Medical Abstracts

Keyword: lung cancer

1. Nature. 2019 Nov;575(7782):380-384. doi: 10.1038/s41586-019-1715-0. Epub 2019 Oct

30.

In vivo imaging of mitochondrial membrane potential in non-small-cell lung

cancer.

Momcilovic M(1), Jones A(2), Bailey ST(3), Waldmann CM(2), Li R(1), Lee

JT(2)(4)(5), Abdelhady G(1), Gomez A(6), Holloway T(2), Schmid E(7), Stout D(8),

Fishbein MC(9), Stiles L(10), Dabir DV(11), Dubinett SM(1)(2)(5)(9)(12),

Christofk H(2)(5)(7)(13), Shirihai O(5)(10), Koehler CM(6), Sadeghi S(2),

Shackelford DB(14)(15).

Author information:

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

David Geffen School of Medicine at the University of California, Los Angeles, CA,

USA.

。。。

Erratum in

Nature. 2020 Jan;577(7791):E7.

Comment in

Nature. 2019 Nov;575(7782):296-297.

Mitochondria are essential regulators of cellular energy and metabolism, and have

a crucial role in sustaining the growth and survival of cancer cells. A central

function of mitochondria is the synthesis of ATP by oxidative phosphorylation,

known as mitochondrial bioenergetics. Mitochondria maintain oxidative

phosphorylation by creating a membrane potential gradient that is generated by

the electron transport chain to drive the synthesis of ATP1. Mitochondria are

essential for tumour initiation and maintaining tumour cell growth in cell

culture and xenografts2,3. However, our understanding of oxidative mitochondrial

metabolism in cancer is limited because most studies have been performed in vitro

in cell culture models. This highlights a need for in vivo studies to better

understand how oxidative metabolism supports tumour growth. Here we measure

mitochondrial membrane potential in non-small-cell lung cancer in vivo using a

voltage-sensitive, positron emission tomography (PET) radiotracer known as

4-[18F]fluorobenzyl-triphenylphosphonium (18F-BnTP)4. By using PET imaging of

18F-BnTP, we profile mitochondrial membrane potential in autochthonous mouse

models of lung cancer, and find distinct functional mitochondrial heterogeneity

within subtypes of lung tumours. The use of 18F-BnTP PET imaging enabled us to

functionally profile mitochondrial membrane potential in live tumours.

DOI: 10.1038/s41586-019-1715-0

PMID: 31666695

2. Lancet. 2019 Nov 23;394(10212):1929-1939. doi: 10.1016/S0140-6736(19)32222-6.

Epub 2019 Oct 4.

Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line

treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised,

controlled, open-label, phase 3 trial.

Paz-Ares L(1), Dvorkin M(2), Chen Y(3), Reinmuth N(4), Hotta K(5), Trukhin D(6),

Statsenko G(7), Hochmair MJ(8), Özgüro?lu M(9), Ji JH(10), Voitko O(11),

Poltoratskiy A(12), Ponce S(13), Verderame F(14), Havel L(15), Bondarenko I(16),

Kazarnowicz A(17), Losonczy G(18), Conev NV(19), Armstrong J(20), Byrne N(20),

Shire N(21), Jiang H(21), Goldman JW(22); CASPIAN investigators.

Author information:

(1)Department of Medical Oncology, Hospital Universitario 12 de Octubre,

H120-CNIO Lung Cancer Unit, Universidad Complutense and Ciberonc, Madrid, Spain.

Electronic address: lpazaresr@seom.org.

。。。

Comment in

Lancet. 2019 Nov 23;394(10212):1884-1885.

BACKGROUND: Most patients with small-cell lung cancer (SCLC) have extensive-stage

disease at presentation, and prognosis remains poor. Recently, immunotherapy has

demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN

trial assessed durvalumab, with or without tremelimumab, in combination with

etoposide plus either cisplatin or carboplatin (platinum-etoposide) in

treatment-naive patients with ES-SCLC.

METHODS: This randomised, open-label, phase 3 trial was done at 209 sites across

23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO

performance status 0 or 1 and measurable disease as per Response Evaluation

Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a

1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab

plus platinum-etoposide; or platinum-etoposide alone. All drugs were administered

intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m2 on days 1-3

of each cycle with investigator's choice of either carboplatin area under the

curve 5-6 mg/mL per min or cisplatin 75-80 mg/m2 (administered on day 1 of each

cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab

1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance

durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles

of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation

(investigator's discretion) in the platinum-etoposide group. The primary endpoint

was overall survival in the intention-to-treat population. We report results for

the durvalumab plus platinum-etoposide group versus the platinum-etoposide group

from a planned interim analysis. Safety was assessed in all patients who received

at least one dose of their assigned study treatment. This study is registered at

ClinicalTrials.gov, NCT03043872, and is ongoing.

FINDINGS: Patients were enrolled between March 27, 2017, and May 29, 2018. 268

patients were allocated to the durvalumab plus platinum-etoposide group and 269

to the platinum-etoposide group. Durvalumab plus platinum-etoposide was

associated with a significant improvement in overall survival, with a hazard

ratio of 0·73 (95% CI 0·59-0·91; p=0·0047]); median overall survival was 13·0

months (95% CI 11·5-14·8) in the durvalumab plus platinum-etoposide group versus

10·3 months (9·3-11·2) in the platinum-etoposide group, with 34% (26·9-41·0)

versus 25% (18·4-31·6) of patients alive at 18 months. Any-cause adverse events

of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab

plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide

group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients.

INTERPRETATION: First-line durvalumab plus platinum-etoposide significantly

improved overall survival in patients with ES-SCLC versus a clinically relevant

control group. Safety findings were consistent with the known safety profiles of

all drugs received.

FUNDING: AstraZeneca.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S0140-6736(19)32222-6

PMID: 31590988 [Indexed for MEDLINE]

3. Lancet Oncol. 2019 Dec;20(12):1691-1701. doi: 10.1016/S1470-2045(19)30655-2. Epub

2019 Oct 25.

Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre,

open-label, single-arm, phase 1-2 trial.

Shaw AT(1), Solomon BJ(2), Chiari R(3), Riely GJ(4), Besse B(5), Soo RA(6), Kao

S(7), Lin CC(8), Bauer TM(9), Clancy JS(10), Thurm H(11), Martini JF(11), Peltz

G(12), Abbattista A(13), Li S(11), Ou SI(14).

Author information:

(1)Massachusetts General Hospital, Boston, MA, USA. Electronic address:

ashaw1@mgh.harvard.edu.

。。。

BACKGROUND: Lorlatinib is a potent, brain-penetrant, third-generation tyrosine

kinase inhibitor (TKI) that targets ALK and ROS1 with preclinical activity

against most known resistance mutations in ALK and ROS1. We investigated the

antitumour activity and safety of lorlatinib in advanced, ROS1-positive

non-small-cell lung cancer (NSCLC).

METHODS: In this open-label, single-arm, phase 1-2 trial, we enrolled patients

(aged ≥18 years) with histologically or cytologically confirmed advanced

ROS1-positive NSCLC, with or without CNS metastases, with an Eastern Cooperative

Oncology Group performance status of 2 or less (≤1 for phase 1 only) from 28

hospitals in 12 countries worldwide. Lorlatinib 100 mg once daily (escalating

doses of 10 mg once daily to 100 mg twice daily in phase 1 only) was given orally

in continuous 21-day cycles until investigator-determined disease progression,

unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was

overall and intracranial tumour response, assessed by independent central review.

Activity endpoints were assessed in patients who received at least one dose of

lorlatinib. This study is ongoing and is registered with ClinicalTrials.gov,

NCT01970865.

FINDINGS: Between Jan 22, 2014, and Oct 2, 2016, we assessed 364 patients, of

whom 69 with ROS1-positive NSCLC were enrolled. 21 (30%) of 69 patients were

TKI-naive, 40 (58%) had previously received crizotinib as their only TKI, and

eight (12%) had previously received one non-crizotinib ROS1 TKI or two or more

ROS1 TKIs. The estimated median duration of follow-up for response was 21·1

months (IQR 15·2-30·3). 13 (62%; 95% CI 38-82) of 21 TKI-naive patients and 14

(35%; 21-52) of 40 patients previously treated with crizotinib as their only TKI

had an objective response. Intracranial responses were achieved in seven (64%;

95% CI 31-89) of 11 TKI-naive patients and 12 (50%; 29-71) of 24 previous

crizotinib-only patients. The most common grade 3-4 treatment-related adverse

events were hypertriglyceridaemia (13 [19%] of 69 patients) and

hypercholesterolaemia (ten [14%]). Serious treatment-related adverse events

occurred in five (7%) of 69 patients. No treatment-related deaths were reported.

INTERPRETATION: Lorlatinib showed clinical activity in patients with advanced

ROS1-positive NSCLC, including those with CNS metastases and those previously

treated with crizotinib. Because crizotinib-refractory patients have few

treatment options, lorlatinib could represent an important next-line targeted

agent.

FUNDING: Pfizer.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(19)30655-2

PMID: 31669155

4. Lancet Oncol. 2019 Dec;20(12):1670-1680. doi: 10.1016/S1470-2045(19)30519-4. Epub

2019 Oct 7.

Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III,

unresectable non-small-cell lung cancer (PACIFIC): a randomised, controlled,

phase 3 study.

Hui R(1), Özgüro?lu M(2), Villegas A(3), Daniel D(4), Vicente D(5), Murakami

S(6), Yokoi T(7), Chiappori A(8), Lee KH(9), de Wit M(10), Cho BC(11), Gray

JE(8), Rydén A(12), Viviers L(13), Poole L(14), Zhang Y(15), Dennis PA(15),

Antonia SJ(8).

Author information:

(1)Department of Medical Oncology, Westmead Hospital and the University of

Sydney, Sydney, NSW, Australia. Electronic address: rina.hui@sydney.edu.au.

。。。

BACKGROUND: In the ongoing, phase 3 PACIFIC trial, durvalumab improved the

primary endpoints of progression-free survival and overall survival compared with

that for placebo, with similar safety, in patients with unresectable, stage III

non-small-cell lung cancer. In this analysis, we aimed to evaluate one of the

secondary endpoints, patient-reported outcomes (PROs).

METHODS: PACIFIC is an ongoing, international, multicentre, double-blind,

randomised, controlled, phase 3 trial. Eligible patients were aged at least 18

years, had a WHO performance status of 0 or 1, with histologically or

cytologically documented stage III, unresectable non-small-cell lung cancer, for

which they had received at least two cycles of platinum-based chemoradiotherapy,

with no disease progression after this treatment. We randomly assigned patients

(2:1) using an interactive voice response system and a blocked design (block

size=3) stratified by age, sex, and smoking history to receive 10 mg/kg

intravenous durvalumab or matching placebo 1-42 days after concurrent

chemoradiotherapy, then every 2 weeks up to 12 months. The primary endpoints of

progression-free survival and overall survival have been reported previously.

PROs were a prespecified secondary outcome. We assessed PRO symptoms,

functioning, and global health status or quality of life in the

intention-to-treat population with the European Organisation for Research and

Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30)

version 3 and its lung cancer module, the Quality of Life Questionnaire-Lung

Cancer 13 (QLQ-LC13) at the time of random allocation to groups, at weeks 4 and

8, every 8 weeks until week 48, and then every 12 weeks until progression.

Changes from baseline to 12 month in key symptoms were analysed with mixed model

for repeated measures (MMRM) and time-to-event analyses. A 10-point or greater

change from baseline (deterioration or improvement) was deemed clinically

relevant. This study is registered with ClinicalTrials.gov, NCT02125461, and

EudraCT, 2014-000336-42.

FINDINGS: Between May 9, 2014, and April 22, 2016, 476 patients were assigned to

receive durvalumab, and 237 patients were assigned to receive placebo. As of

March 22, 2018, the median follow-up was 25·2 months (IQR 14·1-29·5). More than

79% of patients given durvalumab and more than 82% of patients given placebo

completed questionnaires up to week 48. Between baseline and 12 months, the

prespecified longitudinal PROs of interest, cough (MMRM-adjusted mean change 1·8

[95% CI 0·06 to 3·54] in the durvalumab group vs 0·7 [-1·91 to 3·30] in the

placebo group), dyspnoea (3·1 [1·75 to 4·36] vs 1·4 [-0·51 to 3·34]), chest pain

(-3·1 [-4·57 to -1·60] vs -3·5 [-5·68 to -1·29]), fatigue (-3·0 [-4·53 to -1·50]

vs -5·2 [-7·45 to -2·98]), appetite loss (-5·8 [-7·28 to -4·36] vs -7·0 [-9·17 to -4·87]), physical functioning (0·1 [-1·10 to 1·28] vs 2·0 [0·22 to 3·73]), and global health status or quality of life (2·6 [1·21 to 3·94] vs 1·8 [-0·25 to

3·81]) remained stable with both treatments, with no clinically relevant changes

from baseline. The between-group differences in changes from baseline to 12

months in cough (difference in adjusted mean changes 1·1, 95% CI -1·89 to 4·11),

dyspnoea (1·6, -0·58 to 3·87), chest pain (0·4, -2·13 to 2·93), fatigue (2·2,

-0·38 to 4·78), appetite loss (1·2, -1·27 to 3·67), physical functioning (-1·9,

-3·91 to 0·15), or global health status or quality of life (0·8, -1·55 to 3·14)

were not clinically relevant. Generally, there were no clinically important

between-group differences in time to deterioration of prespecified key PRO

endpoints.

INTERPRETATION: Our findings suggest that a clinical benefit with durvalumab can

be attained without compromising PROs. This result is of note because the

previous standard of care was observation alone, with no presumed detriment to

PROs.

FUNDING: AstraZeneca.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(19)30519-4

PMID: 31601496

5. Nat Med. 2019 Oct;25(10):1549-1559. doi: 10.1038/s41591-019-0592-2. Epub 2019 Oct

7.

Spatial heterogeneity of the T cell receptor repertoire reflects the mutational

landscape in lung cancer.

Joshi K(1)(2), Robert de Massy M(1), Ismail M(3), Reading JL(1), Uddin I(3),

Woolston A(3), Hatipoglu E(1)(2), Oakes T(3), Rosenthal R(4)(5), Peacock T(3)(6),

Ronel T(3)。。。

Author information:

(1)Cancer Immunology Unit, Research Department of Haematology, University College

London Cancer Institute, London, UK.

(2)Department of Medical Oncology, The Royal Marsden NHS Foundation Trust,

London, UK.

。。。

Somatic mutations together with immunoediting drive extensive heterogeneity

within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the

T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively

expanded in tumors varies within and between tumors and correlates with the

number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs

found in all tumor regions (ubiquitous) and those present in a subset of regions

(regional). The number of ubiquitous and regional TCRs correlates with the number

of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs

form part of clusters of TCRs of similar sequence, suggestive of a spatially

constrained antigen-driven process. CD8+ tumor-infiltrating lymphocytes harboring

ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous

TCRs are preferentially detected in the blood at the time of tumor resection as

compared to routine follow-up. These findings highlight a noninvasive method to

identify and track relevant tumor-reactive TCRs for use in adoptive T cell

immunotherapy.

DOI: 10.1038/s41591-019-0592-2

PMCID: PMC6890490 [Available on 2020-04-01]

PMID: 31591606 [Indexed for MEDLINE]

6. Nat Med. 2019 Oct;25(10):1540-1548. doi: 10.1038/s41591-019-0595-z. Epub 2019 Oct

7.

A clonal expression biomarker associates with lung cancer mortality.

Biswas D(1)(2)(3), Birkbak NJ(4)(5)(6)(7), Rosenthal R(1)(2)(3), Hiley CT(1)(3),

Lim EL(1)(3),。。。

Author information:

(1)Cancer Research UK Lung Cancer Centre of Excellence, University College London

Cancer Institute, Paul O'Gorman Building, London, UK.

。。。

An aim of molecular biomarkers is to stratify patients with cancer into disease

subtypes predictive of outcome, improving diagnostic precision beyond clinical

descriptors such as tumor stage1. Transcriptomic intratumor heterogeneity

(RNA-ITH) has been shown to confound existing expression-based biomarkers across

multiple cancer types2-6. Here, we analyze multi-region whole-exome and RNA

sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx

study to explore and control for RNA-ITH in non-small cell lung cancer. We find

that chromosomal instability is a major driver of RNA-ITH, and existing

prognostic gene expression signatures are vulnerable to tumor sampling bias. To

address this, we identify genes expressed homogeneously within individual tumors

that encode expression modules of cancer cell proliferation and are often driven

by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic

biomarkers overcome tumor sampling bias, associate with survival independent of

clinicopathological risk factors, and may provide a general strategy to refine

biomarker design across cancer types.

DOI: 10.1038/s41591-019-0595-z

PMCID: PMC6984959 [Available on 2020-04-01]

PMID: 31591602 [Indexed for MEDLINE]

7. Lancet Oncol. 2019 Dec;20(12):1655-1669. doi: 10.1016/S1470-2045(19)30634-5. Epub

2019 Oct 4.

Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced

non-small-cell lung cancer (RELAY): a randomised, double-blind,

placebo-controlled, phase 3 trial.

Nakagawa K(1), Garon EB(2), Seto T(3), Nishio M(4), Ponce Aix S(5), 。。。

Author information:

(1)Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka,

Japan. Electronic address: nakagawa@med.kindai.ac.jp.

。。。

BACKGROUND: Dual blockade of the EGFR and VEGF pathways in EGFR-mutated

metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and

clinical data, yet the approach is not widely implemented. RELAY assessed

erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus

ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with

untreated EGFR-mutated metastatic NSCLC.

METHODS: This is a worldwide, double-blind, phase 3 trial done in 100 hospitals,

clinics, and medical centres in 13 countries. Eligible patients were aged 18

years or older (20 years or older in Japan and Taiwan) at the time of study

entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21

substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group

performance status of 0 or 1, and no CNS metastases. We randomly assigned

eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus

either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks.

Randomisation was done by an interactive web response system with a

computer-generated sequence and stratified by sex, geographical region, EGFR

mutation type, and EGFR testing method. The primary endpoint was

investigator-assessed progression-free survival in the intention-to-treat

population. Safety was assessed in all patients who received at least one dose of

study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and

is ongoing for long-term survival follow-up.

FINDINGS: Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were

enrolled and randomly assigned to treatment with ramucirumab plus erlotinib

(n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7

months (IQR 15·8-27·2). At the time of primary analysis, progression-free

survival was significantly longer in the ramucirumab plus erlotinib group (19·4

months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months

[11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76;

p<0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%)

of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225

in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent

adverse events in the ramucirumab plus erlotinib group were hypertension (52

[24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus

erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine

aminotransferase (17 [8%]). Treatment-emergent serious adverse events were

reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and

47 (21%) of 225 in the placebo plus erlotinib group. The most common serious

adverse events of any grade in the ramucirumab plus erlotinib group were

pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the

most common in the placebo plus erlotinib group were pyrexia (four [2%]) and

pneumothorax (three [1%]). One on-study treatment-related death due to an adverse

event occurred (haemothorax after a thoracic drainage procedure for a pleural

empyema) in the ramucirumab plus erlotinib group.

INTERPRETATION: Ramucirumab plus erlotinib demonstrated superior progression-free

survival compared with placebo plus erlotinib in patients with untreated

EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of

the individual compounds in advanced lung cancer. The RELAY regimen is a viable

new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.

FUNDING: Eli Lilly.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(19)30634-5

PMID: 31591063

8. Lancet Oncol. 2019 Dec;20(12):1681-1690. doi: 10.1016/S1470-2045(19)30504-2. Epub

2019 Oct 3.

Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung

cancer: results from the dose escalation and dose expansion parts of a

first-in-human, open-label, multicentre, phase 1-2 study.

Ahn MJ(1), Han JY(2), Lee KH(3), Kim SW(4), Kim DW(5), Lee YG(6), Cho EK(7), Kim

JH(8), Lee GW(9), Lee JS(10), Min YJ(11), Kim JS(12), Lee SS(13), Kim HR(14),

Hong MH(14), Ahn JS(1), Sun JM(1), Kim HT(2), Lee DH(4), Kim S(15), Cho BC(16).

Author information:

(1)Division of Hematology-Oncology, Department of Medicine, Samsung Medical

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

。。。

Erratum in

Lancet Oncol. 2020 Feb;21(2):e70.

BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) given

EGFR tyrosine kinase inhibitors (TKIs) inevitably become resistant to

first-generation or second-generation drugs. We assessed the safety,

tolerability, pharmacokinetics, and activity of lazertinib-an irreversible,

third-generation, mutant-selective, EGFR TKI-in patients with advanced NSCLC

progressing after EGFR TKI therapy.

METHODS: This first-in-human, open-label, multicentre, phase 1-2 study had three

parts: dose escalation, dose expansion, and dose extension; here, we report

results on dose escalation and dose expansion. The study was done in 14 hospitals

in Korea. Eligible patients were aged 20 years or older and had advanced NSCLC

harbouring an activating EGFR mutation and progressing after first-generation or

second-generation EGFR TKI treatment, a defined tumour T790M mutation status, an

Eastern Cooperative Oncology Group performance status of 0-1, at least one

measurable extracranial lesion, defined according to Response Evaluation Criteria

in Solid Tumors (RECIST) version 1.1, and adequate organ function. Patients were

enrolled to seven dose-escalation cohorts according to a rolling six design; five

cohorts were expanded. Patients were given oral lazertinib 20 mg, 40 mg, 80 mg,

120 mg, 160 mg, 240 mg, or 320 mg once daily continuously in 21-day cycles.

Primary endpoints were safety and tolerability and secondary endpoints included

objective response in evaluable patients. This study is registered with

ClinicalTrials.gov, NCT03046992, and the phase 2 extension study is ongoing.

FINDINGS: Between Feb 15, 2017, and May 28, 2018, 127 patients were enrolled into

the dose escalation group (n=38) and dose expansion group (n=89). No

dose-limiting toxicities occurred. There was no dose-dependent increase in

adverse events. The most commonly reported adverse events were grade 1-2 rash or

acne (in 38 [30%] of 127 patients) and pruritus (in 34 [27%]). Grade 3 or grade 4

adverse events occurred in 20 (16%) patients, with the most common being grade 3

pneumonia (four [3%]). Treatment-related grade 3 or 4 adverse events occurred in

four (3%) patients; treatment-related serious adverse events were reported in six

patients (5%). There were no adverse events with an outcome of death and no

treatment-related deaths. The proportion of patients achieving an objective

response by independent central review assessment was 69 (54%; 95% CI 46-63) of

127.

INTERPRETATION: Lazertinib had a tolerable safety profile and showed promosing

clinical activity in patients with NSCLC progressing on or after EGFR TKI

therapy. Our findings provide a rationale for further clinical investigations.

FUNDING: Yuhan Corporation.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(19)30504-2

PMID: 31587882

9. Lancet Oncol. 2019 Oct;20(10):e582-e589. doi: 10.1016/S1470-2045(19)30335-3. Epub

2019 Sep 30.

US Food and Drug Administration review of statistical analysis of

patient-reported outcomes in lung cancer clinical trials approved between

January, 2008, and December, 2017.

Fiero MH(1), Roydhouse JK(2), Vallejo J(3), King-Kallimanis BL(2), Kluetz PG(4),

Sridhara R(3).

Author information:

(1)Office of Biostatistics, Center for Drug Evaluation and Research, US Food and

Drug Administration, Silver Spring, MD, USA. Electronic address:

mallorie.fiero@fda.hhs.gov.

(2)Office of Hematology and Oncology Products, Center for Drug Evaluation and

Research, US Food and Drug Administration, Silver Spring, MD, USA.

(3)Office of Biostatistics, Center for Drug Evaluation and Research, US Food and

Drug Administration, Silver Spring, MD, USA.

(4)Oncology Center of Excellence, US Food and Drug Administration, Silver Spring,

MD, USA.

With the advent of patient-focused drug development, the US Food and Drug

Administration (FDA) has redoubled its efforts to review patient-reported outcome

(PRO) data in cancer trials submitted as part of a drug's marketing application.

This Review aims to characterise the statistical analysis of PRO data from

pivotal lung cancer trials submitted to support FDA drug approval between

January, 2008, and December, 2017. For each trial and PRO instrument identified,

we evaluated prespecified PRO concepts, statistical analysis, missing data and

sensitivity analysis, instrument completion, and clinical relevance. Of the 37

pivotal lung cancer trials used to support FDA drug approval, 25 (68%) trials

included PRO measures. The most common prespecified PRO concepts were cough,

dyspnoea, and chest pain. At the trial level, the most common statistical

analyses were descriptive (24 trials [96%]), followed by time-to-event analyses

(19 trials [76%]), longitudinal analyses (12 trials [48%]), and basic inferential

tests or general linear models (10 trials [40%]). Our findings indicate a wide

variation in the analytic techniques and data presentation methods used, with

very few trials reporting clear PRO research objectives and sensitivity analyses

for PRO results. Our work further supports the need for focused research

objectives to justify and to guide the analytic strategy of PROs to facilitate

the interpretation of patient experience.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(19)30335-3

PMID: 31579004

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.

。。。

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 Commun. 2019 Oct 25;10(1):4892. doi: 10.1038/s41467-019-12801-6.

YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression.

Shi Y(1)(2), Fan S(3), Wu M(4), Zuo Z(5), Li X(5), Jiang L(1), Shen Q(1)(2), Xu

P(1), Zeng L(1)(2), Zhou Y(4), Huang Y(4), Yang Z(4), Zhou J(1), Gao J(6), Zhou

H(6), Xu S(7)(8), Ji H(9), Shi P(8)(10), Wu DD(11)(12), Yang C(13), Chen

Y(14)(15).

Author information:

(1)Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese

Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming,

Yunnan, 650223, China.

。。。

Hypoxia occurs naturally at high-altitudes and pathologically in hypoxic solid

tumors. Here, we report that genes involved in various human cancers evolved

rapidly in Tibetans and six Tibetan domestic mammals compared to reciprocal

lowlanders. Furthermore, m6A modified mRNA binding protein YTHDF1, one of

evolutionary positively selected genes for high-altitude adaptation is amplified

in various cancers, including non-small cell lung cancer (NSCLC). We show that

YTHDF1 deficiency inhibits NSCLC cell proliferation and xenograft tumor formation

through regulating the translational efficiency of CDK2, CDK4, and cyclin D1, and

that YTHDF1 depletion restrains de novo lung adenocarcinomas (ADC) progression.

However, we observe that YTHDF1 high expression correlates with better clinical

outcome, with its depletion rendering cancerous cells resistant to cisplatin

(DDP) treatment. Mechanistic studies identified the Keap1-Nrf2-AKR1C1 axis as the

downstream mediator of YTHDF1. Together, these findings highlight the critical

role of YTHDF1 in both hypoxia adaptation and pathogenesis of NSCLC.

DOI: 10.1038/s41467-019-12801-6

PMCID: PMC6814821

PMID: 31653849

12. Ann Intern Med. 2019 Oct 22. doi: 10.7326/M19-1263. [Epub ahead of print]

Life-Gained-Based Versus Risk-Based Selection of Smokers for Lung Cancer

Screening.

Cheung LC(1), Berg CD(1), Castle PE(2), Katki HA(1), Chaturvedi AK(1).

Author information:

(1)National Cancer Institute, Bethesda, Maryland (L.C.C., C.D.B., H.A.K.,

A.K.C.).

(2)Albert Einstein School of Medicine, Bronx, New York (P.E.C.).

Background: Although risk-based selection of ever-smokers for screening could

prevent more lung cancer deaths than screening according to the U.S. Preventive

Services Task Force (USPSTF) guidelines, it preferentially selects older

ever-smokers with shorter life expectancies due to comorbidities.

Objective: To compare selection of ever-smokers for screening based on gains in

life expectancy versus lung cancer risk.

Design: Cohort analyses and model-based projections.

Setting: U.S. population of ever-smokers aged 40 to 84 years.

Participants: 130 964 National Health Interview Survey participants, representing

about 60 million U.S. ever-smokers during 1997 to 2015.

Intervention: Annual computed tomography (CT) screening for 3 years versus no

screening.

Measurements: Estimated number of lung cancer deaths averted and life-years

gained after development of a mortality model.

Results: Using the calibrated and validated mortality model in U.S. ever-smokers

aged 40 to 84 years and selecting 8.3 million ever-smokers to match the number

selected by the USPSTF criteria in 2013 to 2015, the analysis estimated that

life-gained-based selection would increase the total life expectancy from CT

screening (633 400 vs. 607 800 years) but prevent fewer lung cancer deaths

(52 600 vs. 55 000) compared with risk-based selection. The 1.56 million persons

selected by the life-gained-based strategy but not the risk-based strategy were

younger (mean age, 59 vs. 75 years) and had fewer comorbidities (mean, 0.75 vs.

3.7).

Limitation: Estimates are model-based and assume implementation of lung cancer

screening with short-term effectiveness similar to that from trials.

Conclusion: Life-gained-based selection could maximize the benefits of lung

cancer screening in the U.S. population by including ever-smokers who have both

high lung cancer risk and long life expectancy.

Primary Funding Source: Intramural Research Program of the National Cancer

Institute, National Institutes of Health.

DOI: 10.7326/M19-1263

PMID: 31634914

13. Cell Metab. 2019 Dec 3;30(6):1107-1119.e8. doi: 10.1016/j.cmet.2019.09.014. Epub

2019 Oct 10.

A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and

Metastasis of Non-Small-Cell Lung Cancer.

Huang K(1), Liang Q(2), Zhou Y(2), Jiang LL(1), Gu WM(2), Luo MY(2), Tang YB(2),

Wang Y(2), Lu W(3), Huang M(4), Zhang SZ(5), Zhuang GL(5), Dai Q(6), Shen QC(7),

Zhang J(7), Lei HM(2), Zhu L(2), Ye DY(1), Chen HZ(8), Zhou L(9), Shen Y(10).

Author information:

(1)Department of Medicinal Chemistry, School of Pharmacy, Fudan University,

Shanghai 201203, China.

。。。

Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and

tumor progression via its metabolic activity and interaction with other proteins

like α-smooth muscle actin (ACTA2). Allosteric regulation is considered to be an

innovative strategy to discover a highly selective and potent inhibitor targeting

PGAM1. Here, we identified a novel PGAM1 allosteric inhibitor, HKB99, via

structure-based optimization. HKB99 acted to allosterically block conformational

change of PGAM1 during catalytic process and PGAM1-ACTA2 interaction. HKB99

suppressed tumor growth and metastasis and overcame erlotinib resistance in

non-small-cell lung cancer (NSCLC). Mechanistically, HKB99 enhanced the oxidative

stress and altered multiple signaling pathways including the activation of

JNK/c-Jun and suppression of AKT and ERK. Collectively, the study highlights the

potential of PGAM1 as a therapeutic target in NSCLC and reveals a distinct

mechanism by which HKB99 inhibits both metabolic activity and nonmetabolic

function of PGAM1 by allosteric regulation.

Copyright © 2019 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cmet.2019.09.014

PMID: 31607564

14. Cancer Discov. 2019 Oct;9(10):1340-1342. doi: 10.1158/2159-8290.CD-19-0850.

Temozolomide plus PARP Inhibition in Small-Cell Lung Cancer: Could

Patient-Derived Xenografts Accelerate Discovery of Biomarker Candidates?

Pacheco JM(1), Byers LA(2).

Author information:

(1)Department of Internal Medicine, Division of Medical Oncology, University of

Colorado Anschutz Cancer Center, Aurora, Colorado. jose.m.pacheco@cuanschutz.edu.

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

MD Anderson Cancer Center, Houston, Texas.

Comment on

Cancer Discov. 2019 Aug 15;:.

Effective options are limited for patients with small-cell lung cancer who

develop progressive disease during or after etoposide plus platinum-based

therapy. In this issue of Cancer Discovery, Farago and colleagues highlight the

data for temozolomide plus olaparib in this patient population and demonstrate

the potential to accelerate biomarker discovery through co-clinical trials

utilizing patient-derived xenografts.See related article by Farago et al., p.

1372.

©2019 American Association for Cancer Research.

DOI: 10.1158/2159-8290.CD-19-0850

PMID: 31575562 [Indexed for MEDLINE]

15. 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.

(4)Beth Israel Deaconess Medical Center, Boston, Massachusetts.

(5)Department of Radiology, Massachusetts General Hospital, Boston,

Massachusetts.

(6)Howard Hughes Medical Institute, Bethesda, Maryland.

(7)Harvard Medical School, 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

16. Am J Respir Crit Care Med. 2019 Oct 1;200(7):888-899. doi:

10.1164/rccm.201807-1292OC.

YES1 Drives Lung Cancer Growth and Progression and Predicts Sensitivity to

Dasatinib.

Garmendia I(1)(2), Pajares MJ(1)(2)(3)(4), Hermida-Prado F(3)(5), Ajona

D(1)(6)(3)(4), Bértolo C(1)(3), Sainz C(1), Lavín A(1), Remírez AB(1), 。。。

Author information:

(1)Program in Solid Tumors, Center for Applied Medical Research, Pamplona, Spain.

。。。

Comment in

Am J Respir Crit Care Med. 2019 Oct 1;200(7):802-804.

Rationale: The characterization of new genetic alterations is essential to assign

effective personalized therapies in non-small cell lung cancer (NSCLC).

Furthermore, finding stratification biomarkers is essential for successful

personalized therapies. Molecular alterations of YES1, a member of the SRC

(proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found

in a significant subset of patients with lung cancer.Objectives: To evaluate YES1

(v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a

therapeutic target and predictive biomarker of response to dasatinib in

NSCLC.Methods: Functional significance was evaluated by in vivo models of NSCLC

and metastasis and patient-derived xenografts. The efficacy of pharmacological

and genetic (CRISPR [clustered regularly interspaced short palindromic

repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated.

In vitro functional assays for signaling, survival, and invasion were also

performed. The association between YES1 alterations and prognosis was evaluated

in clinical samples.Measurements and Main Results: We demonstrated that YES1 is

essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced

metastatic spread in preclinical in vivo models. YES1 genetic depletion by

CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1

effects were mainly driven by mTOR (mammalian target of rapamycin) signaling.

Interestingly, cell lines and patient-derived xenograft models with YES1 gene

amplifications presented a high sensitivity to dasatinib, an SFK inhibitor,

pointing out YES1 status as a stratification biomarker for dasatinib response.

Moreover, high YES1 protein expression was an independent predictor for poor

prognosis in patients with lung cancer.Conclusions: YES1 is a promising

therapeutic target in lung cancer. Our results provide support for the clinical

evaluation of dasatinib treatment in a selected subset of patients using YES1

status as predictive biomarker for therapy.

DOI: 10.1164/rccm.201807-1292OC

PMID: 31166114