Medical Abstracts

Keyword: lung cancer

1. Nat Commun. 2019 Aug 26;10(1):3856. doi: 10.1038/s41467-019-11808-3.

Liquid biopsy-based single-cell metabolic phenotyping of lung cancer patients for

informative diagnostics.

Li Z(1), Wang Z(2), Tang Y(3)(4), Lu X(5), Chen J(3), Dong Y(3), Wu B(3), Wang

C(3), Yang L(6), Guo Z(7), Xue M(7), Lu S(8), Wei W(9)(10)(11), Shi

Q(12)(13)(14).

Author information:

(1)Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong

University, 200030, Shanghai, China.

(2)Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical

Sciences, Fudan University, 200032, Shanghai, China.

(3)Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center

for Systems Biomedicine, Shanghai Jiao Tong University, 200240, Shanghai, China.

...

Accurate prediction of chemo- or targeted therapy responses for patients with

similar driver oncogenes through a simple and least-invasive assay represents an

unmet need in the clinical diagnosis of non-small cell lung cancer. Using a

single-cell on-chip metabolic cytometry and fluorescent metabolic probes, we show

metabolic phenotyping on the rare disseminated tumor cells in pleural effusions

across a panel of 32 lung adenocarcinoma patients. Our results reveal extensive

metabolic heterogeneity of tumor cells that differentially engage in glycolysis

and mitochondrial oxidation. The cell number ratio of the two metabolic

phenotypes is found to be predictive for patient therapy response, physiological

performance, and survival. Transcriptome analysis reveals that the glycolytic

phenotype is associated with mesenchymal-like cell state with elevated expression

of the resistant-leading receptor tyrosine kinase AXL and immune checkpoint

ligands. Drug targeting AXL induces a significant cell killing in the glycolytic

cells without affecting the cells with active mitochondrial oxidation.

DOI: 10.1038/s41467-019-11808-3

PMCID: PMC6710267

PMID: 31451693

2. Autophagy. 2019 Aug 30:1-12. doi: 10.1080/15548627.2019.1659654. [Epub ahead of

print]

PAQR3 suppresses the growth of non-small cell lung cancer cells via modulation of

EGFR-mediated autophagy.

Cao Q(1), You X(1)(2), Xu L(1)(2), Wang L(3), Chen Y(1)(2).

Author information:

(1)CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai

Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences,

University of Chinese Academy of Sciences, Chinese Academy of Sciences , Shanghai

, China.

(2)School of Life Sciences and Technology, Shanghai Tech University , Shanghai ,

China.

(3)China Animal Health and Epidemiology Center , Qingdao , Shandong , China.

Macroautophagy/autophagy is an evolutionarily conserved intracellular process

that recycles and degrades intracellular components to sustain homeostasis in

response to deficiency of nutrients or growth factors. PAQR3 is a newly

discovered tumor suppressor that also regulates autophagy induced by nutrient

starvation via AMPK and MTORC1 signaling pathways. In this study, we investigated

whether PAQR3 modulates EGFR-mediated autophagy and whether such regulation is

associated with the tumor suppressive activity of PAQR3. PAQR3 is able to inhibit

the in vitro and in vivo growth of non-small cell lung cancer (NSCLC) cells.

PAQR3 potentiates autophagy induced by EGFR inhibitor erlotinib. Knockdown of

PAQR3 abrogates erlotinib-mediated reduction of BECN1 interaction with autophagy

inhibitory proteins RUBCN/Rubicon and BCL2. PAQR3 blocks the interaction of BECN1

with the activated form of EGFR and inhibits tyrosine phosphorylation of BECN1.

Furthermore, inhibition of autophagy by knocking down ATG7 abrogates the tumor

suppressive activity of PAQR3 in NSCLC cells. Collectively, these data indicate

that PAQR3 suppresses tumor progression of NSCLC cells through modulating

EGFR-regulated autophagy. Abbreviations : AKT: thymoma viral proto-oncogene;

ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related

14; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1; CCK-8: cell counting

kit-8; CQ: chloroquine diphosphate; DMEM: Dulbecco's modified Eagle's medium;

EdU: 5-ethynyl-2'-deoxyuridine; EGFR: epidermal growth factor receptor; FBS:

fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IgG:

Immunoglobulin G; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3

beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of

rapamycin kinase complex 1; MTT: thiazolyl blue tetrazolium bromide; NSCLC:

Non-small cell lung cancer; MAP2K/MEK: mitogen-activated protein kinase kinase;

MAPK/ERK: mitogen-activated protein kinase; PAQR3: progestin and adipoQ receptor

family member 3; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase;

PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3;

PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PRKAA/AMPK: protein

kinase, AMP-activated alpha catalytic; RUBCN: rubicon autophagy regulator; RPS6:

ribosomal protein S6; RAS: Ras proto-oncogene; RAF: Raf proto-oncogene; TKI:

tyrosine kinase inhibitor; TUBA4A: tubulin alpha 4a; UVRAG: UV radiation

resistance associated.

DOI: 10.1080/15548627.2019.1659654

PMID: 31448672

3. Am J Respir Crit Care Med. 2019 Aug 21. doi: 10.1164/rccm.201901-0096OC. [Epub

ahead of print]

Pleural Plaques and the Risk of Lung Cancer in Asbestos-exposed Subjects.

Brims FJ(1)(2), Kong K(3), Harris EJ(1)(3), Sodhi-Berry N(4), Reid A(5), Murray

CP(6), Franklin PJ(7), Musk AW(8), de Klerk NH(9).

Author information:

(1)Curtin Medical School , Perth, Western Australia, Australia.

(2)Sir Charles Gairdner Hospital, 5728, Respiratory Medicine, Nedlands, Western

Australia, Australia; fraser.brims@curtin.edu.au.

(3)Sir Charles Gairdner Hospital, 5728, Respiratory Medicine, Nedlands, Western

Australia, Australia.

...

RATIONALE: Asbestos exposure is associated with a dose-dependent risk of lung

cancer. The association between lung cancer and the presence of pleural plaques

remains controversial.

OBJECTIVES: To define the relationship between pleural plaques and lung cancer

risk.

METHODS: Subjects were from two cohorts: (1) crocidolite mine and mill workers,

and Wittenoom township residents and (2) a mixed asbestos fiber, mixed occupation

cohort. All subjects underwent annual review since 1990, chest x-ray (CXR) or low

dose computed tomography (LDCT) scan and outcome linkage to national cancer and

mortality registry data. Cox regression, with adjustment for age (as the

underlying matching time variable), was used to estimate hazard ratios for lung

cancer incidence by sex, tobacco smoking, asbestos exposure, and presence of

asbestosis and pleural plaques.

MEASUREMENTS AND MAIN RESULTS: For all 4240 subjects, mean age at follow up was

65.4 years, 3486 (82.0%) were male, 1315 (31.0%) had pleural plaques and 1353

(32.0%) had radiographic asbestosis. 3042 (71.7%) were ever-smokers with mean

tobacco exposure of 33 pack-years. 200 lung cancers were recorded. Risk of lung

cancer increased with cumulative exposure to cigarettes, asbestos and presence of

asbestosis. Pleural plaques did not confer any additional lung cancer risk in

either cohort (cohort 1: HR 1.03, 95% CI 0.64-1.67, p=0.89; cohort 2: HR 0.75,

95% CI 0.45-1.25, p=0.28).

CONCLUSIONS: The presence of pleural plaques on radiological imaging does not

confer an additional increase in the risk of lung cancer. This result is

consistent across two cohorts with differing asbestos fiber exposures and

intensity.

DOI: 10.1164/rccm.201901-0096OC

PMID: 31433952

4. Cancer Discov. 2019 Oct;9(10):1372-1387. doi: 10.1158/2159-8290.CD-19-0582. Epub

2019 Aug 15.

Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer.

Farago AF(1)(2), Yeap BY(3)(2), Stanzione M(3), Hung YP(3)(2), Heist RS(3)(2),

Marcoux JP(2)(4), Zhong J(3), Rangachari D(2)(5), Barbie DA(2)(4), Phat S(3),

Myers DT(3), Morris R(3), Kem M(3), Dubash TD(3), Kennedy EA(3), Digumarthy

SR(2)(6), Sequist LV(3)(2), Hata AN(3)(2), Maheswaran S(3)(2), Haber DA(3)(2)(7),

Lawrence MS(3)(2), Shaw AT(3)(2), Mino-Kenudson M(3)(2), Dyson NJ(3)(2), Drapkin

BJ(1)(2).

Author information:

(1)Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

afarago@mgh.harvard.edu bjdrapkin@partners.org.

(2)Dana-Farber Cancer Center, Boston, Massachusetts.

(3)Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

...

Comment in

Cancer Discov. 2019 Oct;9(10):1340-1342.

Small-cell lung cancer (SCLC) is an aggressive malignancy in which inhibitors of

PARP have modest single-agent activity. We performed a phase I/II trial of

combination olaparib tablets and temozolomide (OT) in patients with previously

treated SCLC. We established a recommended phase II dose of olaparib 200 mg

orally twice daily with temozolomide 75 mg/m2 daily, both on days 1 to 7 of a

21-day cycle, and expanded to a total of 50 patients. The confirmed overall

response rate was 41.7% (20/48 evaluable); median progression-free survival was

4.2 months [95% confidence interval (CI), 2.8-5.7]; and median overall survival

was 8.5 months (95% CI, 5.1-11.3). Patient-derived xenografts (PDX) from trial

patients recapitulated clinical OT responses, enabling a 32-PDX coclinical trial.

This revealed a correlation between low basal expression of inflammatory-response

genes and cross-resistance to both OT and standard first-line chemotherapy

(etoposide/platinum). These results demonstrate a promising new therapeutic

strategy in SCLC and uncover a molecular signature of those tumors most likely to

respond. SIGNIFICANCE: We demonstrate substantial clinical activity of

combination olaparib/temozolomide in relapsed SCLC, revealing a promising new

therapeutic strategy for this highly recalcitrant malignancy. Through an

integrated coclinical trial in PDXs, we then identify a molecular signature

predictive of response to OT, and describe the common molecular features of

cross-resistant SCLC.See related commentary by Pacheco and Byers, p. 1340.This

article is highlighted in the In This Issue feature, p. 1325.

©2019 American Association for Cancer Research.

DOI: 10.1158/2159-8290.CD-19-0582

PMID: 31416802

5. J Clin Oncol. 2019 Aug 14:JCO1901154. doi: 10.1200/JCO.19.01154. [Epub ahead of

print]

Gefitinib Versus Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in

EGFR-Mutated Lung Cancer.

Noronha V(1), Patil VM(1), Joshi A(1), Menon N(1), Chougule A(1), Mahajan A(1),

Janu A(1), Purandare N(1), Kumar R(1), More S(1), Goud S(1), Kadam N(2), Daware

N(2), Bhattacharjee A(1), Shah S(1), Yadav A(1), Trivedi V(1), Behel V(1), Dutt

A(3), Banavali SD(1), Prabhash K(1).

Author information:

(1)Tata Memorial Center, Mumbai, India.

(2)Gunvati J. Kapoor Medical Relief Charitable Foundation, Mumbai, India.

(3)Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai,

India.

PURPOSE: Standard first-line therapy for EGFR-mutant advanced non-small-cell lung

cancer (NSCLC) is an epidermal growth factor receptor (EGFR)-directed oral

tyrosine kinase inhibitor. Adding pemetrexed and carboplatin chemotherapy to an

oral tyrosine kinase inhibitor may improve outcomes.

PATIENTS AND METHODS: This was a phase III randomized trial in patients with

advanced NSCLC harboring an EGFR-sensitizing mutation and a performance status of

0 to 2 who were planned to receive first-line palliative therapy. Random

assignment was 1:1 to gefitinib 250 mg orally per day (Gef) or gefitinib 250 mg

orally per day plus pemetrexed 500 mg/m2 and carboplatin area under curve 5

intravenously every 3 weeks for four cycles, followed by maintenance pemetrexed

(gefitinib plus chemotherapy [Gef+C]). The primary end point was progression-free

survival (PFS); secondary end points included overall survival (OS), response

rate, and toxicity.

RESULTS: Between 2016 and 2018, 350 patients were randomly assigned to Gef (n =

176) and Gef+C (n = 174). Twenty-one percent of patients had a performance status

of 2, and 18% of patients had brain metastases. Median follow-up time was 17

months (range, 7 to 30 months). Radiologic response rates were 75% and 63% in the

Gef+C and Gef arms, respectively (P = .01). Estimated median PFS was

significantly longer with Gef+C than Gef (16 months [95% CI, 13.5 to 18.5 months]

v 8 months [95% CI, 7.0 to 9.0 months], respectively; hazard ratio for disease

progression or death, 0.51 [95% CI, 0.39 to 0.66]; P < .001). Estimated median OS

was significantly longer with Gef+C than Gef (not reached v 17 months [95% CI,

13.5 to 20.5 months]; hazard ratio for death, 0.45 [95% CI, 0.31 to 0.65]; P <

.001). Clinically relevant grade 3 or greater toxicities occurred in 51% and 25%

of patients in the Gef+C and Gef arms, respectively (P < .001).

CONCLUSION: Adding pemetrexed and carboplatin chemotherapy to gefitinib

significantly prolonged PFS and OS but increased toxicity in patients with NSCLC.

DOI: 10.1200/JCO.19.01154

PMID: 31411950

6. Nat Commun. 2019 Aug 8;10(1):3578. doi: 10.1038/s41467-019-11452-x.

Proteogenomic landscape of squamous cell lung cancer.

Stewart PA(1)(2), Welsh EA(2), Slebos RJC(1), Fang B(3), Izumi V(3), Chambers

M(2), Zhang G(1), Cen L(2), Pettersson F(2), Zhang Y(2), Chen Z(2), Cheng CH(2),

Thapa R(2), Thompson Z(2), Fellows KM(1), Francis JM(1), Saller JJ(4), Mesa T(5),

Zhang C(5), Yoder S(5), DeNicola GM(6), Beg AA(7), Boyle TA(4), Teer JK(8), Ann

Chen Y(8), Koomen JM(9), Eschrich SA(8), Haura EB(10).

Author information:

(1)Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research

Institute, Tampa, FL, 33612, USA.

(2)Biostatistics and Bioinformatics Shared Resource, H. Lee Moffitt Cancer Center

and Research Institute, Tampa, FL, 33612, USA.

(3)Proteomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute,

Tampa, FL, 33612, USA.

...

How genomic and transcriptomic alterations affect the functional proteome in lung

cancer is not fully understood. Here, we integrate DNA copy number, somatic

mutations, RNA-sequencing, and expression proteomics in a cohort of 108 squamous

cell lung cancer (SCC) patients. We identify three proteomic subtypes, two of

which (Inflamed, Redox) comprise 87% of tumors. The Inflamed subtype is enriched

with neutrophils, B-cells, and monocytes and expresses more PD-1. Redox tumours

are enriched for oxidation-reduction and glutathione pathways and harbor more

NFE2L2/KEAP1 alterations and copy gain in the 3q2 locus. Proteomic subtypes are

not associated with patient survival. However, B-cell-rich tertiary lymph node

structures, more common in Inflamed, are associated with better survival. We

identify metabolic vulnerabilities (TP63, PSAT1, and TFRC) in Redox. Our work

provides a powerful resource for lung SCC biology and suggests therapeutic

opportunities based on redox metabolism and immune cell infiltrates.

DOI: 10.1038/s41467-019-11452-x

PMCID: PMC6687710

PMID: 31395880

7. Nat Commun. 2019 Aug 2;10(1):3485. doi: 10.1038/s41467-019-11371-x.

MYC paralog-dependent apoptotic priming orchestrates a spectrum of

vulnerabilities in small cell lung cancer.

Dammert MA(1)(2)(3), Brägelmann J(1)(2)(3)(4), Olsen RR(5), Böhm S(2)(3),

Monhasery N(1)(2)(3), Whitney CP(5), Chalishazar MD(5), Tumbrink HL(1)(2)(3),

Guthrie MR(5), Klein S(2)(3)(4)(6), Ireland AS(5), Ryan J(7), Schmitt A(8)(9),

Marx A(1)(2)(3), Ozreti? L(10), Castiglione R(4)(6), Lorenz C(1)(2)(3),

Jachimowicz RD(8)(9), Wolf E(11), Thomas RK(2), Poirier JT(12), Büttner R(6), Sen

T(13), Byers LA(13), Reinhardt HC(4)(8)(9), Letai A(7), Oliver TG(14), Sos

ML(15)(16)(17).

Author information:

(1)Molecular Pathology, Institute of Pathology, University Hospital of Cologne,

50937, Cologne, Germany.

(2)Department of Translational Genomics, Center of Integrated Oncology

Cologne-Bonn, Medical Faculty, University of Cologne, 50931, Cologne, Germany.

(3)Center for Molecular Medicine Cologne, University of Cologne, 50931, Cologne,

Germany.

...

MYC paralogs are frequently activated in small cell lung cancer (SCLC) but

represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific

vulnerabilities may help to develop effective therapies for SCLC patients. Using

a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN

and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a.

The resulting lack of BCL2 expression promotes sensitivity to cell cycle control

inhibition and dependency on MCL1. Furthermore, MYC activation leads to

heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to

DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition

substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that

of combination chemotherapy. These analyses uncover MYC-paralog-specific

regulation of the apoptotic machinery with implications for genotype-based

selection of targeted therapeutics in SCLC patients.

DOI: 10.1038/s41467-019-11371-x

PMCID: PMC6677768

PMID: 31375684

8. J Clin Oncol. 2019 Aug 1;37(22):1927-1934. doi: 10.1200/JCO.19.00189. Epub 2019

Jun 17.

Immune Checkpoint Inhibitor Outcomes for Patients With Non-Small-Cell Lung Cancer

Receiving Baseline Corticosteroids for Palliative Versus Nonpalliative

Indications.

Ricciuti B(1), Dahlberg SE(1), Adeni A(1), Sholl LM(2), Nishino M(2), Awad MM(1).

Author information:

(1)1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

(2)2Brigham and Women's Hospital, Boston, MA.

PURPOSE: Baseline use of corticosteroids is associated with poor outcomes in

patients with non-small-cell lung cancer (NSCLC) treated with programmed cell

death-1 axis inhibition. To approach the question of causation versus correlation

for this association, we examined outcomes in patients treated with immunotherapy

depending on whether corticosteroids were administered for cancer-related

palliative reasons or cancer-unrelated indications.

PATIENTS AND METHODS: Clinical outcomes in patients with NSCLC treated with

immunotherapy who received ≥ 10 mg prednisone were compared with outcomes in

patients who received 0 to < 10 mg of prednisone.

RESULTS: Of 650 patients, the 93 patients (14.3%) who received ≥ 10 mg of

prednisone at the time of immunotherapy initiation had shorter median

progression-free survival (mPFS) and median overall survival (mOS) times than

patients who received 0 to < 10 mg of prednisone (mPFS, 2.0 v 3.4 months,

respectively; P = .01; mOS, 4.9 v 11.2 months, respectively; P < .001). When

analyzed by reason for corticosteroid administration, mPFS and mOS were

significantly shorter only among patients who received ≥ 10 mg prednisone for

palliative indications compared with patients who received ≥ 10 mg prednisone for

cancer-unrelated reasons and with patients receiving 0 to < 10 mg of prednisone

(mPFS, 1.4 v 4.6 v 3.4 months, respectively; log-rank P < .001 across the three

groups; mOS, 2.2 v 10.7 v 11.2 months, respectively; log-rank P < .001 across the

three groups). There was no significant difference in mPFS or mOS in patients

receiving ≥ 10 mg of prednisone for cancer-unrelated indications compared with

patients receiving 0 to < 10 mg of prednisone.

CONCLUSION: Although patients with NSCLC treated with ≥ 10 mg of prednisone at

the time of immunotherapy initiation have worse outcomes than patients who

received 0 to < 10 mg of prednisone, this difference seems to be driven by a

poor-prognosis subgroup of patients who receive corticosteroids for palliative

indications.

DOI: 10.1200/JCO.19.00189

PMID: 31206316

9. JAMA. 2019 Aug 27;322(8):764-774. doi: 10.1001/jama.2019.11058.

Systemic Therapy for Locally Advanced and Metastatic Non-Small Cell Lung Cancer:

A Review.

Arbour KC(1), Riely GJ(1).

Author information:

(1)Thoracic Oncology Service, Division of Solid Tumor, Department of Medicine,

Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York,

New York.

Importance: Non-small cell lung cancer remains the leading cause of cancer death

in the United States. Until the last decade, the 5-year overall survival rate for

patients with metastatic non-small cell lung cancer was less than 5%. Improved

understanding of the biology of lung cancer has resulted in the development of

new biomarker-targeted therapies and led to improvements in overall survival for

patients with advanced or metastatic disease.

Observations: Systemic therapy for metastatic non-small cell lung cancer is

selected according to the presence of specific biomarkers. Therefore, all

patients with metastatic non-small cell lung cancer should undergo molecular

testing for relevant mutations and expression of the protein PD-L1 (programmed

death ligand 1). Molecular alterations that predict response to treatment (eg,

EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E

mutations) are present in approximately 30% of patients with non-small cell lung

cancer. Targeted therapy for these alterations improves progression-free survival

compared with cytotoxic chemotherapy. For example, somatic activating mutations

in the EGFR gene are present in approximately 20% of patients with advanced

non-small cell lung cancer. Tyrosine kinase inhibitors such as gefitinib,

erlotinib, and afatinib improve progression-free survival in patients with

susceptible EGFR mutations. In patients with overexpression of ALK protein, the

response rate was significantly better with crizotinib (a tyrosine kinase

inhibitor) than with the combination of pemetrexed and either cisplatin or

carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively; P < .001)

and progression-free survival (median, 10.9 months vs 7.0 months; P < .001).

Subsequent generations of tyrosine kinase inhibitors have improved these agents.

For patients without biomarkers indicating susceptibility to specific targeted

treatments, immune checkpoint inhibitor-containing regimens either as monotherapy

or in combination with chemotherapy are superior vs chemotherapy alone. These

advances in biomarker-directed therapy have led to improvements in overall

survival. For example, the 5-year overall survival rate currently exceeds 25%

among patients whose tumors have high PD-L1 expression (tumor proportion score of

≥50%) and 40% among patients with ALK-positive tumors.

Conclusions and Relevance: Improved understanding of the biology and molecular

subtypes of non-small cell lung cancer have led to more biomarker-directed

therapies for patients with metastatic disease. These biomarker-directed

therapies and newer empirical treatment regimens have improved overall survival

for patients with metastatic non-small cell lung cancer.

DOI: 10.1001/jama.2019.11058

PMID: 31454018 [Indexed for MEDLINE]

10. Lancet Oncol. 2019 Oct;20(10):1395-1408. doi: 10.1016/S1470-2045(19)30407-3. Epub

2019 Aug 14.

Four-year survival with nivolumab in patients with previously treated advanced

non-small-cell lung cancer: a pooled analysis.

Antonia SJ(1), Borghaei H(2), Ramalingam SS(3), Horn L(4), De Castro Carpeño

J(5), Pluzanski A(6), Burgio MA(7), Garassino M(8), Chow LQM(9), Gettinger S(10),

Crinò L(7), Planchard D(11), Butts C(12), Drilon A(13), Wojcik-Tomaszewska J(14),

Otterson GA(15), Agrawal S(16), Li A(16), Penrod JR(16), Brahmer J(17).

Author information:

(1)H Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. Electronic

address: scott.antonia@duke.edu.

(2)Fox Chase Cancer Center, Philadelphia, PA, USA.

(3)Winship Cancer Institute, Emory University, Atlanta, GA, USA.

...

BACKGROUND: Phase 3 clinical data has shown higher proportions of patients with

objective response, longer response duration, and longer overall survival with

nivolumab versus docetaxel in patients with previously treated advanced

non-small-cell lung cancer (NSCLC). We aimed to evaluate the long-term benefit of

nivolumab and the effect of response and disease control on subsequent survival.

METHODS: We pooled data from four clinical studies of nivolumab in patients with

previously treated NSCLC (CheckMate 017, 057, 063, and 003) to evaluate survival

outcomes. Trials of nivolumab in the second-line or later setting with at least 4

years follow-up were included. Comparisons of nivolumab versus docetaxel included

all randomised patients from the phase 3 CheckMate 017 and 057 studies. We did

landmark analyses by response status at 6 months to determine post-landmark

survival outcomes. We excluded patients who did not have a radiographic tumour

assessment at 6 months. Safety analyses included all patients who received at

least one dose of nivolumab.

FINDINGS: Across all four studies, 4-year overall survival with nivolumab was 14%

(95% CI 11-17) for all patients (n=664), 19% (15-24) for those with at least 1%

PD-L1 expression, and 11% (7-16) for those with less than 1% PD-L1 expression. In

CheckMate 017 and 057, 4-year overall survival was 14% (95% CI 11-18) in patients

treated with nivolumab, compared with 5% (3-7) in patients treated with

docetaxel. Survival subsequent to response at 6 months on nivolumab or docetaxel

was longer than after progressive disease at 6 months, with hazard ratios for

overall survival of 0·18 (95% 0·12-0·27) for nivolumab and 0·43 (0·29-0·65) for

docetaxel; for stable disease versus progressive disease, hazard ratios were 0·52

(0·37-0·71) for nivolumab and 0·80 (0·61-1·04) for docetaxel. Long-term data did

not show any new safety signals.

INTERPRETATION: Patients with advanced NSCLC treated with nivolumab achieved a

greater duration of response compared with patients treated with docetaxel, which

was associated with a long-term survival advantage.

FUNDING: Bristol-Myers Squibb.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(19)30407-3

PMID: 31422028

11. Nat Rev Cancer. 2019 Sep;19(9):495-509. doi: 10.1038/s41568-019-0179-8. Epub 2019

Aug 12.

Co-occurring genomic alterations in non-small-cell lung cancer biology and

therapy.

Skoulidis F(1), Heymach JV(2).

Author information:

(1)Department of Thoracic and Head and Neck Medical Oncology, The University of

Texas MD Anderson Cancer Center, Houston, TX, USA. fskoulidis@mdanderson.org.

(2)Department of Thoracic and Head and Neck Medical Oncology, The University of

Texas MD Anderson Cancer Center, Houston, TX, USA.

The impressive clinical activity of small-molecule receptor tyrosine kinase

inhibitors for oncogene-addicted subgroups of non-small-cell lung cancer (for

example, those driven by activating mutations in the gene encoding epidermal

growth factor receptor (EGFR) or rearrangements in the genes encoding the

receptor tyrosine kinases anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1

(ROS1) and rearranged during transfection (RET)) has established an

oncogene-centric molecular classification paradigm in this disease. However,

recent studies have revealed considerable phenotypic diversity downstream of

tumour-initiating oncogenes. Co-occurring genomic alterations, particularly in

tumour suppressor genes such as TP53 and LKB1 (also known as STK11), have emerged

as core determinants of the molecular and clinical heterogeneity of

oncogene-driven lung cancer subgroups through their effects on both tumour

cell-intrinsic and non-cell-autonomous cancer hallmarks. In this Review, we

discuss the impact of co-mutations on the pathogenesis, biology,

microenvironmental interactions and therapeutic vulnerabilities of non-small-cell

lung cancer and assess the challenges and opportunities that co-mutations present

for personalized anticancer therapy, as well as the expanding field of precision

immunotherapy.

DOI: 10.1038/s41568-019-0179-8

PMID: 31406302

12. Clin Cancer Res. 2019 Aug 1;25(15):4691-4700. doi: 10.1158/1078-0432.CCR-19-0624.

Epub 2019 Apr 15.

Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic

Biomarkers in Patients with Newly Diagnosed Metastatic Non-small Cell Lung

Cancer.

Leighl NB(#)(1), Page RD(#)(2), Raymond VM(3), Daniel DB(4), Divers SG(5),

Reckamp KL(6), Villalona-Calero MA(7), Dix D(3), Odegaard JI(3), Lanman RB(3),

Papadimitrakopoulou VA(8).

Author information:

(1)Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Natasha.Leighl@uhn.ca.

(2)Center for Cancer and Blood Disorders, Fort Worth, Texas.

(3)Guardant Health, In, Redwood City, California.

(4)Tennessee Oncology, Chattanooga, Tennessee.

(5)Genesis Cancer Center, Hot Springs, Arkansas.

(6)City of Hope Comprehensive Cancer Center, Duarte, California.

(7)Miami Cancer Institute, Miami, Florida.

(8)MD Anderson Comprehensive Cancer Center, Houston, Texas.

(#)Contributed equally

Comment in

Clin Cancer Res. 2019 Aug 1;25(15):4583-4585.

Comment on

Clin Cancer Res. 2019 Aug 1;25(15):4583-4585.

PURPOSE: Complete and timely tissue genotyping is challenging, leading to

significant numbers of patients with newly diagnosed metastatic non-small cell

lung cancer (mNSCLC) being undergenotyped for all eight genomic biomarkers

recommended by professional guidelines. We aimed to demonstrate noninferiority of

comprehensive cell-free DNA (cfDNA) relative to physician discretion

standard-of-care (SOC) tissue genotyping to identify guideline-recommended

biomarkers in patients with mNSCLC.

PATIENTS AND METHODS: Prospectively enrolled patients with previously untreated

mNSCLC undergoing physician discretion SOC tissue genotyping submitted a

pretreatment blood sample for comprehensive cfDNA analysis (Guardant360).

RESULTS: Among 282 patients, physician discretion SOC tissue genotyping

identified a guideline-recommended biomarker in 60 patients versus 77 cfDNA

identified patients (21.3% vs. 27.3%; P < 0.0001 for noninferiority). In

tissue-positive patients, the biomarker was identified alone (12/60) or

concordant with cfDNA (48/60), an 80% cfDNA clinical sensitivity for any

guideline-recommended biomarker. For FDA-approved targets (EGFR, ALK, ROS1, BRAF)

concordance was >98.2% with 100% positive predictive value for cfDNA versus

tissue (34/34 EGFR-, ALK-, or BRAF-positive patients). Utilizing cfDNA, in

addition to tissue, increased detection by 48%, from 60 to 89 patients, including

those with negative, not assessed, or insufficient tissue results. cfDNA median

turnaround time was significantly faster than tissue (9 vs. 15 days; P < 0.0001).

Guideline-complete genotyping was significantly more likely (268 vs. 51; P <

0.0001).

CONCLUSIONS: In the largest cfDNA study in previously untreated mNSCLC, a

validated comprehensive cfDNA test identifies guideline-recommended biomarkers at

a rate at least as high as SOC tissue genotyping, with high tissue concordance,

more rapidly and completely than tissue-based genotyping.See related commentary

by Meador and Oxnard, p. 4583.

©2019 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-19-0624

PMID: 30988079 [Indexed for MEDLINE]

13. Thorax. 2019 Aug;74(8):787-796. doi: 10.1136/thoraxjnl-2018-212996. Epub 2019 May

2.

Multidisciplinary home-based rehabilitation in inoperable lung cancer: a

randomised controlled trial.

Edbrooke L(1)(2), Aranda S(3)(4), Granger CL(1)(5), McDonald CF(6)(7),

Krishnasamy M(8)(9), Mileshkin L(10)(11), Clark RA(12), Gordon I(13), Irving

L(14), Denehy L(15)(16).

Author information:

(1)Department of Physiotherapy, The University of Melbourne, Parkville, Victoria,

Australia.

(2)Allied Health Service, The Peter MacCallum Cancer Centre, Melbourne, Victoria,

Australia.

(3)Cancer Council Australia, Sydney, New South Wales, Australia.

...

BACKGROUND: Lung cancer is associated with poor health-related quality of life

(HRQoL) and high symptom burden. This trial aimed to assess the efficacy of

home-based rehabilitation versus usual care in inoperable lung cancer.

METHODS: A parallel-group, assessor-blinded, allocation-concealed, randomised

controlled trial. Eligible participants were allocated (1:1) to usual care (UC)

plus 8 weeks of aerobic and resistance exercise with behaviour change strategies

and symptom support (intervention group (IG)) or UC alone. Assessments occurred

at baseline, 9 weeks and 6 months. The primary outcome, change in between-group 6

min walk distance (6MWD), was analysed using intention-to-treat (ITT). Subsequent

analyses involved modified ITT (mITT) and included participants with at least one

follow-up outcome measure. Secondary outcomes included HRQoL and symptoms.

RESULTS: Ninety-two participants were recruited. Characteristics of participants

(UC=47, IG=45): mean (SD) age 64 (12) years; men 55%; disease stage n (%) III=35

(38) and IV=48 (52); radical treatment 46%. There were no significant

between-group differences for the 6MWD (n=92) at 9 weeks (p=0.308) or 6 months

(p=0.979). The mITT analyses of 6MWD between-group differences were again

non-significant (mean difference (95% CI): 9 weeks: -25.4 m (-64.0 to 13.3),

p=0.198 and 6 months: 41.3 m (-26.7 to 109.4), p=0.232). Significant 6-month

differences, favouring the IG, were found for HRQoL (Functional Assessment of

Cancer Therapy-Lung: 13.0 (3.9 to 22.1), p=0.005) and symptom severity (MD

Anderson Symptom Inventory-Lung Cancer: -2.2 (-3.6 to -0.9), p=0.001).

CONCLUSIONS: Home-based rehabilitation did not improve functional exercise

capacity but there were improvements in patient-reported exploratory secondary

outcomes measures observed at 6 months.

TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry

(ACTRN12614001268639).

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and

permissions. Published by BMJ.

DOI: 10.1136/thoraxjnl-2018-212996

PMID: 31048509

14. Clin Cancer Res. 2019 Aug 1;25(15):4663-4673. doi: 10.1158/1078-0432.CCR-18-4142.

Epub 2019 May 3.

Expression Analysis and Significance of PD-1, LAG-3, and TIM-3 in Human Non-Small

Cell Lung Cancer Using Spatially Resolved and Multiparametric Single-Cell

Analysis.

Datar I(#)(1)(2), Sanmamed MF(#)(3)(4)(5), Wang J(3), Henick BS(1)(2), Choi J(6),

Badri T(3), Dong W(6), Mani N(1), Toki M(1), Mejías LD(4), Lozano MD(4),

Perez-Gracia JL(4), Velcheti V(7), Hellmann MD(8)(9)(10), Gainor JF(11),

McEachern K(12), Jenkins D(12), Syrigos K(13), Politi K(1)(2), Gettinger S(2),

Rimm DL(1)(2), Herbst RS(2), Melero I(4)(5), Chen L(3), Schalper KA(14)(2).

Author information:

(1)Department of Pathology, Yale University School of Medicine, New Haven,

Connecticut.

(2)Department of Medical Oncology, Yale University, Yale Cancer Center, New

Haven, Connecticut.

(3)Department of Immunobiology, Yale University School of Medicine, New Haven,

Connecticut.

...

PURPOSE: To determine the tumor tissue/cell distribution, functional

associations, and clinical significance of PD-1, LAG-3, and TIM-3 protein

expression in human non-small cell lung cancer (NSCLC).

EXPERIMENTAL DESIGN: Using multiplexed quantitative immunofluorescence, we

performed localized measurements of CD3, PD-1, LAG-3, and TIM-3 protein in >800

clinically annotated NSCLCs from three independent cohorts represented in tissue

microarrays. Associations between the marker's expression and major genomic

alterations were studied in The Cancer Genome Atlas NSCLC dataset. Using mass

cytometry (CyTOF) analysis of leukocytes collected from 20 resected NSCLCs, we

determined the levels, coexpression, and functional profile of PD-1, LAG-3, and

TIM-3 expressing immune cells. Finally, we measured the markers in baseline

samples from 90 patients with advanced NSCLC treated with PD-1 axis blockers and

known response to treatment.

RESULTS: PD-1, LAG-3, and TIM-3 were detected in tumor-infiltrating lymphocytes

(TIL) from 55%, 41.5%, and 25.3% of NSCLC cases, respectively. These markers

showed a prominent association with each other and limited association with major

clinicopathologic variables and survival in patients not receiving immunotherapy.

Expression of the markers was lower in EGFR-mutated adenocarcinomas and displayed

limited association with tumor mutational burden. In single-cell CyTOF analysis,

PD-1 and LAG-3 were predominantly localized on T-cell subsets/NKT cells, whereas

TIM-3 expression was higher in NK cells and macrophages. Coexpression of PD-1,

LAG-3, and TIM-3 was associated with prominent T-cell activation (CD69/CD137),

effector function (Granzyme-B), and proliferation (Ki-67), but also with elevated

levels of proapoptotic markers (FAS/BIM). LAG-3 and TIM-3 were present in TIL

subsets lacking PD-1 expression and showed a distinct functional profile. In

baseline samples from 90 patients with advanced NSCLC treated with PD-1 axis

blockers, elevated LAG-3 was significantly associated with shorter

progression-free survival.

CONCLUSIONS: PD-1, LAG-3, and TIM-3 have distinct tissue/cell distribution,

functional implications, and genomic correlates in human NSCLC. Expression of

these immune inhibitory receptors in TILs is associated with prominent

activation, but also with a proapoptotic T-cell phenotype. Elevated LAG-3

expression is associated with insensitivity to PD-1 axis blockade, suggesting

independence of these immune evasion pathways.

©2019 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-18-4142

PMID: 31053602

15. Clin Cancer Res. 2019 Aug 15;25(16):5061-5068. doi:

10.1158/1078-0432.CCR-18-4275. Epub 2019 May 21.

Tumor Characteristics Associated with Benefit from Pembrolizumab in Advanced

Non-Small Cell Lung Cancer.

Hu-Lieskovan S(#)(1)(2), Lisberg A(#)(1), Zaretsky JM(#)(1), Grogan TR(1), Rizvi

H(3), Wells DK(2), Carroll J(1), Cummings A(1), Madrigal J(1), Jones B(1),

Gukasyan J(1), Shintaku IP(1), Slamon D(1), Dubinett S(1), Goldman JW(1),

Elashoff D(1), Hellmann MD(3)(4), Ribas A(1)(2), Garon EB(5).

Author information:

(1)David Geffen School of Medicine at the University of California Los Angeles,

Los Angeles, California.

(2)Parker Institute for Cancer Immunotherapy, San Francisco, California.

(3)Memorial Sloan Kettering Cancer Center, New York, New York.

(4)Weill Cornell Medical College, New York, New York.

(5)David Geffen School of Medicine at the University of California Los Angeles,

Los Angeles, California. egaron@mednet.ucla.edu.

(#)Contributed equally

PURPOSE: Several biomarkers have been individually associated with response to

PD-1 blockade, including PD-L1 and tumor mutational burden (TMB) in non-small

cell lung cancer (NSCLC), and CD8 cells in melanoma. We sought to examine the

relationship between these distinct variables with response to PD-1 blockade and

long-term benefit.

EXPERIMENTAL DESIGN: We assessed the association between baseline tumor

characteristics (TMB, PD-L1, CD4, and CD8) and clinical features and outcome in

38 patients with advanced NSCLC treated with pembrolizumab (median follow-up of

4.5 years, range 3.8-5.5 years).

RESULTS: PD-L1 expression and CD8 infiltration correlated with each other and

each significantly associated with objective response rate (ORR) and

progression-free survival (PFS). TMB was independent of PD-L1 and CD8 expression,

and trended towards association with ORR and PFS. There was no association

between CD4 infiltration and outcomes. Only PD-L1 expression was correlated with

overall survival (OS). Among 5 patients with long-term survival >3 years with no

additional systemic therapy, PD-L1 expression was the only discriminating

feature. The increased predictive value for PFS and OS of composite biomarker

inclusive of PD-L1, CD8, CD4, and TMB was limited.

CONCLUSIONS: In patients with NSCLC treated with PD-1 blockade with long-term

follow up, TMB, PD-L1, and CD8 were each associated with benefit from PD-1

blockade. Pretreatment PD-L1 expression was correlated with T lymphocyte

infiltration and OS, whereas models incorporating TMB and infiltrating CD4 and

CD8 lymphocytes did not substantially add to the predictive value of PD-L1 alone

for OS.

©2019 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-18-4275

PMID: 31113840

16. Clin Cancer Res. 2019 Aug 15. doi: 10.1158/1078-0432.CCR-19-0994. [Epub ahead of

print]

Crizotinib in MET-Deregulated or ROS1-Rearranged Pretreated Non-Small Cell Lung

Cancer (METROS): A Phase II, Prospective, Multicenter, Two-Arms Trial.

Landi L(1), Chiari R(2), Tiseo M(3), D'Incà F(4), Dazzi C(1), Chella A(5),

Delmonte A(6), Bonanno L(7), Giannarelli D(8), Cortinovis DL(9), de Marinis

F(10), Borra G(11), Morabito A(12), Gridelli C(13), Galetta D(14), Barbieri

F(15), Grossi F(16), Capelletto E(17), Minuti G(1), Mazzoni F(18), Verusio C(19),

Bria E(20)(21), Alì G(22), Bruno R(23), Proietti A(22), Fontanini G(23), Crinò

L(6), Cappuzzo F(24).

Author information:

(1)AUSL Romagna, Dipartimento di Oncologia ed Ematologia, Ravenna, Italy.

(2)Ospedale Santa Maria della Misericordia, Perugia, Italy.

(3)Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma e

Oncologia Medica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.

...

INTRODUCTION: MET-deregulated NSCLC represents an urgent clinical need because of

unfavorable prognosis and lack of specific therapies. Although recent studies

have suggested a potential role for crizotinib in patients harboring MET

amplification or exon 14 mutations, no conclusive data are currently available.

This study aimed at investigating activity of crizotinib in patients harboring

MET or ROS1 alterations.

PATIENTS AND METHODS: Patients with pretreated advanced NSCLC and evidence of

ROS1 rearrangements (cohort A) or MET deregulation (amplification, ratio MET/CEP7

>2.2 or MET exon 14 mutations, cohort B) were treated with crizotinib 250 mg

twice daily orally. The coprimary endpoint was objective response rate in the two

cohorts.

RESULTS: From December 2014 to March 2017, 505 patients were screened and a total

of 52 patients (26 patients per cohort) were enrolled onto the study. At data

cutoff of September 2017, in cohort A, objective response rate was 65%, and

median progression-free survival and overall survival were 22.8 months [95%

confidence interval (CI) 15.2-30.3] and not reached, respectively. In cohort B,

objective response rate was 27%, median progression-free survival was 4.4 months

(95% CI 3.0-5.8), and overall survival was 5.4 months (95% CI, 4.2-6.5). No

difference in any clinical endpoint was observed between MET-amplified and exon

14-mutated patients. No response was observed among the 5 patients with

cooccurrence of a second gene alteration. No unexpected toxicity was observed in

both cohorts.

CONCLUSION: Crizotinib induces response in a fraction of MET-deregulated NSCLC.

Additional studies and innovative therapies are urgently needed.

©2019 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-19-0994

PMID: 31416808