Medical Abstracts

Keyword: lung cancer

1. Cell. 2019 Feb 21;176(5):998-1013.e16. doi: 10.1016/j.cell.2018.12.040. Epub 2019 Jan 31.

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),

Germain R(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. Lancet Oncol. 2019 Feb 12. pii: S1470-2045(18)30896-9. doi:

10.1016/S1470-2045(18)30896-9. [Epub ahead of print]

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.

(4)Christchurch Hospital, Christchurch, New Zealand.

…

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路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路6%) patients in the SABR group and two (6路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路1 years (IQR 1路2-3路6) for patients randomly

assigned to standard radiotherapy and 2路6 years (IQR 1路6-3路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路32, 95%

CI 0路13-0路77, p=0路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 漏 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(18)30896-9

PMID: 30770291

3. J Clin Oncol. 2019 Feb 20:JCO1801042. doi: 10.1200/JCO.18.01042. [Epub ahead of

print]

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

PMID: 30785829

4. Sci Transl Med. 2019 Feb 13;11(479). pii: eaat1500. doi:

10.1126/scitranslmed.aat1500.

Human tumor-associated monocytes/macrophages and their regulation of T cell

responses in early-stage lung cancer.

Singhal S(1), Stadanlick J(1), Annunziata MJ(1), Rao AS(1), Bhojnagarwala PS(1),

O'Brien S(2), Moon EK(2), Cantu E(3), Danet-Desnoyers G(4), Ra HJ(4), Litzky

L(5), Akimova T(5)(6), Beier UH(7), Hancock WW(5)(6), Albelda SM(2), Eruslanov

EB(8).

Author information:

(1)Division of Thoracic Surgery, Department of Surgery, University of

Pennsylvania, Philadelphia, PA 19104, USA.

(2)Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania,

Philadelphia, PA 19104, USA.

(3)Division of Cardiovascular Surgery, Department of Surgery, University of

Pennsylvania, Philadelphia, PA 19104, USA.

…

Data from mouse tumor models suggest that tumor-associated monocyte/macrophage

lineage cells (MMLCs) dampen antitumor immune responses. However, given the

fundamental differences between mice and humans in tumor evolution, genetic

heterogeneity, and immunity, the function of MMLCs might be different in human

tumors, especially during early stages of disease. Here, we studied MMLCs in

early-stage human lung tumors and found that they consist of a mixture of

classical tissue monocytes and tumor-associated macrophages (TAMs). The TAMs

coexpressed M1/M2 markers, as well as T cell coinhibitory and costimulatory

receptors. Functionally, TAMs did not primarily suppress tumor-specific effector

T cell responses, whereas tumor monocytes tended to be more T cell inhibitory.

TAMs expressing relevant MHC class I/tumor peptide complexes were able to

activate cognate effector T cells. Mechanistically, programmed death-ligand 1

(PD-L1) expressed on bystander TAMs, as opposed to PD-L1 expressed on tumor

cells, did not inhibit interactions between tumor-specific T cells and tumor

targets. TAM-derived PD-L1 exerted a regulatory role only during the interaction

of TAMs presenting relevant peptides with cognate effector T cells and thus may

limit excessive activation of T cells and protect TAMs from killing by these T

cells. These results suggest that the function of TAMs as primarily

immunosuppressive cells might not fully apply to early-stage human lung cancer

and might explain why some patients with strong PD-L1 positivity fail to respond

to PD-L1 therapy.

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.aat1500

PMID: 30760579

5. Nat Commun. 2019 Feb 4;10(1):557. doi: 10.1038/s41467-019-08380-1.

SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung

cancer.

Xue Y(1)(2), Meehan B(3), Fu Z(1)(2), Wang XQD(1), Fiset PO(4), Rieker R(5),

Levins C(6), Kong T(1)(2), Zhu X(1)(2), Morin G(1)(2), Skerritt L(1)(2), Herpel

E(7), Venneti S(8), Martinez D(9), Judkins AR(10), Jung S(4), Camilleri-Broet

S(4), Gonzalez AV(11), Guiot MC(12), Lockwood WW(13)(14)(15), Spicer JD(16),

Agaimy A(5), Pastor WA(1)(2), Dostie J(1), Rak J(3), Foulkes WD(6)(17)(18), Huang

S(19)(20).

Author information:

(1)Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.

(2)The Rosalind & Morris Goodman Cancer Research Centre, McGill University,

Montreal, QC, H3A 1A3, Canada.

(3)Department of Pediatrics, McGill University, and Research Institute of McGill

University Health Centre, Montreal Children's Hospital, Montreal, QC, H4A 3J1,

Canada.

(4)Department of Pathology, Glen Site, McGill University Health Centre, Montreal,

QC, H4A 3J1, Canada.

…

Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is

frequently inactivated in cancers and is not directly druggable. We recently

uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1

deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that

this vulnerability is conserved in non-small cell lung cancer (NSCLC), where

SMARCA4 loss also results in reduced cyclin D1 expression and selective

sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit

lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when

SMARCA4 is absent. Mechanistically, SMARCA4/2 loss reduces cyclin D1 expression

by a combination of restricting CCND1 chromatin accessibility and suppressing

c-Jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic

lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that

FDA-approved CDK4/6 inhibitors could be effective to treat this significant

subgroup of NSCLCs.

DOI: 10.1038/s41467-019-08380-1

PMCID: PMC6362083

PMID: 30718506

6. 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),

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

Mitter R(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)Instituto Maimónides de Investigación Biomédica de Córdoba, Córdoba, Spain.

(3)Unidad de Cirugía Torácica y Trasplante Pulmonar, Hospital Universitario Reina

Sofía, Córdoba, Spain.

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

London, UK.

(5)Proteomics, The Francis Crick Institute, 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

7. J Clin Oncol. 2019 Feb 1;37(4):278-285. doi: 10.1200/JCO.18.01585. Epub 2018 Dec

14.

EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other

Neuroendocrine Carcinomas: Clinical Outcomes.

Marcoux N(1)(2), Gettinger SN(3), O'Kane G(4), Arbour KC(5), Neal JW(6), Husain

H(7), Evans TL(8)(9), Brahmer JR(10), Muzikansky A(1), Bonomi PD(11), Del Prete

S(12), Wurtz A(3), Farago AF(1), Dias-Santagata D(1), Mino-Kenudson M(1), Reckamp

KL(13), Yu HA(5), Wakelee HA(6), Shepherd FA(4), Piotrowska Z(1), Sequist LV(1).

Author information:

(1)1 Massachusetts General Hospital, Boston, MA.

(2)12 CHU de Québec, Quebec City, Quebec, Canada.

(3)2 Yale Cancer Center, New Haven, CT.

(4)3 Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

PURPOSE: Approximately 3% to 10% of EGFR (epidermal growth factor receptor)

-mutant non-small cell lung cancers (NSCLCs) undergo transformation to small-cell

lung cancer (SCLC), but their clinical course is poorly characterized.

METHODS: We retrospectively identified patients with EGFR-mutant SCLC and other

high-grade neuroendocrine carcinomas seen at our eight institutions.

Demographics, disease features, and outcomes were analyzed.

RESULTS: We included 67 patients-38 women and 29 men; EGFR mutations included

exon 19 deletion (69%), L858R (25%), and other (6%). At the initial lung cancer

diagnosis, 58 patients had NSCLC and nine had de novo SCLC or mixed histology.

All but these nine patients received one or more EGFR tyrosine kinase inhibitor

before SCLC transformation. Median time to transformation was 17.8 months (95%

CI, 14.3 to 26.2 months). After transformation, both platinum-etoposide and

taxanes yielded high response rates, but none of 17 patients who received

immunotherapy experienced a response. Median overall survival since diagnosis was

31.5 months (95% CI, 24.8 to 41.3 months), whereas median survival since the time

of SCLC transformation was 10.9 months (95% CI, 8.0 to 13.7 months). Fifty-nine

patients had tissue genotyping at first evidence of SCLC. All maintained their

founder EGFR mutation, and 15 of 19 with prior EGFR T790M positivity were T790

wild-type at transformation. Other recurrent mutations included TP53, Rb1, and

PIK3CA. Re-emergence of NSCLC clones was identified in some cases. CNS metastases

were frequent after transformation.

CONCLUSION: There is a growing appreciation that EGFR-mutant NSCLCs can undergo

SCLC transformation. We demonstrate that this occurs at an average of 17.8 months

after diagnosis and cases are often characterized by Rb1, TP53, and PIK3CA

mutations. Responses to platinum-etoposide and taxanes are frequent, but

checkpoint inhibitors yielded no responses. Additional investigation is needed to

better elucidate optimal strategies for this group.

DOI: 10.1200/JCO.18.01585

PMID: 30550363

8. Cell Metab. 2019 Feb 5;29(2):285-302.e7. doi: 10.1016/j.cmet.2018.10.005. Epub

2018 Nov 8.

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

PMCID: PMC6365213 [Available on 2020-02-05]

PMID: 30415923

9. Int J Cancer. 2019 Feb 26. doi: 10.1002/ijc.32235. [Epub ahead of print]

Improved Treatment Outcome of Pembrolizumab in Patients with Non-small Cell Lung

Cancer and Chronic Obstructive Pulmonary Disease.

Shin SH(1), Park HY(1), Im Y(1), Jung HA(2), Sun JM(2), Ahn JS(2), Ahn MJ(2),

Park K(2), Lee HY(3), Lee SH(2)(4).

Author information:

(1)Division of Pulmonary and Critical Care Medicine, Department of Medicine,

Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South

Korea.

(2)Division of Hematology and Oncology, Department of Medicine, Samsung Medical

Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

(3)Department of Radiology, Samsung Medical Center, Sungkyunkwan University

School of Medicine, Seoul, Korea.

(4)Department of Health Sciences and Technology, Samsung Advanced Institute of

Health Science and Technology, Sungkyunkwan University, Seoul, Korea.

Emerging immune profiling data suggest a higher sensitivity to immune checkpoint

inhibitors (ICIs) in non-small cell lung cancer (NSCLC) patients with chronic

obstructive pulmonary disease (COPD), compared with those without COPD. This

study aimed to investigate the clinical impact of COPD on the treatment response

to ICIs in a large number of patients with NSCLC. In total, 133 patients with

spirometry test results were retrospectively identified among those who received

palliative pembrolizumab for NSCLC. COPD was defined as pre-bronchodilator forced

expiratory volume in 1 s/forced vital capacity < 0.7. Overall survival (OS),

progression-free survival (PFS), and objective response rate were analyzed

according to the presence of COPD. Spirometry-based COPD was present in 59 (44%)

patients. Patients with COPD had better OS (hazard ratio [HR] for death, 0.45;

95% confidence interval [CI], 0.26-0.78) and PFS (HR for disease progression or

death, 0.50; 95% CI, 0.31-0.79) than did those without COPD. These associations

persisted after adjusting for potential confounders including smoking history.

The response rate was also higher in patients with COPD than in those without

COPD (38.2% vs. 20.5%, p = 0.028). Spirometry-defined COPD was associated with a

significantly longer OS and PFS in patients with NSCLC treated with palliative

pembrolizumab. Identifying coexisting COPD could predict favorable treatment

outcomes in patients with NSCLC treated with pembrolizumab. This article is

protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

DOI: 10.1002/ijc.32235

PMID: 30807641

10. Ann Oncol. 2019 Feb 22. pii: mdz060. doi: 10.1093/annonc/mdz060. [Epub ahead of print]

Analysis of Time to Treatment Discontinuation of Targeted Therapy, Immunotherapy,

and Chemotherapy in clinical trials of patients with non-small cell lung cancer.

Blumenthal GM(1), Gong Y(1), Kehl K(2), Mishra-Kalyani P(1), Goldberg KB(1),

Khozin S(1), Kluetz PG(1), Oxnard GR(2), Pazdur R(1).

Author information:

(1)Center for Drug Evaluation and Research & Oncology Center of Excellence, U.S.

Food and Drug Administration, White Oak, Maryland.

(2)Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston,

Massachusetts.

BACKGROUND: Pragmatic Endpoints such as Time to Treatment Discontinuation (TTD),

defined as the date of starting a medication to the date of treatment

discontinuation or death has been proposed as a potential efficacy endpoint for

Real World Evidence (RWE) Trials, where imaging evaluation is less structured and

standardized.

PATIENTS AND METHODS: We studied 18 randomized clinical trials of patients with

metastatic non-small cell lung cancer (mNSCLC), initiated after 2007 and

submitted to US Food and Drug Administration. TTD was calculated as date of

randomization to date of discontinuation or death and compared to

progression-free survival (PFS) and overall survival (OS) across all patients, as

well as in treatment-defined subgroups (EGFR mutation positive treated with

Tyrosine Kinase Inhibitor (TKI), EGFR wild-type treated with TKI, ALK-positive

treated with TKI, Immune Checkpoint Inhibitor (ICI), Chemotherapy doublet with

maintenance, Chemotherapy monotherapy).

RESULTS: Overall across 8947 patients, TTD was more closely associated with PFS

(r = 0.87, 95% CI 0.86-0.87) than with OS (0.68, 95% CI 0.67-0.69). Early TTD

(PFS - TTD ≥ 3 months) occurred in 7.7% of patients overall, and was more common

with chemo monotherapy (15.0%) while late TTD (TTD - PFS ≥ 3 months) occurred in

6.0% of patients overall, and was more common in EGFR positive and ALK positive

patients (12.4% and 22.9%). In oncogene-targeted subgroups (EGFR positive and ALK

positive), median TTDs (13.4 and 14.1 months) exceeded median PFS (11.4 and 11.3

months).

CONCLUSIONS: At the patient level, TTD is associated with PFS across therapeutic

classes. Median TTD exceeds median PFS for biomarker-selected patients receiving

oncogene-targeted therapies. TTD should be prospectively studied further as an

endpoint for pragmatic randomized RWE trials only for continuously administered

therapies.

Published by Oxford University Press on behalf of the European Society for

Medical Oncology 2019.

DOI: 10.1093/annonc/mdz060

PMID: 30796424

11. Cancer Res. 2019 Feb 5. pii: canres.1536.2018. doi:

10.1158/0008-5472.CAN-18-1536. [Epub ahead of print]

Whole genome-derived tiled peptide arrays detect pre-diagnostic autoantibody

signatures in non-small cell lung cancer.

Yan Y(1), Sun N(2), Wang H(3), Kobayashi M(3), Ladd JJ(4), Long JP(5), Lo KC(6),

Patel J(7), Sullivan E(8), Albert T(9), Goodman GE(10), Do KA(11), Hanash SM(12).

Author information:

(1)Neurosurgery, The University of Texas Health Science Center at Houston.

(2)Thoracic surgery, National Cancer Center/Cancer Hospital, Peking Union Medical

College and Chinese Academy of Medical Sciences.

(3)Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center.

…

The majority of non-small cell lung cancer (NSCLC) cases are diagnosed at

advanced stages, primarily because earlier stages of the disease are either

asymptomatic or may be attributed to other causes such as infection or long-term

effects from smoking. Therefore, early detection of NSCLC would likely increase

response and survival rates due to timely intervention. Here we utilize a novel

approach based on whole genome-derived tiled peptide arrays to identify epitopes

associated with autoantibody reactivity in NSCLC as a potential means for early

detection. Arrays consisted of 2,781,902 tiled peptides representing 20,193

proteins encoded in the human genome. Analysis of 86 pre-diagnostic samples and

86 matched normal controls from a high-risk cohort revealed 48 proteins with

three or more reactive epitopes in NSCLC samples relative to controls.

Independent mass spectrometry analysis identified 40 of the 48 proteins in

pre-diagnostic sera from NSCLC samples, of which 21 occurred in the

immunoglobulin bound fraction. Additionally, 63 and 34 proteins encompassed three

or more epitopes that were distinct for squamous cell lung cancer and lung

adenocarcinoma, respectively. Collectively, these data show that tiled peptide

arrays provide a means to delineate epitopes encoded across the genome that

trigger an autoantibody response associated with tumor development.

Copyright ©2019, American Association for Cancer Research.

DOI: 10.1158/0008-5472.CAN-18-1536

PMID: 30723114

12. Cancer Res. 2019 Feb 15;79(4):689-698. doi: 10.1158/0008-5472.CAN-18-1281. Epub

2019 Feb 4.

Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome

Therapeutic Resistance in Lung Cancer.

Murtuza A(#)(1), Bulbul A(#)(1), Shen JP(1), Keshavarzian P(1), Woodward BD(1),

Lopez-Diaz FJ(1), Lippman SM(1), Husain H(2).

Author information:

(1)University of California San Diego, Moores Cancer Center, La Jolla,

California.

(2)University of California San Diego, Moores Cancer Center, La Jolla,

California. hhusain@ucsd.edu.

(#)Contributed equally

EGFR-activating mutations are observed in approximately 15% to 20% of patients

with non-small cell lung cancer. Tyrosine kinase inhibitors have provided an

illustrative example of the successes in targeting oncogene addiction in cancer

and the role of tumor-specific adaptations conferring therapeutic resistance. The

compound osimertinib is a third-generation tyrosine kinase inhibitor, which was

granted full FDA approval in March 2017 based on targeting EGFR T790M resistance.

The compound has received additional FDA approval as first-line therapy with

improvement in progression-free survival by suppressing the activating mutation

and preventing the rise of the dominant resistance clone. Drug development has

been breathtaking in this space with other third-generation compounds at various

stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib

(EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010. However,

therapeutic resistance after the administration of third-generation inhibitors is

complex and not fully understood, with significant intertumoral and intratumoral

heterogeneity. Repeat tissue and plasma analyses on therapy have revealed

insights into multiple mechanisms of resistance, including novel second site EGFR

mutations, activated bypass pathways such as MET amplification, HER2

amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion

events. Strategies to understand and predict patterns of mutagenesis are still in

their infancy; however, technologies to understand synthetically lethal

dependencies and track cancer evolution through therapy are being explored. The

expansion of combinatorial therapies is a direction forward targeting minimal

residual disease and bypass pathways early based on projected resistance.

©2019 American Association for Cancer Research.

DOI: 10.1158/0008-5472.CAN-18-1281

PMID: 30718357

13. Eur J Cancer. 2019 Feb;108:120-128. doi: 10.1016/j.ejca.2018.11.028. Epub 2019

Jan 14.

Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus

placebo in patients with previously treated advanced non-small cell lung cancer.

Levy BP(1), Giaccone G(2), Besse B(3), Felip E(4), Garassino MC(5), Domine Gomez

M(6), Garrido P(7), Piperdi B(8), Ponce-Aix S(9), Menezes D(10), MacBeth KJ(10),

Risueño A(11), Slepetis R(10), Wu X(10), Fandi A(10), Paz-Ares L(12).

Author information:

(1)Johns Hopkins Sidney Kimmel Cancer Center, Washington, DC, USA. Electronic

address: blevy11@jhmi.edu.

(2)Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC,

USA.

(3)Department of Cancer Medicine, Gustave Roussy, Villejuif and Paris-Sud

University, Orsay, France.

…

INTRODUCTION: Preclinical and early clinical studies suggest that combining

epigenetic agents with checkpoint inhibitors can potentially improve outcomes in

patients with previously treated advanced non-small cell lung cancer (NSCLC).

This phase 2 trial examined second-line pembrolizumab + CC-486 (oral azacitidine)

in patients with advanced NSCLC.

METHODS: Patients with one prior line of platinum-containing therapy were

randomised in a ratio of 1:1 to CC-486 or placebo, on days 1-14, in combination

with pembrolizumab on day 1 of a 21-day cycle. The primary end-point was

progression-free survival (PFS). Key secondary end-points included overall

survival (OS), overall response rate (ORR) and safety.

RESULTS: Among 100 patients randomised (pembrolizumab + CC-486: 51;

pembrolizumab + placebo: 49), most were male (57.0%), were white (87.0%) and had

Eastern Cooperative Oncology Group performance status 1 (68.0%). No significant

difference in PFS was observed between the pembrolizumab + CC-486 and

pembrolizumab + placebo arms (median, 2.9 and 4.0 months, respectively; hazard

ratio [HR], 1.374; 90% confidence interval [CI], 0.926-2.038; P = 0.1789). Median

OS was 11.9 months versus not estimable (HR, 1.375; 90% CI, 0.830-2.276;

P = 0.2968); ORR was 20% versus 14%. Median treatment duration was shorter (15.0

versus 24.1 weeks), and the number of cycles was lower (5.0 versus 7.0) with

pembrolizumab + CC-486 versus pembrolizumab + placebo. No new safety signals for CC-486 or pembrolizumab were detected. Treatment-emergent adverse events were

more common in the pembrolizumab + CC-486 arm, particularly gastrointestinal,

potentially impacting treatment feasibility.

CONCLUSIONS: No improvement in PFS was observed with pembrolizumab + CC-486

versus pembrolizumab + placebo. Decreased treatment exposure due to adverse

events may have impacted efficacy with pembrolizumab + CC-486.

Copyright © 2018 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.ejca.2018.11.028

PMID: 30654297

14. Clin Cancer Res. 2019 Feb 1;25(3):957-966. doi: 10.1158/1078-0432.CCR-18-1940.

Epub 2018 Aug 28.

Exome Analysis Reveals Genomic Markers Associated with Better Efficacy of

Nivolumab in Lung Cancer Patients.

Richard C(1)(2)(3), Fumet JD(1)(2)(3)(4), Chevrier S(1)(3), Derangère V(1)(3),

Ledys F(1)(2)(3), Lagrange A(4), Favier L(4), Coudert B(4), Arnould L(1)(3)(5),

Truntzer C(1)(3), Boidot R(1)(2)(3)(5)(6), Ghiringhelli F(7)(2)(3)(4)(5)(6).

Author information:

(1)Platform of Transfer in Cancer Biology, France.

(2)University of Burgundy Franche-Comté, France.

(3)Genetic and Immunology Medical Institute, Dijon, France.

…

PURPOSE: Immune checkpoint inhibitors revolutionized the treatment of non-small

cell lung cancer (NSCLC). However, only one-quarter of patients benefit from

these new therapies. PD-L1 assessment and tumor mutational burden (TMB) are

available tools to optimize use of checkpoint inhibitors but novel tools are

needed. Exome sequencing could generate many variables but their role in

identifying predictors of response is unknown.

EXPERIMENTAL DESIGN: We performed somatic and constitutional exome analyses for

77 patients with NSCLC treated with nivolumab. We studied: one-tumor-related

characteristics: aneuploidy, CNA clonality, mutational signatures, TMB, mutations

in WNT, AKT, MAPK, and DNA repair pathways, and two-immunologic characteristics:

number of intratumoral TCR clones, HLA types, and number of neoantigens; and six

clinical parameters.

RESULTS: A high TMB per Mb, a high number of neoantigens, mutational signatures

1A and 1B, mutations in DNA repair pathways, and a low number of TCR clones are

associated with greater PFS. Using a LASSO method, we established an exome-based

model with nine exome parameters that could discriminate patients with good or

poor PFS (P < 0.0001) and overall survival (P = 0.002). This model shows better

ability to predict outcomes compared with a PD-L1 clinical model with or without

TMB. It was externally validated on two cohorts of patients with NSCLC treated

with pembrolizumab or with nivolumab and ipilimumab as well as in urothelial

tumors treated with atezolizumab.

CONCLUSIONS: Altogether, these data provide a validated biomarker that predicts

the efficacy of nivolumab or pembrolizumab in patients with NSCLC. Our biomarker

seems to be superior to PD-L1 labeling and TMB models.

©2018 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-18-1940

PMID: 30154227