Medical Abstracts

Keyword: lung cancer

1. Cell. 2019 Jan 25.pii: S0092-8674(18)31654-4. doi: 10.1016/j.cell.2018.12.040.

[Epub ahead of print]

Commensal Microbiota Promote Lung Cancer Development via γδ T Cells.

Jin C(1), Lagoudas GK(2), Zhao C(3), Bullman S(4), Bhutkar A(1), Hu B(5),Ameh

S(1), Sandel D(1), Liang XS(1), Mazzilli S(6), Whary MT(7), Meyerson M(4),

GermainR(3), Blainey PC(8), Fox JG(9), Jacks T(10).

Author information:

(1)David H. Koch Institute for Integrative Cancer Research, Massachusetts

Institute of Technology, Cambridge, MA 02142, USA.

(2)Department of Biological Engineering, Massachusetts Institute of Technology,

Cambridge, MA 02139, USA.

(3)Lymphocyte Biology Section, Laboratory of Immune System Biology, National

Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.

。。。

Lung cancer is closely associated with chronic inflammation, but the causes of

inflammation and the specific immune mediators have not been fully elucidated.

The lung is a mucosal tissue colonized by a diverse bacterial community, and

pulmonary infections commonly present in lung cancer patients are linked to

clinical outcomes. Here, we provide evidence that local microbiota provoke

inflammation associated with lung adenocarcinoma by activating lung-resident γδ

T cells. Germ-free or antibiotic-treated mice were significantly protected from

lung cancer development induced by Kras mutation and p53 loss. Mechanistically,

commensal bacteria stimulated Myd88-dependent IL-1β and IL-23 production from

myeloid cells, inducing proliferation and activation of Vγ6+Vδ1+ γδ T cells that

produced IL-17 and other effector molecules to promote inflammation and tumor

cell proliferation. Our findings clearly link local microbiota-immune crosstalk

to lung tumor development and thereby define key cellular and molecular mediators

that may serve as effective targets in lung cancer intervention.

Copyright © 2018 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cell.2018.12.040

PMID: 30712876

2. Nat Med. 2019 Jan 21. doi: 10.1038/s41591-018-0323-0. [Epub ahead of print]

Deciphering the genomic, epigenomic, and transcriptomic landscapes of

pre-invasive lung cancer lesions.

Teixeira VH(1), Pipinikas CP(1)(2), Pennycuick A(1), Lee-Six H(3),

Chandrasekharan D(1), Beane J(4), Morris TJ(2), Karpathakis A(2), Feber A(2),

Breeze CE(2), Ntolios P(1), Hynds RE(1)(5)(6), Falzon M(7), Capitanio A(7),

Carroll B(8), Durrenberger PF(9), Hardavella G(8), Brown JM(1), Lynch AG(10)(11),

FarmeryH(10), Paul DS(2), Chambers RC(9), McGranahan N(5), Navani N(1)(8),

ThakrarRM(1)(8), Swanton C(5)(6), Beck S(2), George PJ(8), Spira A(4)(12),

Campbell PJ(3), Thirlwell C(2), Janes SM(13)(14).

Author information:

(1)Lungs for Living Research Centre, UCL Respiratory, University College London,

London, UK.

(2)Research Department of Cancer Biology and Medical Genomics Laboratory, UCL

Cancer Institute, University College London, London, UK.

(3)The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.

(4)Department of Medicine, Boston University School of Medicine, Boston, MA, USA.

(5)CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, London, UK.

…

The molecular alterations that occur in cells before cancer is manifest are

largely uncharted. Lung carcinoma in situ (CIS) lesions are the pre-invasive

precursor to squamous cell carcinoma. Although microscopically identical, their

future is in equipoise, with half progressing to invasive cancer and half

regressing or remaining static. The cellular basis of this clinical observation

is unknown. Here, we profile the genomic, transcriptomic, and epigenomic

landscape of CIS in a unique patient cohort with longitudinally monitored

pre-invasive disease. Predictive modeling identifies which lesions will progress

with remarkable accuracy. We identify progression-specific methylation changes on

a background of widespread heterogeneity, alongside a strong chromosomal

instability signature. We observed mutations and copy number changes

characteristic of cancer and chart their emergence, offering a window into early

carcinogenesis. We anticipate that this new understanding of cancer precursor

biology will improve early detection, reduce overtreatment, and foster

preventative therapies targeting early clonal events in lung cancer.

DOI: 10.1038/s41591-018-0323-0

PMID: 30664780

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),

HaringsmaHJ(6), Robillard L(6), Simmons AD(6), Harding TC(6), McCormick F(2),

GogaA(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. J Natl Cancer Inst. 2019 Jan 28. doi: 10.1093/jnci/djy206. [Epub ahead of print]

Racial/Ethnic Differences in Lung Cancer Incidence in the Multiethnic Cohort

Study: An Update.

Stram DO, Park SL, Haiman CA, Murphy SE, Patel Y, Hecht SS, Le Marchand L.

Background: We previously found that African Americans and Native Hawaiians were

at highest lung cancer risk compared with Japanese Americans and Latinos; whites

were midway in risk. These differences were more evident at relatively low levels

of smoking intensity, fewer than 20 cigarettes per day (CPD), than at higher

intensity.

Methods: We apportioned lung cancer risk into three parts: age-specific

background risk (among never smokers), an excess relative risk term for

cumulative smoking, and modifiers of the smoking effect: race and years-quit

smoking. We also explored the effect of replacing self-reports of CPD with a

urinary biomarker-total nicotine equivalents-using data from a urinary biomarker

substudy.

Results: Total lung cancers increased from 1979 to 4993 compared to earlier

analysis. Estimated excess relative risks for lung cancer due to smoking for

50 years at 10 CPD (25 pack-years) ranged from 21.9 (95% CI = 18.0 to 25.8) for

Native Hawaiians to 8.0 (95% CI = 6.6 to 9.4) for Latinos over the five groups.

The risk from smoking was higher for squamous cell carcinomas and small cell

cancers than for adenocarcinomas. Racial differences consistent with earlier

patterns were seen for overall cancer and for cancer subtypes. Adjusting for

predicted total nicotine equivalents, Japanese Americans no longer exhibit a

lower risk, and African Americans are no longer at higher risk, compared to

whites. Striking risk differences between Native Hawaiians and Latinos persist.

Conclusions: Racial differences in lung cancer risk persist in the Multiethnic

Cohort study that are not easily explained by variations in self-reported or

urinary biomarker-measured smoking intensities.

DOI: 10.1093/jnci/djy206

PMID: 30698722

5. J Clin Invest. 2019 Jan 28.pii: 122779. doi: 10.1172/JCI122779. [Epub ahead of

print]

Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing

integrin β1.

Zhao G(1), Gong L(1), Su D(2), Jin Y(1), Guo C(1), Yue M(1), Yao S(1), Qin Z(1),

Ye Y(1)(3), Tang Y(1), Wu Q(1), Zhang J(1), Cui B(1), Ding Q(4), Huang H(1), Hu

L(1), Chen Y(1)(3), Zhang P(5), Hu G(5), Chen L(1)(3), Wong KK(6), Gao D(1), Ji

H(1)(3).

Author information:

(1)State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling

Network, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute

of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of

Chinese Academy of Sciences, Shanghai, China.

(2)Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.

(3)School of Life Science and Technology, Shanghai Tech University, Shanghai,

China.

…

Metastasis is the dominant cause of patient death in small-cell lung cancer

(SCLC), and a better understanding of the molecular mechanisms underlying SCLC

metastasis may potentially improve clinical treatment. Through genome-scale

screening for key regulators of mouse Rb1-/- Trp53-/- SCLC metastasis using the

pooled CRISPR/Cas9 library, we identified Cullin5 (CUL5) and suppressor of

cytokine signaling 3 (SOCS3), two components of the Cullin-RING E3 ubiquitin

ligase complex, as top candidates. Mechanistically, the deficiency of CUL5 or

SOCS3 disrupted the functional formation of the E3 ligase complex and prevented

the degradation of integrin β1, which stabilized integrin β1 and activated

downstream focal adhesion kinase/SRC (FAK/SRC) signaling and eventually drove

SCLC metastasis. Low expression levels of CUL5 and SOCS3 were significantly

associated with high integrin β1 levels and poor prognosis in a large cohort of

128 clinical patients with SCLC. Moreover, the CUL5-deficient SCLCs were

vulnerable to the treatment of the FDA-approved SRC inhibitor dasatinib.

Collectively, this work identifies the essential role of CUL5- and SOCS3-mediated

integrin β1 turnover in controlling SCLC metastasis, which might have therapeutic

implications.

DOI: 10.1172/JCI122779

PMID: 30688657

6. J Clin Oncol. 2019 Jan 24:JCO1800177. doi: 10.1200/JCO.18.00177. [Epub ahead of

print]

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

7. J Exp Med. 2019 Feb 4;216(2):450-465. doi: 10.1084/jem.20180742. Epub 2019 Jan

14.

LUBAC determines chemotherapy resistance in squamous cell lung cancer.

Ruiz EJ(1), Diefenbacher ME(1), Nelson JK(1), Sancho R(1), Pucci F(1),

ChakrabortyA(1), Moreno P(2)(3), Annibaldi A(4), Liccardi G(4), Encheva V(5),

MitterR(6), Rosenfeldt M(7), Snijders AP(5), Meier P(4), Calzado MA(2)(8),

Behrens A(9)(10).

Author information:

(1)Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK.

(2)InstitutoMaimónides de InvestigaciónBiomédica de Córdoba, Córdoba, Spain.

(3)Unidad de CirugíaTorácica y TrasplantePulmonar, Hospital Universitario Reina

Sofía, Córdoba, Spain.

(4)Breast Cancer Now, Toby Robins Research Centre, Institute of Cancer Research,

London, UK.

…

Lung squamous cell carcinoma (LSCC) and adenocarcinoma (LADC) are the most common

lung cancer subtypes. Molecular targeted treatments have improved LADC patient

survival but are largely ineffective in LSCC. The tumor suppressor FBW7 is

commonly mutated or down-regulated in human LSCC, and oncogenic KRasG12D

activation combined with Fbxw7 inactivation in mice (KF model) caused both LSCC

and LADC. Lineage-tracing experiments showed that CC10+, but not basal, cells are

the cells of origin of LSCC in KF mice. KF LSCC tumors recapitulated human LSCC

resistance to cisplatin-based chemotherapy, and we identified LUBAC-mediated

NF-κB signaling as a determinant of chemotherapy resistance in human and mouse.

Inhibition of NF-κB activation using TAK1 or LUBAC inhibitors resensitized LSCC

tumors to cisplatin, suggesting a future avenue for LSCC patient treatment.

© 2019 Ruiz et al.

DOI: 10.1084/jem.20180742

PMCID: PMC6363428

PMID: 30642944

8. SciTransl Med. 2019 Jan 9;11(474). pii: eaat5690. doi:

10.1126/scitranslmed.aat5690.

Autologous tumor cell-derived microparticle-based targeted chemotherapy in lung

cancer patients with malignant pleural effusion.

Guo M(1), Wu F(1), Hu G(1), Chen L(1), Xu J(1), Xu P(2), Wang X(1), Li Y(1), Liu

S(1), Zhang S(1), Huang Q(1), Fan J(1), Lv Z(1), Zhou M(1), Duan L(1), Liao T(1),

Yang G(3), Tang K(2), Liu B(4), Liao X(5), Tao X(1), Jin Y(6).

Author information:

(1)Key Laboratory of Pulmonary Diseases of Health Ministry, Department of

Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College,

Huazhong University of Science and Technology, Wuhan 430022, China.

(2)Department of Biochemistry and Molecular Biology, Tongji Medical College,

Huazhong University of Science and Technology, Wuhan 430030, China.

(3)Department of Thoracic Surgery, Union Hospital, Tongji Medical College,

Huazhong University of Science and Technology, Wuhan 430022, China.

…

Cell membrane-derived microparticles (MPs), the critical mediators of

intercellular communication, have gained much interest for use as natural drug

delivery systems. Here, we examined the therapeutic potential of tumor

cell-derived MPs (TMPs) in the context of malignant pleural effusion (MPE). TMPs

packaging the chemotherapeutic drug methotrexate (TMPs-MTX) markedly restricted

MPE growth and provided a survival benefit in MPE models induced by murine Lewis

lung carcinoma and colon adenocarcinoma cells. On the basis of the potential

benefit and minimal toxicity of TMPs-MTX, we conducted a human study of

intrapleural delivery of a single dose of autologous TMPs packaging methotrexate

(ATMPs-MTX) to assess their safety, immunogenicity, and clinical activity. We

report our findings on 11 advanced lung cancer patients with MPE. We found that

manufacturing and infusing ATMPs-MTX were feasible and safe, without evidence of

toxic effects of grade 3 or higher. Evaluation of the tumor microenvironment in

MPE demonstrated notable reductions in tumor cells and CD163+ macrophages in MPE

after ATMP-MTX infusion, which then translated into objective clinical responses.

Moreover, ATMP-MTX treatment stimulated CD4+ T cells to release IL-2 and CD8+

cells to release IFN-γ. Our initial experience with ATMPs-MTX in advanced lung

cancer with MPE suggests that ATMPs targeting malignant cells and the

immunosuppressive microenvironment may be a promising therapeutic platform for

treating malignancies.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American

Association for the Advancement of Science. No claim to original U.S. Government

Works.

DOI: 10.1126/scitranslmed.aat5690

PMID: 30626714

9. J Clin Oncol. 2019 Jan 20;37(3):222-229. doi: 10.1200/JCO.18.00264. Epub 2018 Dec 5.

Randomized Phase II Trial of Cisplatin and Etoposide in Combination With

Veliparib or Placebo for Extensive-Stage Small-Cell Lung Cancer: ECOG-ACRIN 2511

Study.

OwonikokoTK(1), Dahlberg SE(2), Sica GL(1), Wagner LI(3), Wade JL 3rd(4),

SrkalovicG(5), Lash BW(6), Leach JW(7), Leal TB(8), Aggarwal C(9), Ramalingam

SS(1).

Author information:

(1)1 Emory University, Atlanta, GA.

(2)2 Dana-Farber Cancer Institute, Boston, MA.

(3)3 Northwestern University, Chicago, IL.

(4)4 Decatur Memorial Hospital, Decatur, IL.

…

PURPOSE: Veliparib, a poly (ADP ribose) polymerase inhibitor, potentiated

standard chemotherapy against small-cell lung cancer (SCLC) in preclinical

studies. We evaluated the combination of veliparib with cisplatin and etoposide

(CE; CE+V) doublet in untreated, extensive-stage SCLC (ES-SCLC).

MATERIALS AND METHODS: Patients with ES-SCLC, stratified by sex and serum lactate

dehydrogenase levels, were randomly assigned to receive four 3-week cycles of CE

(75 mg/m2 intravenously on day 1 and 100 mg/m2 on days 1 through 3) along with

veliparib (100 mg orally twice per day on days 1 through 7) or placebo (CE+P).

The primary end point was progression-free survival (PFS). Using an overall

one-sided 0.10-level log-rank test, the study had 88% power to demonstrate a

37.5% reduction in the PFS hazard rate.

RESULTS: A total of 128 eligible patients received treatment on protocol. The

median age was 66 years, 52% of patients were men, and Eastern Cooperative

Oncology Group performance status was 0 for 29% of patients and 1 for 71%. The

respective median PFS for the CE+V arm versus the CE+P arm was 6.1 versus 5.5

months (unstratified hazard ratio [HR], 0.75 [one-sided P = .06]; stratified HR,

0.63 [one-sided P = .01]), favoring CE+V. The median overall survival was 10.3

versus 8.9 months (stratified HR, 0.83; 80% CI, 0.64 to 1.07; one-sided P = .17)

for the CE+V and CE+P arms, respectively. The overall response rate was 71.9%

versus 65.6% (two-sided P = .57) for CE+V and CE+P, respectively. There was a

significant treatment-by-strata interaction in PFS: Male patients with high

lactate dehydrogenase levels derived significant benefit (PFS HR, 0.34; 80% CI,

0.22 to 0.51) but there was no evidence of benefit among patients in other strata

(PFS HR, 0.81; 80% CI, 0.60 to 1.09). The following grade ≥ 3 hematology

toxicities were more frequent in the CE+V arm than the CE+P arm: CD4 lymphopenia

(8% v 0%; P = .06) and neutropenia (49% v 32%; P = .08), but treatment delivery

was comparable.

CONCLUSION: The addition of veliparib to frontline chemotherapy showed signal of

efficacy in patients with ES-SCLC and the study met its prespecified end point.

DOI: 10.1200/JCO.18.00264

PMCID: PMC6338394 [Available on 2020-01-20]

PMID: 30523756

10. 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.

…

PURPOSE: Given the pivotal role of epidermal growth factor receptor (EGFR)

inhibitors in advanced EGFR-mutant non-small-cell lung cancer (NSCLC), we tested

adjuvanterlotinib 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

11. Eur J Cancer. 2019 Feb;108:88-96. doi: 10.1016/j.ejca.2018.12.017. Epub 2019 Jan 14.

Circulating innate immune markers and outcomes in treatment-naïve advanced

non-small cell lung cancer patients.

Charrier M(1), Mezquita L(2), Lueza B(3), Dupraz L(4), Planchard D(5), Remon

J(5), Caramella C(6), Cassard L(4), Boselli L(4), Reiners KS(7), Pogge von

StrandmannE(8), Rusakiewicz S(9), Ferrara R(4), Duchemann B(1), Naigeon M(1),

PignonJP(3), Besse B(10), Chaput N(11).

Author information:

(1)GustaveRoussy Cancer Campus, F-94805, Villejuif, France; Laboratory of

Immunomonitoring in Oncology, UMS 3655 CNRS/US 23 INSERM, GustaveRoussy Cancer

Campus, F-94805, Villejuif, France; University Paris-Saclay, Faculty of Medicine,

F-94270, Le Kremlin-Bicêtre, France.

(2)GustaveRoussy Cancer Campus, F-94805, Villejuif, France; Laboratory of

Immunomonitoring in Oncology, UMS 3655 CNRS/US 23 INSERM, GustaveRoussy Cancer

Campus, F-94805, Villejuif, France; Department of Cancer Medicine, GustaveRoussy

Cancer Campus, F-94805, Villejuif, France.

(3)Biostatistics and Epidemiology Department, University Paris Saclay, Gustave

Roussy Cancer Campus, F-94805, Villejuif, France; Oncostat CESP, INSERM,

University Paris-Saclay, France; UVSQ, University Paris-Sud, F-94085, Villejuif,

France.

…

INTRODUCTION: Innate immunity represents the first step of activation of the

immune system and dictates the quality of adaptive immune responses. Studies have

reported links between systemic inflammatory or innate immune markers and

prognosis in patients with lung cancer. To our knowledge, the prospective and

concomitant study of these systemic markers has never been performed.

METHODS: Advanced treatment-naive non-small cell lung cancer (NSCLC) patients

eligible for first-line platinum-based chemotherapy were prospectively included

from December 2012 to July 2015 (N = 148). Blood samples of patients were

collected before the first cycle for fresh NK cell phenotyping. Peripheral blood

mononuclear cells were cryopreserved for natural cytotoxicity receptor (NCR)

genotyping as well as sera for NCR's ligand quantification. Data on leukocytes,

neutrophils and monocyte counts and lactate dehydrogenase (LDH) levels were

extracted from electronic medical records.

RESULTS: Among all studied markers, monocytosis, neutrophilia, leucocytosis, high

LDH and sBAG6 levels and reduced levels of NCR3 transcripts were associated with

poor overall survival (OS) in univariate analysis. The levels of NCR3 transcripts

was linked to age, number of metastatic sites, monocyte counts, LDH and sBAG6

levels. Neutrophilia was associated to high sBAG6 levels. NCR3 was the unique

innate immune parameter that remained as an independent factor associated with

both OS (P = 0.003) and progression-free survival (P = 0.009) in the multivariate

analysis.

CONCLUSION: This study brought evidence that these biomarkers are entangled;

parameters associated with an inflammatory process were related to reduced levels

of NCR3 transcripts. Finally, the level of NCR3 transcripts was independently

associated with outcomes in treatment-naive patients with advanced NSCLC.

Copyright © 2018 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.ejca.2018.12.017

PMID: 30648633

12. Clin Cancer Res. 2019 Jan 14. doi: 10.1158/1078-0432.CCR-18-2243. [Epub ahead of print]

Induction of Peripheral Effector CD8 T-cell Proliferation by Combination of

Paclitaxel, Carboplatin, and Bevacizumab in Non-small Cell Lung Cancer Patients.

deGoeje PL(1)(2), Poncin M(1)(2), Bezemer K(1)(2), Kaijen-Lambers MEH(1)(2),

GroenHJM(3), Smit EF(4), Dingemans AC(5), Kunert A(1)(2)(6), Hendriks RW(1),

AertsJGJV(7)(2).

Author information:

(1)Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.

(2)Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

(3)Groningen University Medical Center, Department of Respiratory Disease,

Groningen, the Netherlands.

…

Purpose: Chemotherapy has long been the standard treatment for advanced stage

non-small cell lung cancer (NSCLC), but checkpoint inhibitors are now approved

for use in several patient groups and combinations. To design optimal combination

strategies, a better understanding of the immune-modulatory capacities of

conventional treatments is needed. Therefore, we investigated the

immune-modulatory effects of paclitaxel/carboplatin/bevacizumab (PCB), focusing

on the immune populations associated with the response to checkpoint inhibitors

in peripheral blood.Experimental Design: A total of 223 patients with stage IV

NSCLC, enrolled in the NVALT12 study, received PCB, with or without nitroglycerin

patch. Peripheral blood was collected at baseline and after the first and second

treatment cycle, proportions of T cells, B cells, and monocytes were determined

by flow cytometry. Furthermore, several subsets of T cells and the expression of

Ki67 and coinhibitory receptors on these subsets were determined.Results:

Although proliferation of CD4 T cells remained stable following treatment,

proliferation of peripheral blood CD8 T cells was significantly increased,

particularly in the effector memory and CD45RA+ effector subsets. The

proliferating CD8 T cells more highly expressed programmed death receptor (PD)-1

and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) compared with

nonproliferating CD8 T cells. Immunologic responders (iR; >2 fold increased

proliferation after treatment) did not show an improved progression-free (PFS) or

overall survival (OS).Conclusions: Paclitaxel/carboplatin/bevacizumab induces

proliferation of CD8 T cells, consisting of effector cells expressing

coinhibitory checkpoint molecules. Induction of proliferation was not correlated

to clinical outcome in the current clinical setting. Our findings provide a

rationale for combining PCB with checkpoint inhibition in lung cancer.

©2019 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-18-2243

PMID: 30642911

13. Eur Respir J. 2019 Jan 11. pii: 1801568. doi: 10.1183/13993003.01568-2018. [Epub

ahead of print]

Surgery or radiotherapy for stage I lung cancer? An intention to treat analysis.

Spencer KL(1)(2), Kennedy MPT(1), Lummis KL(1), Ellames DAB(1), Snee M(1),

BrunelliA(1), Franks K(1), Callister MEJ(1).

Author information:

(1)Leeds Teaching Hospitals NHS Trust, Leeds.

(2)Cancer epidemiology group, Leeds Institute of Cancer and Pathology, University

of Leeds.

INTRODUCTION: Surgery is the standard of care for early stage lung cancer, with

stereotactic ablative radiotherapy (SABR) a lower morbidity alternative for

patients with limited physiological reserve. Comparisons of outcomes between

these treatment options are limited by competing co-morbidities and differences

in pre-treatment pathological information. This study aims to address both issues

by assessing both overall and cancer-specific survival for presumed stage I lung

cancer on an intention-to-treat basis.

METHODS: This retrospective intention to treat analysis identified all patients

treated for presumed stage I lung cancer within a single large UK centre. Overall

survival (OS), cancer-specific survival (CSS) and combined cancer and

treatment-related survival (CTRS) were assessed with adjustment for confounding

variables using cox proportional hazards and Fine and Gray competing risks

analyses.

RESULTS: 468 patients (including 316 surgery, 99 SABR) were included in the study

population. Compared to surgery, SABR was associated with inferior OS on

multivariable Cox modelling (SABR HR 1.84 (95% CI 1.32-2.57)) but there was no

difference in CSS (HR for SABR 1.47 (95% CI 0.80-2.69) or CTRS (HR for SABR 1.27

(95% CI 0.74-2.17)). Cancer and treatment related death was no different between

SABR and surgery on Fine and Gray competing risks multivariable modelling

(sub-distribution hazard 1.03 (95% CI 0.59-1.81)). Non-cancer death was

significantly higher in SABR than surgery (sub-distribution hazard 2.16 (95% CI

1.41-3.32)).

CONCLUSION: In this analysis, no difference in cancer-specific survival was

observed between SABR and surgery. Further work is needed to define predictors of

outcome and help inform treatment decisions.

Copyright ©ERS 2019.

DOI: 10.1183/13993003.01568-2018

PMID: 30635294

14. Mol Cancer. 2019 Jan 9;18(1):7. doi: 10.1186/s12943-019-0939-9.

Intratumor heterogeneity comparison among different subtypes of non-small-cell

lung cancer through multi-region tissue and matched ctDNA sequencing.

Zhang Y(1), Chang L(2), Yang Y(1), Fang W(1), Guan Y(2), Wu A(2), Hong S(1), Zhou

H(1), Chen G(1), Chen X(1), Zhao S(1), Zheng Q(1), Pan H(1), Zhang L(3), Long

H(3), Yang H(3), Wang X(3), Wen Z(3), Wang J(3), Yang H(3), Xia X(2), Zhao Y(1),

Hou X(1), Ma Y(4), Zhou T(1), Zhang Z(1), Zhan J(1), Huang Y(1), Zhao H(4), Zhou

N(1), Yi X(2), Zhang L(5).

Author information:

(1)Department of Medical Oncology, Sun Yat-sen University Cancer Center, State

Key Laboratory of Oncology in South China, Collaborative Innovation Center for

Cancer Medicine, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's

Republic of China.

(2)Geneplus-Beijing Institute, Beijing, China.

(3)Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, State

Key Laboratory of Oncology in South China, Collaborative Innovation Center for

Cancer Medicine, Guangzhou, China.

…

Understanding of intratumor heterogeneity (ITH) among different non-small cell

lung cancer (NSCLC) subtypes is necessary. Whether circulating tumor DNA (ctDNA)

profile could represent these ITH is still an open question. We performed 181

multi-region tumor tissues sequencing and matched ctDNA sequencing from 32

operative NSCLC to compare ITH among different NSCLC subtypes, including

EGFR-mutant lung adenocarcinoma (LUAD), KRAS-mutant LUAD, EGFR&KRAS-wild-type

LUAD, and lung squamous cell carcinoma (LUSC), and examine potential value of

ctDNA for ITH analysis. ITH is evaluated by ITH index (ITHi). If the somatic

genetic alteration is shared by all the tissue regions, it is defined as trunk

mutation. Otherwise, it is called branch mutation. The ITHi will be higher, if

the tumor has less trunk mutations. We found EGFR-mutant LUAD showed

significantly higher ITHi than KRAS-mutant LUAD/wild-type LUAD (P = 0.03) and

numerically higher ITH than LUSC. For trunk mutations, driver mutations were

identified at a higher proportion than passenger mutations (60% vs. 40%,

P = 0.0023) in overall, especially in EGFR-mutant LUAD (86% vs. 14%, P = 0.0004),

while it was opposite in KRAS-mutant LUAD (40% vs. 60%, P = 0.18). For branch

mutations, the proportions of driver mutations and passenger mutations were

similar for each NSCLC subtype. ctDNA analysis showed unsatisfactory detections

of tumor-derived trunk and branch mutations (43% vs. 23%, P = 4.53e-6) among all

NSCLC subtypes. In summary, EGFR-mutant LUAD has the highest ITH than other NSCLC

subtypes, offering further understanding of tumorigenesis mechanisms among

different NSCLC subtypes. Besides, ctDNA maybe not an appropriate method to

reflect ITH.

DOI: 10.1186/s12943-019-0939-9

PMCID: PMC6325778

PMID: 30626401

15. Clin Cancer Res. 2019 Jan 7. pii: clincanres.2702.2018. doi:

10.1158/1078-0432.CCR-18-2702. [Epub ahead of print]

Efficacy & Safety of Biosimilar ABP 215 Compared with Bevacizumab in Patients

with Advanced Non-small Cell Lung Cancer(MAPLE):A Randomized,Double-blind,Phase 3

Study.

Thatcher N(1), Goldschmidt JH(2), Thomas M(3), Schenker M(4), Pan Z(5), Paz-Ares

L(6), Breder V(7), Ostoros G(8), Hanes V(9).

Author information:

(1)Oncology, The Christie Hospital Nick.thatcher@christie.nhs.edu.

(2)Oncology, Blue Ridge Cancer Care.

(3)Heidelberg University Hospital.

(4)Medical Oncology, Centrul de OncologieSfNectarie.

…

PURPOSE: This phase 3 study compared clinical efficacy and safety of the

biosimilar ABP 215 with bevacizumab reference product (RP) in patients with

advanced non-squamous non-small cell lung cancer (NSCLC).

PATIENTS & METHODS: Patients were randomized 1:1 to ABP 215 or bevacizumab 15

mg/kg Q3W for 6 cycles. All patients received carboplatin and paclitaxel Q3W for

≥4 and ≤6 cycles. The primary efficacy endpoint was risk ratio of objective

response rate(ORR); clinical equivalence was confirmed if the 2-sided 90% CI of

the risk ratio was within the margin of 0.67, 1.5. Secondary endpoints included

risk difference of ORR, duration of response(DOR), progression-free

survival(PFS), and overall survival(OS); pharmacokinetics, adverse events(AEs),

and incidence of antidrug antibodies(ADAs) were monitored.

RESULTS: 820 patients were screened; 642 were randomized to ABP 215 (n=328) and

bevacizumab (n=314). 128 (39.0%) and 131 (41.7%) patients in the ABP 215 and

bevacizumab group, respectively, had objective responses (ORR risk ratio: 0.93

[90% CI: 0.80, 1.09]). In the ABP 215 and bevacizumab group, 308 (95.1%) and 289

(93.5%) patients, respectively, had at least 1 AE; 13 (4.0%) and 11 (3.6%)

experienced a fatal AE. Anti-VEGF toxicity was low and comparable between

treatment groups. At week 19, median trough serum drug concentration was 132

μg/mL (ABP 215 group) and 129 μg/mL (bevacizumab group). No patient tested

positive for neutralizing antibodies.

CONCLUSIONS: ABP 215 is similar to bevacizumab RP with respect to clinical

efficacy, safety, immunogenicity, and pharmacokinetics. The totality of evidence

supports clinical equivalence of ABP 215 and bevacizumab.

Copyright ©2019, American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-18-2702

PMID: 30617139

16. Clin Cancer Res. 2019 Jan 23. pii: clincanres.2814.2018. doi:

10.1158/1078-0432.CCR-18-2814. [Epub ahead of print]

Capmatinib (INC280) Is Active Against Models of Non-Small Cell Lung Cancer and

Other Cancer Types with Defined Mechanisms of MET Activation.

BaltschukatS(1), SchacherEngstler B(1), Huang A(2), Hao HX(3), Tam A(4), Wang

HQ(5), Liang J(6), DiMare MT(7), Bhang HC(8), Wang Y(4), Furet P(9), Sellers

WR(10), Hofmann F(11), Schoepfer J(9), Tiedt R(12).

Author information:

(1)Oncology Translational Research, Novartis Institutes for BioMedical Research.

(2)Third Rock Ventures.

(3)Oncology, Novartis Institutes for BioMedical Research.

…

PURPOSE: The selective MET inhibitor capmatinib is being investigated in multiple

clinical trials, both as a single agent and in combination. Here, we describe the

preclinical data of capmatinib that supported the clinical biomarker strategy for

rational patient selection.

EXPERIMENTAL DESIGN: The selectivity and cellular activity of capmatinib were

assessed in large cellular screening panels. Antitumor efficacy was quantified in

a large set of cell line- or patient-derived xenograft models, testing single

agent or combination treatment depending on the genomic profile of the respective

models.

RESULTS: Capmatinib was found to be highly selective for MET over other kinases.

It was active against cancer models that are characterized by MET amplification,

marked MET overexpression, MET exon 14 skipping mutations, or MET activation via

expression of the ligand hepatocyte growth factor (HGF). In cancer models where

MET is the dominant oncogenic driver, anticancer activity could be further

enhanced by combination treatments, for example, by the addition of

apoptosis-inducing BH3 mimetics. The combinations of capmatinib and other kinase

inhibitors resulted in enhanced anticancer activity against models where MET

activation co-occurred with other oncogenic drivers, for example EGFR activating

mutations.

CONCLUSIONS: Activity of capmatinib in preclinical models is associated with a

small number of plausible genomic features. The low fraction of cancer models

that respond to capmatinib as a single agent suggests that the implementation of

patientselection strategies based on these biomarkers is critical for clinical

development. Capmatinib is also a rational combination partner for other kinase

inhibitors to combat MET-driven resistance.

Copyright ©2019, American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-18-2814

PMID: 30674502