for MEDLINE]
11. J Clin Oncol. 2019 May 20;37(15):1316-1325. doi: 10.1200/JCO.18.00622. Epub 2019
Apr 3.
Safety and Efficacy of a Five-Fraction Stereotactic Body Radiotherapy Schedule
for Centrally Located Non-Small-Cell Lung Cancer: NRG Oncology/RTOG 0813 Trial.
Bezjak A(1), Paulus R(2), Gaspar LE(3), Timmerman RD(4), Straube WL(5), Ryan
WF(6), Garces YI(7), Pu AT(8), Singh AK(9), Videtic GM(10), McGarry RC(11),
Iyengar P(4), Pantarotto JR(12), Urbanic JJ(13), Sun AY(1), Daly ME(14), Grills
IS(15), Sperduto P(16), Normolle DP(17), Bradley JD(5), Choy H(4).
Author information:
(1)1 Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
(2)2 NRG Oncology, Philadelphia, PA.
(3)3 University of Colorado Denver, Aurora, CO.
…
PURPOSE: Patients with centrally located early-stage non-small-cell lung cancer
(NSCLC) are at a higher risk of toxicity from high-dose ablative radiotherapy.
NRG Oncology/RTOG 0813 was a phase I/II study designed to determine the maximum
tolerated dose (MTD), efficacy, and toxicity of stereotactic body radiotherapy
(SBRT) for centrally located NSCLC.
MATERIALS AND METHODS: Medically inoperable patients with biopsy-proven, positron
emission tomography-staged T1 to 2 (≤ 5 cm) N0M0 centrally located NSCLC were
accrued into a dose-escalating, five-fraction SBRT schedule that ranged from 10
to 12 Gy/fraction (fx) delivered over 1.5 to 2 weeks. Dose-limiting toxicity
(DLT) was defined as any treatment-related grade 3 or worse predefined toxicity
that occurred within the first year. MTD was defined as the SBRT dose at which
the probability of DLT was closest to 20% without exceeding it.
RESULTS: One hundred twenty patients were accrued between February 2009 and
September 2013. Patients were elderly, there were slightly more females, and the
majority had a performance status of 0 to 1. Most cancers were T1 (65%) and
squamous cell (45%). Organs closest to planning target volume/most at risk were
the main bronchus and large vessels. Median follow-up was 37.9 months. Five
patients experienced DLTs; MTD was 12.0 Gy/fx, which had a probability of a DLT
of 7.2% (95% CI, 2.8% to 14.5%). Two-year rates for the 71 evaluable patients in
the 11.5 and 12.0 Gy/fx cohorts were local control, 89.4% (90% CI, 81.6% to
97.4%) and 87.9% (90% CI, 78.8% to 97.0%); overall survival, 67.9% (95% CI, 50.4%
to 80.3%) and 72.7% (95% CI, 54.1% to 84.8%); and progression-free survival,
52.2% (95% CI, 35.3% to 66.6%) and 54.5% (95% CI, 36.3% to 69.6%), respectively.
CONCLUSION: The MTD for this study was 12.0 Gy/fx; it was associated with 7.2%
DLTs and high rates of tumor control. Outcomes in this medically inoperable group
of mostly elderly patients with comorbidities were comparable with that of
patients with peripheral early-stage tumors.
DOI: 10.1200/JCO.18.00622
PMID: 30943123
12. Nano Lett. 2019 Apr 10;19(4):2231-2242. doi: 10.1021/acs.nanolett.8b04309. Epub
2019 Mar 21.
Optimized Bexarotene Aerosol Formulation Inhibits Major Subtypes of Lung Cancer
in Mice.
Zhang Q, Lee SB, Chen X, Stevenson ME(1), Pan J, Xiong D, Zhou Y, Miller MS(2),
Lubet RA(2), Wang Y, Mirza SP(3), You M.
Author information:
(1)Department of Psychology , University of Wisconsin , Milwaukee , Wisconsin
53211 , United States.
(2)Division of Cancer Prevention , National Cancer Institute , Rockville ,
Maryland 20850 , United States.
(3)Department of Chemistry and Biochemistry , University of Wisconsin , Milwaukee
, Wisconsin 53211 , United States.
Bexarotene has shown inhibition of lung and mammary gland tumorigenesis in
preclinical models and in clinical trials. The main side effects of orally
administered bexarotene are hypertriglyceridemia and hypercholesterolemia. We
previously demonstrated that aerosolized bexarotene administered by nasal
inhalation has potent chemopreventive activity in a lung adenoma preclinical
model without causing hypertriglyceridemia. To facilitate its future clinical
translation, we modified the formula of the aerosolized bexarotene with a
clinically relevant solvent system. This optimized aerosolized bexarotene
formulation was tested against lung squamous cell carcinoma mouse model and lung
adenocarcinoma mouse model and showed significant chemopreventive effect. This
new formula did not cause visible signs of toxicity and did not increase plasma
triglycerides or cholesterol. This aerosolized bexarotene was evenly distributed
to the mouse lung parenchyma, and it modulated the microenvironment in vivo by
increasing the tumor-infiltrating T cell population. RNA sequencing of the lung
cancer cell lines demonstrated that multiple pathways are altered by bexarotene.
For the first time, these studies demonstrate a new, clinically relevant
aerosolized bexarotene formulation that exhibits preventive efficacy against the
major subtypes of lung cancer. This approach could be a major advancement in lung
cancer prevention for high risk populations, including former and present
smokers.
DOI: 10.1021/acs.nanolett.8b04309
PMID: 30873838
13. J Exp Med. 2019 Apr 1;216(4):982-1000. doi: 10.1084/jem.20180870. Epub 2019 Mar
14.
Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small
cell lung cancer.
Gong B(1)(2), Kiyotani K(3), Sakata S(4), Nagano S(5)(6), Kumehara S(5)(6), Baba
S(4), Besse B(7)(8), Yanagitani N(9), Friboulet L(7), Nishio M(9), Takeuchi
K(4)(10), Kawamoto H(5), Fujita N(1)(2), Katayama R(11).
Author information:
(1)Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo,
Japan.
(2)Department of Computational Biology and Medical Sciences, Graduate School of
Frontier Sciences, The University of Tokyo, Chiba, Japan.
(3)Immunopharmacogenomics Group, Cancer Precision Medicine Center, Japanese
Foundation for Cancer Research, Tokyo, Japan.
…
Immune checkpoint blockade against programmed cell death 1 (PD-1) and its ligand
PD-L1 often induces durable tumor responses in various cancers, including
non-small cell lung cancer (NSCLC). However, therapeutic resistance is
increasingly observed, and the mechanisms underlying anti-PD-L1 (aPD-L1) antibody
treatment have not been clarified yet. Here, we identified two unique secreted
PD-L1 splicing variants, which lacked the transmembrane domain, from
aPD-L1-resistant NSCLC patients. These secreted PD-L1 variants worked as "decoys"
of aPD-L1 antibody in the HLA-matched coculture system of iPSC-derived CD8 T
cells and cancer cells. Importantly, mixing only 1% MC38 cells with secreted
PD-L1 variants and 99% of cells that expressed wild-type PD-L1 induced resistance
to PD-L1 blockade in the MC38 syngeneic xenograft model. Moreover, anti-PD-1
(aPD-1) antibody treatment overcame the resistance mediated by the secreted PD-L1
variants. Collectively, our results elucidated a novel resistant mechanism of
PD-L1 blockade antibody mediated by secreted PD-L1 variants.
© 2019 Gong et al.
DOI: 10.1084/jem.20180870
PMCID: PMC6446862
PMID: 30872362
14. J Clin Oncol. 2019 Apr 20;37(12):992-1000. doi: 10.1200/JCO.18.01042. Epub 2019
Feb 20.
First-Line Nivolumab Plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer
(CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational
Burden as Biomarkers.
Ready N(1), Hellmann MD(2), Awad MM(3), Otterson GA(4), Gutierrez M(5), Gainor
JF(6), Borghaei H(7), Jolivet J(8), Horn L(9), Mates M(10), Brahmer J(11),
Rabinowitz I(12), Reddy PS(13), Chesney J(14), Orcutt J(15), Spigel DR(16), Reck
M(17), O'Byrne KJ(18), Paz-Ares L(19), Hu W(20), Zerba K(20), Li X(20), Lestini
B(20), Geese WJ(20), Szustakowski JD(20), Green G(20), Chang H(20), Ramalingam
SS(21).
Author information:
(1)1 Duke University Medical Center, Durham, NC.
(2)2 Memorial Sloan Kettering Cancer Center, New York, NY.
(3)3 Dana-Farber Cancer Institute, Boston, MA.
…
PURPOSE: CheckMate 568 is an open-label phase II trial that evaluated the
efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment
of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the
association of efficacy with programmed death ligand 1 (PD-L1) expression and
tumor mutational burden (TMB).
PATIENTS AND METHODS: Two hundred eighty-eight patients with previously
untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks
plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective
response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1
expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a
secondary end point.
RESULTS: Of treated patients with tumor available for testing, 252 patients (88%)
of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB.
ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than
1% tumor PD-L1 expression, respectively. ORR increased with higher TMB,
plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1
expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48:
PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50:
PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in
patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb
(median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events
occurred in 29% of patients.
CONCLUSION: Nivolumab plus low-dose ipilimumab was effective and tolerable as a
first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was
associated with improved response and prolonged progression-free survival in both
tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus
identified as a potentially relevant cutoff in the assessment of TMB as a
biomarker for first-line nivolumab plus ipilimumab.
DOI: 10.1200/JCO.18.01042
PMCID: PMC6494267 [Available on 2020-04-20]
PMID: 30785829
15. J Natl Cancer Inst. 2019 Apr 1;111(4):342-349. doi: 10.1093/jnci/djy228.
Evaluating Lung Cancer Screening Uptake, Outcomes, and Costs in the United
States: Challenges With Existing Data and Recommendations for Improvement.
Rai A(1), Doria-Rose VP(2), Silvestri GA(3), Yabroff KR(1).
Author information:
(1)Surveillance and Health Services Research Program, Department of Intramural
Research, American Cancer Society, Atlanta, GA (AR, KRY).
(2)Division of Cancer Control and Population Sciences, NCI, Bethesda, MD (VPDR).
(3)Thoracic Oncology Research Group, Division of Pulmonary, Critical Care,
Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC
(GAS).
The National Lung Screening Trial (NLST) reported substantial reduction in lung
cancer mortality among high-risk individuals screened annually with low-dose
helical computed tomography (LDCT). As a result, the US Preventive Services Task
Force issued a B recommendation for annual LDCT in high-risk individuals, which
requires private insurers to cover it without cost-sharing. The Medicare program
also covers LDCT for high-risk beneficiaries without cost-sharing. However, the
NLST findings may not be generalizable to the community setting because of
differences in patients, providers, and practices participating in the NLST.
Thus, examining uptake of LDCT screening in community practice is critical, as is
evaluating the immediate and downstream outcomes of screening, including
false-positive scans, follow-up examinations and adverse events, costs, stage of
disease at diagnosis, and survival. This commentary presents an overview of the
landscape of the data resources currently available to evaluate the uptake,
outcomes, and costs of LDCT screening in the United States. We describe the
strengths and limitations of existing data sources, including administrative
databases, surveys, and registries. Thereafter, we provide recommendations for
improving the data infrastructure pertaining to three overarching research areas:
receipt of guideline-consistent screening and follow-up, weighing benefits and
harms of screening, and costs of screening.
Published by Oxford University Press 2019.
DOI: 10.1093/jnci/djy228
PMID: 30698792
16. J Clin Oncol. 2019 Apr 10;37(11):876-884. doi: 10.1200/JCO.18.00177. Epub 2019
Jan 24.
Clonal MET Amplification as a Determinant of Tyrosine Kinase Inhibitor Resistance
in Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer.
Lai GGY(1), Lim TH(2), Lim J(1), Liew PJR(2), Kwang XL(1), Nahar R(3), Aung
ZW(1), Takano A(2), Lee YY(3), Lau DPX(1), Tan GS(2), Tan SH(1), Tan WL(1), Ang
MK(1), Toh CK(1), Tan BS(2), Devanand A(2), Too CW(2), Gogna A(2), Ong BH(4), Koh
TPT(1), Kanesvaran R(1), Ng QS(1), Jain A(1), Rajasekaran T(1), Yuan J(3), Lim
TKH(2), Lim AST(2), Hillmer AM(3), Lim WT(1), Iyer NG(1), Tam WL(3), Zhai W(3),
Tan EH(1), Tan DSW(1)(3).
Author information:
(1)1 National Cancer Centre Singapore, Singapore.
(2)2 Singapore General Hospital, Singapore.
(3)3 Genome Institute of Singapore, Singapore.
(4)4 National Heart Centre Singapore, Singapore.
PURPOSE: Mesenchymal epithelial transition factor ( MET) activation has been
implicated as an oncogenic driver in epidermal growth factor receptor (
EGFR)-mutant non-small-cell lung cancer (NSCLC) and can mediate primary and
secondary resistance to EGFR tyrosine kinase inhibitors (TKI). High copy number
thresholds have been suggested to enrich for response to MET inhibitors. We
examined the clinical relevance of MET copy number gain (CNG) in the setting of
treatment-naive metastatic EGFR-mutant-positive NSCLC.
PATIENTS AND METHODS: MET fluorescence in situ hybridization was performed in 200
consecutive patients identified as metastatic treatment-naïve
EGFR-mutant-positive. We defined MET-high as CNG greater than or equal to 5, with
an additional criterion of MET/centromeric portion of chromosome 7 ratiο greater
than or equal to 2 for amplification. Time-to-treatment failure (TTF) to EGFR TKI
in patients identified as MET-high and -low was estimated by Kaplan-Meier method
and compared using log-rank test. Multiregion single-nucleotide polymorphism
array analysis was performed on 13 early-stage resected EGFR-mutant-positive
NSCLC across 59 sectors to investigate intratumoral heterogeneity of MET CNG.
RESULTS: Fifty-two (26%) of 200 patients in the metastatic cohort were MET-high
at diagnosis; 46 (23%) had polysomy and six (3%) had amplification. Median TTF
was 12.2 months (95% CI, 5.7 to 22.6 months) versus 13.1 months (95% CI, 10.6 to
15.0 months) for MET-high and -low, respectively ( P = .566), with no significant
difference in response rate regardless of copy number thresholds. Loss of MET was
observed in three of six patients identified as MET-high who underwent
postprogression biopsies, which is consistent with marked intratumoral
heterogeneity in MET CNG observed in early-stage tumors. Suboptimal response
(TTF, 1.0 to 6.4 months) to EGFR TKI was observed in patients with coexisting MET
amplification (five [3.2%] of 154).
CONCLUSION: Although up to 26% of TKI-naïve EGFR-mutant-positive NSCLC harbor
high MET CNG by fluorescence in situ hybridization, this did not significantly
affect response to TKI, except in patients identified as MET-amplified. Our data
underscore the limitations of adopting arbitrary copy number thresholds and the
need for cross-assay validation to define therapeutically tractable MET pathway
dysregulation in EGFR-mutant-positive NSCLC.
DOI: 10.1200/JCO.18.00177
PMID: 30676858
