Medical Abstracts

Keyword: lung cancer

1. Lancet Oncol. 2019 Aug;20(8):1109-1123. doi: 10.1016/S1470-2045(19)30458-9. Epub 2019 Jul 10.

Ramucirumab plus pembrolizumab in patients with previously treated advanced

non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas

(JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial.

Herbst RS(1), Arkenau HT(2), Santana-Davila R(3), Calvo E(4), Paz-Ares L(5),

Cassier PA(6), Bendell J(7), Penel N(8), Krebs MG(9), Martin-Liberal J(10),

Isambert N(11), Soriano A(12), Wermke M(13), Cultrera J(12), Gao L(14), Widau

RC(15), Mi G(15), Jin J(14), Ferry D(14), Fuchs CS(16), Petrylak DP(16), Chau

I(17).

Author information:

(1)Yale University School of Medicine, Yale Cancer Center, New Haven, CT, USA.

Electronic address: roy.herbst@yale.edu.

(2)Drug Development Unit, Sarah Cannon Research Institute UK, London, UK; Cancer

Institute, University College London, London, UK.

(3)Drug Development Unit, University of Washington, Seattle, WA, USA.

…

BACKGROUND: Pre-clinical and clinical evidence suggests that simultaneous

blockade of VEGF receptor-2 (VEGFR-2) and PD-1 or PD-L1 enhances antigen-specific

T-cell migration, antitumour activity, and has favourable toxicity. In this

study, we aimed to assess the safety and preliminary antitumour activity of

ramucirumab (an IgG1 VEGFR-2 antagonist) combined with pembrolizumab (an IgG4

PD-1 antagonist) in patients with previously treated advanced gastric or

gastro-oesophageal junction adenocarcinoma, non-small-cell lung cancer, or

urothelial carcinoma.

METHODS: We did a multicohort, non-randomised, open-label, phase 1a/b trial at 16

academic medical centres, hospitals, and clinics in the USA, France, Germany,

Spain, and the UK. We enrolled adult patients aged 18 years or older with

histologically confirmed gastric or gastro-oesophageal junction adenocarcinoma

(cohorts A and B), non-small-cell lung cancer (cohort C), or urothelial carcinoma

(cohort D), whose disease had progressed on one or two lines of previous therapy

(for those with gastric or gastro-oesophageal junction adenocarcinoma) or one to

three lines of previous therapy (for those with non-small-cell lung cancer and

urothelial carcinoma) that included platinum (for all tumour types) or

fluoropyrimidine or both (for gastric or gastro-oesophageal junction

adenocarcinoma). Eligibility criteria included presence of measurable disease and

an Eastern Cooperative Oncology Group performance status of 0-1. Patients with

previously untreated gastric or gastro-oesophageal junction adenocarcinoma and

non-small-cell lung cancer were also enrolled (in two additional separate

cohorts); the results for these cohorts will be reported separately. The first

21-day treatment cycle was a dose-limiting toxicity observation period (phase 1a;

safety run-in), followed by a phase 1b cohort expansion stage. Pembrolizumab 200

mg was administered intravenously on day 1, and intravenous ramucirumab was

administered at 8 mg/kg on days 1 and 8 for cohort A or at 10 mg/kg on day 1 for

cohorts B, C, and D, every 3 weeks, until disease progression or other

discontinuation criteria were met. The primary endpoint was the safety and

tolerability of ramucirumab in combination with pembrolizumab assessed by the

incidence of adverse events in both phase 1a and 1b and as dose-limiting

toxicities during phase 1a. The safety and activity analysis set included all

patients who received at least one dose of study treatment. This trial is

registered with ClinicalTrials.gov, number NCT02443324, and is no longer

enrolling patients.

FINDINGS: Between July 30, 2015 and June 24, 2016, we enrolled and treated 92

patients (41 with gastric or gastro-oesophageal junction adenocarcinoma, 27 with

non-small-cell lung cancer, and 24 with urothelial carcinoma). Median follow-up

was 32·8 months (IQR 28·1-33·6). During the first cycle of treatment (phase 1a

safety run-in; n=11), one patient with gastro-oesophageal junction adenocarcinoma

who received the 8 mg/kg dose of ramucirumab had grade 3 abdominal pain, colitis,

hepatitis, interstitial lung disease, and jaundice, and grade 4 cholestasis, and

died on treatment on day 40; the death was deemed related to progressive disease.

No additional dose-limiting toxicities occurred and the decision was made to

maintain the full planned doses of ramucirumab and pembrolizumab in phase 1b

(n=81). Treatment-related adverse events occurred in 75 (82%) of 92 patients, the

most common of which was fatigue (in 33 patients [36%]), predominantly of grade 1

or 2 severity. 22 patients (24%) had one or more treatment-related adverse events

of grade 3 or worse, most commonly hypertension (six patients; 7%) and colitis

(five patients; 5%). Serious adverse events occurred in 53 (58%) of 92 patients,

and were deemed related to treatment in 22 (24%) patients. The most common

treatment-related serious adverse events were abdominal pain in patients with

gastric or gastro-oesophageal junction adenocarcinoma (in three [7%] of 41

patients); asthenia and myocardial infarction in patients with non-small-cell

lung cancer (two [7%] of 27 patients), and colitis in patients with urothelial

carcinoma (two [8%] of 24 patients). Six (7%) of 92 patients discontinued

treatment because of treatment-related adverse events, and one death (from

pulmonary sepsis in a patient with gastric or gastro-oesophageal junction

adenocarcinoma) was deemed related to treatment. The number of patients achieving

an objective response was three (7%; 95% CI 1·5-19·9) of 41 in the gastric or

gastro-oesophageal junction adenocarcinoma cohort, eight (30%; 13·8-50·2) of 27

in the non-small-cell lung cancer cohort, and three (13%, 2·7-32·4) in the

urothelial carcinoma cohort.

INTERPRETATION: Ramucirumab in combination with pembrolizumab showed a manageable

safety profile with favourable antitumour activity in patients with previously

treated advanced gastric or gastro-oesophageal junction adenocarcinoma,

non-small-cell lung cancer, and urothelial carcinoma. Our results contribute to

the growing evidence that supports dual inhibition of the VEGF-VEGFR2 and

PD-1-PD-L1 pathways. This combination could be further explored with or without

chemotherapy, especially for patients with tumours for which single-agent

checkpoint inhibitors have shown no additional benefit over chemotherapy.

FUNDING: Eli Lilly and Company, and Merck and Co.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(19)30458-9

PMID: 31301962

2. Lancet Oncol. 2019 Jul;20(7):924-937. doi: 10.1016/S1470-2045(19)30167-6. Epub

2019 May 20.

Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy

compared with chemotherapy alone as first-line treatment for metastatic

non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised,

open-label, phase 3 trial.

West H(1), McCleod M(2), Hussein M(3), Morabito A(4), Rittmeyer A(5), Conter

HJ(6), Kopp HG(7), Daniel D(8), McCune S(9), Mekhail T(10), Zer A(11), Reinmuth

N(12), Sadiq A(13), Sandler A(14), Lin W(15), Ochi Lohmann T(16), Archer V(17),

Wang L(18), Kowanetz M(19), Cappuzzo F(20).

Author information:

(1)Thoracic Oncology Program, Swedish Cancer Institute, Seattle, WA, USA.

(2)Sarah Cannon Research Institute, Florida Cancer Specialists, Fort Myers, FL,

USA.

(3)Sarah Cannon Research Institute, Florida Cancer Specialists, Leesburg, FL,

USA.

…

BACKGROUND: Atezolizumab (a monoclonal antibody against PD-L1), which restores

anticancer immunity, improved overall survival in patients with previously

treated non-small-cell lung cancer and also showed clinical benefit when combined

with chemotherapy as first-line treatment of non-small-cell lung cancer.

IMpower130 aimed to assess the efficacy and safety of atezolizumab plus

chemotherapy versus chemotherapy alone as first-line therapy for non-squamous

non-small-cell lung cancer.

METHODS: IMpower130 was a multicentre, randomised, open-label, phase 3 study done

in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany,

Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had

histologically or cytologically confirmed stage IV non-squamous non-small-cell

lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1,

and received no previous chemotherapy for stage IV disease. Patients were

randomly assigned (2:1; permuted block [block size of six] with an interactive

voice or web response system) to receive atezolizumab (1200 mg intravenously

every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per

min every 3 weeks] plus nab-paclitaxel [100 mg/m2 intravenously every week]) or

chemotherapy alone for four or six 21-day cycles followed by maintenance therapy.

Stratification factors were sex, baseline liver metastases, and PD-L1 tumour

expression. Co-primary endpoints were investigator-assessed progression-free

survival and overall survival in the intention-to-treat wild-type (ie, EGFRwt and

ALKwt) population. The safety population included patients who received at least

one dose of the study drug. This study is registered with ClinicalTrials.gov,

number NCT02367781.

FINDINGS: Between April 16, 2015, and Feb 13, 2017, 724 patients were randomly

assigned and 723 were included in the intention-to-treat population (one patient

died before randomisation, but was assigned to a treatment group; this patient

was excluded from the intention-to-treat population) of the atezolizumab plus

chemotherapy group (483 patients in the intention-to-treat population and 451

patients in the intention-to-treat wild-type population) or the chemotherapy

group (240 patients in the intention-to-treat population and 228 patients in the

intention-to-treat wild-type population). Median follow-up in the

intention-to-treat wild-type population was similar between groups (18·5 months

[IQR 15·2-23·6] in the atezolizumab plus chemotherapy group and 19·2 months

[15·4-23·0] in the chemotherapy group). In the intention-to-treat wild-type

population, there were significant improvements in median overall survival (18·6

months [95% CI 16·0-21·2] in the atezolizumab plus chemotherapy group and 13·9

months [12·0-18·7] in the chemotherapy group; stratified hazard ratio [HR] 0·79

[95% CI 0·64-0·98]; p=0·033) and median progression-free survival (7·0 months

[95% CI 6·2-7·3] in the atezolizumab plus chemotherapy group and 5·5 months

[4·4-5·9] in the chemotherapy group; stratified HR 0·64 [95% CI 0·54-0·77];

p<0·0001]). The most common grade 3 or worse treatment-related adverse events

were neutropenia (152 [32%] of 473 in the atezolizumab plus chemotherapy group vs

65 [28%] of 232 in the chemotherapy group), anaemia (138 [29%] vs 47 [20%]), and

decreased neutrophil count (57 [12%] vs 19 [8%]). Treatment-related serious

adverse events were reported in 112 (24%) of 473 patients in the atezolizumab

plus chemotherapy group and 30 (13%) of 232 patients in the chemotherapy group.

Treatment-related (any treatment) deaths occurred in eight (2%) of 473 patients

in the atezolizumab plus chemotherapy group and one (<1%) of 232 patients in the

chemotherapy group.

INTERPRETATION: IMpower130 showed a significant and clinically meaningful

improvement in overall survival and a significant improvement in progression-free

survival with atezolizumab plus chemotherapy versus chemotherapy as first-line

treatment of patients with stage IV non-squamous non-small-cell lung cancer and

no ALK or EGFR mutations. No new safety signals were identified. This study

supports the benefit of atezolizumab, in combination with platinum-based

chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer.

FUNDING: F. Hoffmann-La Roche.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(19)30167-6

PMID: 31122901

3. J Clin Oncol. 2019 Sep 10;37(26):2360-2367. doi: 10.1200/JCO.19.01006. Epub 2019

Jul 30.

Pemetrexed, Bevacizumab, or the Combination As Maintenance Therapy for Advanced

Nonsquamous Non-Small-Cell Lung Cancer: ECOG-ACRIN 5508.

Ramalingam SS(1), Dahlberg SE(2), Belani CP(3), Saltzman JN(4), Pennell NA(5),

Nambudiri GS(6), McCann JC(7), Winegarden JD(8), Kassem MA(9), Mohamed MK(10),

Rothman JM(11), Lyss AP(12), Horn L(13), Stinchcombe TE(14), Schiller JH(15).

Author information:

(1)Winship Cancer Institute of Emory University, Atlanta, GA.

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

(3)Penn State Health Milton S. Hershey Medical Center, Hershey, PA.

…

PURPOSE: Pemetrexed or bevacizumab is used for maintenance therapy of advanced

nonsquamous non-small-cell lung cancer (NSCLC). The combination of bevacizumab

and pemetrexed has also demonstrated efficacy. We conducted a randomized study to

determine the optimal maintenance therapy.

PATIENTS AND METHODS: Patients with advanced nonsquamous NSCLC and no prior

systemic therapy received carboplatin (area under the curve, 6), paclitaxel (200

mg/m2), and bevacizumab (15 mg/kg) for up to four cycles. Patients without

progression after four cycles were randomly assigned to maintenance therapy with

bevacizumab (15 mg/kg), pemetrexed (500 mg/m2), or a combination of the two

agents. The primary end point was overall survival, with bevacizumab serving as

the control group.

RESULTS: Of the 1,516 patients enrolled, 874 (57%) were randomly assigned after

induction therapy to one of the three maintenance therapy groups. With a median

follow-up of 50.6 months, median survival with pemetrexed was 15.9 months,

compared with 14.4 months with bevacizumab (hazard ratio [HR], 0.86; P = .12);

median survival with pemetrexed and bevacizumab was 16.4 months (HR, 0.9; P =

.28); median progression-free survival was 4.2, 5.1 (HR, 0.85; P = .06), and 7.5

months (HR, 0.67; P < .001) for the three groups, respectively. Incidence of

worst grade 3 to 4 toxicity was 29%, 37%, and 51%, respectively, for bevacizumab,

pemetrexed, and the combination regimen.

CONCLUSION: Single-agent bevacizumab or pemetrexed is efficacious as maintenance

therapy for advanced nonsquamous NSCLC. Because of a lack of survival benefit and

higher toxicity, the combination of bevacizumab and pemetrexed cannot be

recommended.

DOI: 10.1200/JCO.19.01006

PMID: 31361535

4. Cell. 2019 Jul 11;178(2):330-345.e22. doi: 10.1016/j.cell.2019.06.005. Epub 2019

Jun 27.

BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis.

Wiel C(1), Le Gal K(2), Ibrahim MX(3), Jahangir CA(4), Kashif M(4), Yao H(4),

Ziegler DV(3), Xu X(4), Ghosh T(5), Mondal T(5), Kanduri C(5), Lindahl P(6),

Sayin VI(7), Bergo MO(8).

Author information:

(1)Department of Biosciences and Nutrition, Karolinska Institutet, 141 83

Huddinge, Sweden; Sahlgrenska Cancer Center, Department of Molecular and Clinical

Medicine, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg,

Sweden.

(2)Sahlgrenska Cancer Center, Department of Surgery, Institute of Clinical

Sciences, University of Gothenburg, 405 30 Gothenburg, Sweden; Wallenberg Centre

for Molecular and Translational Medicine, University of Gothenburg, 405 30

Gothenburg, Sweden.

(3)Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine,

Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden.

…

For tumors to progress efficiently, cancer cells must overcome barriers of

oxidative stress. Although dietary antioxidant supplementation or activation of

endogenous antioxidants by NRF2 reduces oxidative stress and promotes early lung

tumor progression, little is known about its effect on lung cancer metastasis.

Here, we show that long-term supplementation with the antioxidants

N-acetylcysteine and vitamin E promotes KRAS-driven lung cancer metastasis. The

antioxidants stimulate metastasis by reducing levels of free heme and stabilizing

the transcription factor BACH1. BACH1 activates transcription of Hexokinase 2 and

Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion,

thereby stimulating glycolysis-dependent metastasis of mouse and human lung

cancer cells. Targeting BACH1 normalized glycolysis and prevented

antioxidant-induced metastasis, while increasing endogenous BACH1 expression

stimulated glycolysis and promoted metastasis, also in the absence of

antioxidants. We conclude that BACH1 stimulates glycolysis-dependent lung cancer

metastasis and that BACH1 is activated under conditions of reduced oxidative

stress.

Copyright © 2019 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cell.2019.06.005

PMID: 31257027

5. Cell. 2019 Jul 11;178(2):316-329.e18. doi: 10.1016/j.cell.2019.06.003. Epub 2019

Jun 27.

Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of

Bach1.

Lignitto L(1), LeBoeuf SE(2), Homer H(1), Jiang S(1), Askenazi M(3), Karakousi

TR(2), Pass HI(4), Bhutkar AJ(5), Tsirigos A(2), Ueberheide B(1), Sayin VI(2),

Papagiannakopoulos T(6), Pagano M(7).

Author information:

(1)Department of Biochemistry and Molecular Pharmacology, New York University

School of Medicine, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New

York University School of Medicine, New York, NY 10016, USA.

(2)Perlmutter NYU Cancer Center, New York University School of Medicine, New

York, NY 10016, USA; Department of Pathology, New York University School of

Medicine, New York, NY 10016, USA.

(3)Department of Biochemistry and Molecular Pharmacology, New York University

School of Medicine, New York, NY 10016, USA; Biomedical Hosting LLC, 33 Lewis

Avenue, Arlington, MA 02474, USA.

…

Approximately 30% of human lung cancers acquire mutations in either Keap1 or

Nfe2l2, resulting in the stabilization of Nrf2, the Nfe2l2 gene product, which

controls oxidative homeostasis. Here, we show that heme triggers the degradation

of Bach1, a pro-metastatic transcription factor, by promoting its interaction

with the ubiquitin ligase Fbxo22. Nrf2 accumulation in lung cancers causes the

stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme. In mouse

models of lung cancers, loss of Keap1 or Fbxo22 induces metastasis in a

Bach1-dependent manner. Pharmacological inhibition of Ho1 suppresses metastasis

in a Fbxo22-dependent manner. Human metastatic lung cancer display high levels of

Ho1 and Bach1. Bach1 transcriptional signature is associated with poor survival

and metastasis in lung cancer patients. We propose that Nrf2 activates a

metastatic program by inhibiting the heme- and Fbxo22-mediated degradation of

Bach1, and that Ho1 inhibitors represent an effective therapeutic strategy to

prevent lung cancer metastasis.

Copyright © 2019 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cell.2019.06.003

PMCID: PMC6625921 [Available on 2020-07-11]

PMID: 31257023

6. Nature. 2019 Jul;571(7763):127-131. doi: 10.1038/s41586-019-1340-y. Epub 2019 Jun 26.

UDP-glucose accelerates SNAI1 mRNA decay and impairs lung cancer metastasis.

Wang X(1)(2)(3), Liu R(1)(2), Zhu W(1), Chu H(4), Yu H(1)(2), Wei P(5), Wu X(6),

Zhu H(7), Gao H(1)(2), Liang J(1)(2), Li G(8), Yang W(9)(10).

Author information:

(1)State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular

Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of

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

Chinese Academy of Sciences, Shanghai, China.

(2)Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of

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

Chinese Academy of Sciences, Shanghai, China.

(3)Precise Genome Engineering Center, School of Life Sciences, Guangzhou

University, Guangzhou, China.

…

Comment in

Nature. 2019 Jul;571(7763):39-40.

Cancer metastasis is the primary cause of morbidity and mortality, and accounts

for up to 95% of cancer-related deaths1. Cancer cells often reprogram their

metabolism to efficiently support cell proliferation and survival2,3. However,

whether and how those metabolic alterations contribute to the migration of tumour

cells remain largely unknown. UDP-glucose 6-dehydrogenase (UGDH) is a key enzyme

in the uronic acid pathway, and converts UDP-glucose to UDP-glucuronic acid4.

Here we show that, after activation of EGFR, UGDH is phosphorylated at tyrosine

473 in human lung cancer cells. Phosphorylated UGDH interacts with Hu antigen R

(HuR) and converts UDP-glucose to UDP-glucuronic acid, which attenuates the

UDP-glucose-mediated inhibition of the association of HuR with SNAI1 mRNA and

therefore enhances the stability of SNAI1 mRNA. Increased production of SNAIL

initiates the epithelial-mesenchymal transition, thus promoting the migration of

tumour cells and lung cancer metastasis. In addition, phosphorylation of UGDH at

tyrosine 473 correlates with metastatic recurrence and poor prognosis of patients

with lung cancer. Our findings reveal a tumour-suppressive role of UDP-glucose in

lung cancer metastasis and uncover a mechanism by which UGDH promotes tumour

metastasis by increasing the stability of SNAI1 mRNA.

DOI: 10.1038/s41586-019-1340-y

PMID: 31243371 [Indexed for MEDLINE]

7. Mol Oncol. 2019 Aug;13(8):1725-1743. doi: 10.1002/1878-0261.12521. Epub 2019 Jul

10.

Genomic signatures defining responsiveness to allopurinol and combination therapy

for lung cancer identified by systems therapeutics analyses.

Tavassoly I(1), Hu Y(1)(2), Zhao S(1), Mariottini C(1), Boran A(1), Chen Y(1), Li

L(1), Tolentino RE(1), Jayaraman G(1), Goldfarb J(1), Gallo J(1), Iyengar R(1).

Author information:

(1)Department of Pharmacological Sciences, Systems Biology Center New York, Icahn

School of Medicine at Mount Sinai, New York, NY, USA.

(2)Clinical Pharmacology and Pharmacy, Chinese PLA General Hospital, Beijing,

China.

The ability to predict responsiveness to drugs in individual patients is limited.

We hypothesized that integrating molecular information from databases would yield

predictions that could be experimentally tested to develop transcriptomic

signatures for specific drugs. We analyzed lung adenocarcinoma patient data from

The Cancer Genome Atlas and identified a subset of patients in which xanthine

dehydrogenase (XDH) expression correlated with decreased survival. We tested

allopurinol, an FDA-approved drug that inhibits XDH, on human non-small-cell lung

cancer (NSCLC) cell lines obtained from the Broad Institute Cancer Cell Line

Encyclopedia and identified sensitive and resistant cell lines. We utilized the

transcriptomic profiles of these cell lines to identify six-gene signatures for

allopurinol-sensitive and allopurinol-resistant cell lines. Transcriptomic

networks identified JAK2 as an additional target in allopurinol-resistant lines.

Treatment of resistant cell lines with allopurinol and CEP-33779 (a JAK2

inhibitor) resulted in cell death. The effectiveness of allopurinol alone or

allopurinol and CEP-33779 was verified in vivo using tumor formation in NCR-nude

mice. We utilized the six-gene signatures to predict five additional

allopurinol-sensitive NSCLC cell lines and four allopurinol-resistant cell lines

susceptible to combination therapy. We searched the transcriptomic data from a

library of patient-derived NSCLC tumors from the Jackson Laboratory to identify

tumors that would be predicted to be sensitive to allopurinol or

allopurinol + CEP-33779 treatment. Patient-derived tumors showed the predicted

drug sensitivity in vivo. These data indicate that we can use integrated

molecular information from cancer databases to predict drug responsiveness in

individual patients and thus enable precision medicine.

© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

DOI: 10.1002/1878-0261.12521

PMCID: PMC6670022

PMID: 31116490

8. Cancer Res. 2019 Jul 15;79(14):3737-3748. doi: 10.1158/0008-5472.CAN-19-0596.

Epub 2019 May 13.

Low-Dose IFNγ Induces Tumor Cell Stemness in Tumor Microenvironment of Non-Small

Cell Lung Cancer.

Song M(#)(1)(2)(3), Ping Y(#)(1)(2), Zhang K(1)(2), Yang L(1)(2), Li F(1)(2),

Zhang C(1)(2)(4), Cheng S(1)(2), Yue D(1)(2), Maimela NR(1)(2), Qu J(1)(2), Liu

S(1)(2), Sun T(1), Li Z(5), Xia J(3), Zhang B(6), Wang L(7), Zhang Y(8)(2).

Author information:

(1)Biotherapy Center, The First Affiliated Hospital of Zhengzhou University,

Zhengzhou, China.

(2)Cancer Center, The First Affiliated Hospital of Zhengzhou University,

Zhengzhou, China.

(3)Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou,

China.

…

IFNγ is conventionally recognized as an inflammatory cytokine that plays a

central role in antitumor immunity. Although it has been used clinically to treat

a variety of malignancies, low levels of IFNγ in the tumor microenvironment (TME)

increase the risk of tumor metastasis during immunotherapy. Accumulating evidence

suggests that IFNγ can induce cancer progression, yet the mechanisms underlying

the controversial role of IFNγ in tumor development remain unclear. Here, we

reveal a dose-dependent effect of IFNγ in inducing tumor stemness to accelerate

cancer progression in patients with a variety of cancer types. Low levels of IFNγ

endowed cancer stem-like properties via the intercellular adhesion molecule-1

(ICAM1)-PI3K-Akt-Notch1 axis, whereas high levels of IFNγ activated the

JAK1-STAT1-caspase pathway to induce apoptosis in non-small cell lung cancer

(NSCLC). Inhibition of ICAM1 abrogated the stem-like properties of NSCLC cells

induced by the low dose of IFNγ both in vitro and in vivo. This study unveils the

role of low levels of IFNγ in conferring tumor stemness and elucidates the

distinct signaling pathways activated by IFNγ in a dose-dependent manner, thus

providing new insights into cancer treatment, particularly for patients with low

expression of IFNγ in the TME. SIGNIFICANCE: These findings reveal the

dose-dependent effect of IFNγ in inducing tumor stemness and elucidate the

distinct molecular mechanisms activated by IFNγ in a dose-dependent manner.

©2019 American Association for Cancer Research.

DOI: 10.1158/0008-5472.CAN-19-0596

PMID: 31085700

9. Ann Oncol. 2019 Jul 1;30(7):1127-1133. doi: 10.1093/annonc/mdz128.

A phase III, randomized, open-label study of ASP8273 versus erlotinib or

gefitinib in patients with advanced stage IIIB/IV non-small-cell lung cancer.

Kelly RJ(1), Shepherd FA(2), Krivoshik A(3), Jie F(4), Horn L(5).

Author information:

(1)The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University,

Baltimore and The Charles A. Sammons Cancer Center at Baylor University Medical

Center, Dallas, USA.

(2)Department of Medical Oncology and Hematology, Princess Margaret Cancer

Centre, Toronto, Canada.

(3)Departments of Oncology.

(4)Biostatistics, Astellas Pharma US, Inc., Northbrook.

(5)Department of Medicine, Vanderbilt University Medical Center, Nashville, USA.

BACKGROUND: ASP8273, a novel, small molecule, irreversible tyrosine kinase

inhibitor (TKI) specifically inhibits the epidermal growth factor receptor (EGFR)

in patients with activating mutations or EGFR T790M resistance mutations. The

current study examines the efficacy, safety, and tolerability of ASP8273 versus

erlotinib or gefitinib in patients with non-small-cell lung cancer (NSCLC) with

activating EGFR mutations not previously treated with an EGFR inhibitor.

PATIENTS AND METHODS: This global, phase III, open-label, randomized study

evaluated ASP8273 versus erlotinib/gefitinib in patients with locally advanced,

metastatic, or unresectable stage IIIB/IV NSCLC with activating EGFR mutations.

They were ineligible if they received prior chemotherapy for metastatic disease.

The primary end point was progression-free survival (PFS), and secondary end

points included overall survival, investigator-assessed PFS, best overall

response rate (ORR), disease control rate, duration of response (DoR), and the

safety/tolerability profile.

RESULTS: Patients (n = 530) were randomized 1 : 1 to receive ASP8273 (n = 267) or

erlotinib/gefitinib (n = 263). Patient demographics between both treatment groups

were generally balanced. Median PFS was 9.3 months (95% CI 5.6-11.1 months) for

patients receiving ASP8273 and 9.6 months (95% CI 8.8-NE) for the

erlotinib/gefitinib group, with a hazard ratio of 1.611 (P = 0.992). The ORR in

the ASP8273 group was 33% (95% CI 27.4-39.0) versus 47.9% (95% CI 41.7-54.1) in

the erlotinib/gefitinib group. Median DoR was similar for both groups (9.2 months

for ASP8273 versus 9.0 months for erlotinib/gefitinib). More grade ≥3

treatment-emergent adverse events (TEAEs) occurred in patients receiving ASP8273

than in those receiving erlotinib/gefitinib (54.7% versus 43.5%). An independent

data monitoring committee carried out an interim safety analysis and recommended

discontinuing the study due to toxicity and limited predicted efficacy of ASP8273

relative to erlotinib/gefitinib.

CONCLUSIONS: First-line ASP8273 did not show improved PFS or equivalent

toxicities versus erlotinib/gefitinib.

CLINICALTRIAL.GOV NUMBER: NCT02588261.

© The Author(s) 2019. Published by Oxford University Press on behalf of the

European Society for Medical Oncology.

DOI: 10.1093/annonc/mdz128

PMCID: PMC6736319

PMID: 31070709

10. Clin Cancer Res. 2019 Jul 15;25(14):4343-4350. doi:

10.1158/1078-0432.CCR-18-1084. Epub 2019 Apr 16.

Machine Learning to Build and Validate a Model for Radiation Pneumonitis

Prediction in Patients with Non-Small Cell Lung Cancer.

Yu H(1)(2), Wu H(2), Wang W(3), Jolly S(4), Jin JY(3), Hu C(5), Kong FS(6)(7)(8).

Author information:

(1)Biomedical Engineering, Shenzhen Polytechnic, Shenzhen, China.

(2)BioHealth Informatics, School Of Informatics and Computing, Indiana University

- Purdue University Indianapolis, Indianapolis, Indiana.

(3)University Hospitals/Cleveland Medical Center, Seidman Cancer Center and Case

Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.

…

PURPOSE: Radiation pneumonitis is an important adverse event in patients with

non-small cell lung cancer (NSCLC) receiving thoracic radiotherapy. However, the

risk of radiation pneumonitis grade ≥ 2 (RP2) has not been well predicted. This

study hypothesized that inflammatory cytokines or the dynamic changes during

radiotherapy can improve predictive accuracy for RP2.

EXPERIMENTAL DESIGN: Levels of 30 inflammatory cytokines and clinical information

in patients with stages I-III NSCLC treated with radiotherapy were from our

prospective studies. Statistical analysis was used to select predictive cytokine

candidates and clinical covariates for adjustment. Machine learning algorithm was

used to develop the generalized linear model for predicting risk RP2.

RESULTS: A total of 131 patients were eligible and 17 (13.0%) developed RP2. IL8

and CCL2 had significantly (Bonferroni) lower expression levels in patients with

RP2 than without RP2. But none of the changes in cytokine levels during

radiotherapy was significantly associated with RP2. The final predictive GLM

model for RP2 was established, including IL8 and CCL2 at baseline level and two

clinical variables. Nomogram was constructed based on the GLM model. The model's

predicting ability was validated in the completely independent test set (AUC =

0.863, accuracy = 80.0%, sensitivity = 100%, specificity = 76.5%).

CONCLUSIONS: By machine learning, this study has developed and validated a

comprehensive model integrating inflammatory cytokines with clinical variables to

predict RP2 before radiotherapy that provides an opportunity to guide clinicians.

©2019 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-18-1084

PMID: 30992302

11. Cancer. 2019 Jul 15;125(14):2394-2399. doi: 10.1002/cncr.32114. Epub 2019 Apr 1.

Association between depth of response and survival in patients with

advanced-stage non-small cell lung cancer treated with first-line chemotherapy.

Morgensztern D(1), Ko A(2), O'Brien M(3), Ong TJ(2), Waqar SN(1), Socinski MA(4),

Postmus PE(5), Bhore R(2).

Author information:

(1)Washington University School of Medicine, St. Louis, Missouri.

(2)Celgene Corporation, Summit, New Jersey.

(3)Royal Marsden NHS Foundation Trust, London, United Kingdom.

(4)Florida Hospital Cancer Institute, Orlando, Florida.

(5)Leiden University, Leiden, the Netherlands.

BACKGROUND: A partial response according to the Response Evaluation Criteria in

Solid Tumors includes a wide range of changes in tumor size. This study evaluated

whether further specification of tumor reduction based on the depth of response

(DpR) would provide a more precise association with outcomes for patients with

non-small cell lung cancer (NSCLC) treated with first-line platinum-based

chemotherapy.

METHODS: A retrospective analysis was performed for the randomized phase 3 CA031

trial in patients with NSCLC treated with carboplatin in combination with

nab-paclitaxel or solvent-based paclitaxel. Quartiles according to the maximum

tumor reduction from the baseline were defined (quartile 1 [Q1], >0% to 25%;

quartile 2 [Q2], >25% to 50%; quartile 3 [Q3], >50% to 75%; and quartile 4 [Q4],

>75%) and were compared with those patients with no tumor reduction (NTR). The

primary objective was to evaluate the association between DpR and overall

survival (OS).

RESULTS: Of the 1052 patients enrolled in the CA031 trial, 959 (91%) were

evaluable, and they included 365 (38.1%) who were classified as Q1, 327 (34.1%)

who were classified as Q2, 131 (13.7%) who were classified as Q3, and 34 (3.5%)

who were classified as Q4; 102 had NTR (10.6%). The median OS values for patients

in the NTR, Q1, Q2, Q3, and Q4 groups were 4.8, 10.4, 14.5, 19.3, and

23.5 months, respectively. The maximum DpR on treatment was an independent

predictor of improved OS in comparison with patients with NTR; the hazard ratio

decreased from 0.43 in Q1 to 0.16 in Q4.

CONCLUSIONS: DpR was strongly associated with OS in patients with NSCLC receiving

first-line platinum-based therapy. Additional studies may help to define the role

of DpR in solid tumors.

© 2019 American Cancer Society.

DOI: 10.1002/cncr.32114

PMID: 30933354

12. Eur J Nucl Med Mol Imaging. 2019 Jul;46(7):1439-1447. doi:

10.1007/s00259-019-4270-x. Epub 2019 Feb 1.

Pretreatment metabolic tumour volume in stage IIIA/B non-small-cell lung cancer

uncovers differences in effectiveness of definitive radiochemotherapy schedules:

analysis of the ESPATUE randomized phase 3 trial.

Guberina M(1), Eberhardt W(2), Stuschke M(3)(4), Gauler T(1), Aigner C(5)(6),

Schuler M(2)(5), Stamatis G(6), Theegarten D(7), Jentzen W(8), Herrmann K(5)(8),

Pöttgen C(1).

Author information:

(1)Department of Radiation Oncology, West German Cancer Center, University of

Duisburg-Essen Medical School, Hufelandstr. 55, 45122, Essen, Germany.

(2)Department of Medical Oncology, West German Cancer Center, University of

Duisburg-Essen Medical School, 45122, Essen, Germany.

(3)Department of Radiation Oncology, West German Cancer Center, University of

Duisburg-Essen Medical School, Hufelandstr. 55, 45122, Essen, Germany.

martin.stuschke@uk-essen.de.

…

PURPOSE: According to the ACRIN 6668/RTOG 0235 trial, pretreatment metabolic

tumour volume (MTV) as detected by 18F-fluorodeoxyglucose PET/CT is a prognostic

factor in patients with stage III non-small-cell lung cancer (NSCLC) after

definitive radiochemotherapy (RCT). To validate the prognostic value of MTV in

patients with stage III NSCLC after RCT, we analysed mature survival data from

the German phase III trial ESPATUE.

METHODS: This analysis included patients who were staged by PET/CT and who were

enrolled in the ESPATUE trial, a randomized study comparing definitive RCT (arm

A) with surgery (arm B) after induction chemotherapy and RCT in patients with

resectable stage IIIA/IIIB NSCLC. Patients refusing surgery and those with

nonresectable disease were scheduled to receive definitive RCT. MTV was measured

using a fixed threshold-based approach and a model-based iterative volume

thresholding approach. Data were analysed using proportional hazards models and

Kaplan-Meier survival functions.

RESULTS: MTV as a continuous variable did not reveal differences in survival

between the 117 patients scheduled to receive definitive RCT and all 169 enrolled

patients who underwent pretreatment PET/CT (p > 0.5). Five-year survival rates

were 33% (95% CI 17-49%) in patients scheduled for definitive RCT with a high MTV

(>95.4 ml) and 32% (95% CI: 22-42%) in those with a low MTV. The hazard ratio for

survival was 0.997 (95% CI 0.973-1.022) per 10-ml increase in MTV and the slope

was significantly shallower than that in the ACRIN 6668/RTOG 0235 trial (random

effects model, p = 0.002). There were no differences in MTV size distributions

between the ACRIN and ESPATUE trials (p = 0.97).

CONCLUSION: Patients with stage III NSCLC and a large MTV in whom definitive RCT

had a particularly good survival in the ESPATUE trial. Treatment

individualization according to MTV is not supported by this study. The ESPATUE

and ACRIN trials differed by the use of cisplatin-containing induction

chemotherapy and an intensified radiotherapy regimen that were particularly

effective in patients with large MTV disease.

DOI: 10.1007/s00259-019-4270-x

PMID: 30710323

13. Theranostics. 2019 Jul 28;9(19):5532-5541. doi: 10.7150/thno.34070. eCollection 2019.

Tumor-derived DNA from pleural effusion supernatant as a promising alternative to

tumor tissue in genomic profiling of advanced lung cancer.

Tong L(1)(2), Ding N(1)(2), Tong X(3), Li J(1)(2), Zhang Y(1)(2), Wang X(1)(2),

Xu X(1)(2), Ye M(1)(2), Li C(1)(2), Wu X(3), Bao H(4), Zhang X(1)(2), Hong

Q(1)(2), Song Y(1)(2), Shao YW(4)(5), Bai C(1)(2), Zhou J(1)(2), Hu J(1)(2).

Author information:

(1)Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University,

Shanghai, 200032, China.

(2)Shanghai Respiratory Research Institute, Shanghai, 200032, China.

(3)Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto,

Ontario, M5G 1L7, Canada.

(4)Medical Department, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu,

210032, China.

(5)School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, 210029,

China.

Pleural effusion (PE) is commonly observed in advanced lung cancer and was

suggested to contain both cell-free tumor DNA and tumor cells. Molecular

profiling of PE represents a minimally invasive approach of detecting tumor

driver mutations for clinical decision making, especially when tumor tissues are

not available. The objective of this study is to investigate the efficacy and

precision of detecting gene alterations in PE samples to address the feasibility

in clinical use. Methods: Sixty-three metastatic lung cancer patients with (n=30,

cohort 1) or without (n=33, cohort 2) matched tumor tissues were enrolled in this

study. PE and plasma samples of each patient were collected simultaneously.

Supernatant and cell precipitate of PE were processed separately to extract cfDNA

(PE-cfDNA) and sediment DNA (sDNA). All samples were subjected to targeted

next-generation sequencing (NGS) of 416 cancer-related genes. Results: PE

supernatants contain more abundant tumor DNA than PE sediments and plasma

samples, suggested by higher mutant allele frequencies (MAF) and elevated

mutation detection rate in PE-cfDNA (98.4% vs. 90.5% in PE sDNA vs. 87% in plasma

cfDNA). In Cohort 1 with matched tumor tissue, tumor mutational burden (TMB) of

PE-cfDNA was similar as tumor tissues (6.4 vs. 5.6), but significantly higher

than PE sDNA (median TMB: 3.3) and plasma cfDNA (median TMB: 3.4). Ninety-three

percent (27 out of 29) of tissue-determined driver mutations were detected in

PE-cfDNA, including alterations in ALK, BRAF, EGFR, ERBB2, KRAS, NF1, PIK3CA, and

RET, while only 62% were captured in plasma cfDNA. PE-cfDNA also has the highest

detection rate of EGFR driver mutations in the full cohort (71% vs. 68% in PE

sDNA vs. 59% in plasma cfDNA). Mutation detection from cytological negative and

hemorrhagic PE is challenging. Comparatively, PE-cfDNA demonstrated absolute

superiority than PE sDNA in such a scenario, suggesting that it is an independent

source of tumor DNA and therefore less influenced by the abundance of tumor

cells. Conclusion: Genomic profiling of PE-cfDNA offers an alternative, and

potentially more meticulous approach in assessing tumor genomics in advanced lung

cancer when tumor tissue is not available. Our data further demonstrate that in

hemorrhagic or cytologically negative PE samples, PE-cfDNA has higher mutation

detection sensitivity than sDNA and plasma cfDNA, and therefore is a more

reliable source for genetic testing.

DOI: 10.7150/thno.34070

PMCID: PMC6735385

PMID: 31534501