NSCLC, LOCALLY ADVANCED
LBA3ePR
An international randomized trial, comparing post-operative
conformal radiotherapy (PORT) to no PORT, in patients with
completely resected non-small cell lung cancer (NSCLC) and
mediastinal N2 involvement: Primary end-point analysis of
LungART (IFCT-0503, UK NCRI, SAKK) NCT00410683
C. Le Pechoux
1, N. Pourel
2, F. Barlesi
3, C. Faivre-Finn
4, D. Lerouge
5, G. Zalcman
6,
D. Antoni
7, B. Lamezec
8, U. Nestle
9, P. Boisselier
10, F. Thillays
11, A. Paumier
12,
E. Dansin
13, K. Peignaux
14, J. Madelaine
15, E. Pichon
16, A. Larrouy
17, O. Riesterer
18,
A. Lavole
19, A. Bardet
201
Radiation Oncology, Gustave Roussy, Villejuif, France;
2Radiation Oncology, Institut
Sainte Catherine, Avignon, France;
3France and Institut Gustave Roussy, Aix Marseille
Université, Aix-Marseille University, CRCM, AP-HM, Marseille, Villejuif, France;
4Clinical
Oncology, The University of Manchester and The Christie NHS Foundation Trust,
Manchester, UK;
5Radiation Oncology, Centre Baclesse, Caen, France;
6Department of
Thoracic Oncology and CIC1425, Hôpital Bichat-Claude Bernard, Assistance Publique
Hôpitaux de Paris, Université Paris-Diderot, Paris, France;
7Radiation Oncology, Institut de
Cancérologie Strasbourg Europe, Strasbourg, France;
8Radiation Oncology, Clinique
Armoricaine de Radiologie, St. Brieuc, France;
9Radiation Oncology, Universitätsklinikum
Freiburg Klinik für Innere Medizin Hämatologie, Onkologie und Stammzelltransplantation,
Freiburg Im Breisgau, Germany;
10Radiation Oncology, ICM Regional Cancer Institute of
Montpellier, Montpellier, France;
11Radiation Oncology, Institut de Cancérologie de
l
’Ouest, Saint Herblain, France;
12Radiation Oncology, ICO Site Paul Papin, Angers, France;
13Medical Oncology, Centre Oscar Lambret, Lille, France;
14Radiation Oncology, Centre
Georges Francois Leclerc, Dijon, France;
15Medical Oncology, Centre Hospitalier Caen,
Caen, France;
16Pneumology, CHRU Bretonneau, Tours, France;
17Radiation Oncology,
Centre de Cancerologie Paris Nord, Sarcelles, France;
18Radiation Oncology, University
Hospital Zurich and Center for Radiation Oncology KSA-KSB, Cantonal Hospital Aurau,
Zurich, Switzerland;
19Pneumology, Hopital Tenon, Paris, France;
20Biostatistics, Institut
Gustave Roussy, Villejuif, France
Background:
Adjuvant PORT has been controversial since publication of a
meta-analysis showing PORT could be deleterious especially in pN0 pN1 pts. However,
changes have taken place in the management of stage IIIAN2 NSCLC pts including use
of adjuvant chemotherapy (CT), patients
’ workup, quality of surgery and radiotherapy.
Therefore the role of PORT warranted further investigations in high risk pts.
Methods:
LungART is a multi-institutional randomized phase III trial comparing
medi-astinal PORT (54 Gy/27-30 fractions) to no PORT. Pts were eligible if they were PS 0-2, had
a complete resection with nodal exploration, proven N2 disease; prior (neo)-adjuvant CT
was allowed. The main end-point was disease-free survival (DFS). 500 pts and 292 events
were required to show an improvement in DFS from 30% to 42% with PORT (bilateral test).
Secondary endpoints included toxicity, local control, patterns of recurrence, overall
sur-vival (OS), second cancers, prognostic and predictive factors of treatment effect.
Results:
Between August 2007 and July 2018, 501 patients were randomized after
surgery or after CT: 252 pts allocated to PORT, and 249 to CA. Median age was 61
(range
¼36-85), 66% male, histology: mostly adenocarcinoma (73%) and work-up
included PET scan in 91% pts. Most patients received CT (post op 77%, pre-op 18%).
Analysis for DFS was performed with a median FU of 4.8 yrs; toxicity evaluated on 487
pts (246 in CA). Early and late Gr 3-5 cardio-pulmonary toxicity was respectively 7 and
20% in PORT vs 3,2 and 7,7 % in CA. DFS hazard ratio was 0.85 (95% CI 0.67; 1.07);
p
¼0.16; median DFS was 30.5 months in PORT arm [24;48] and 22.8 in CA [17;37];
3-year DFS was 47.1% with PORT vs 43.8% with no PORT. 3-3-year OS was 66.5% with
PORT vs 68.5% with no PORT.
Conclusions:
LungART is the
first European randomized study evaluating modern
PORT after complete resection, in pts selected predominantly with PET scan and
having received (neo)adjuvant CT. 3-year DFS was higher than expected in both arms
and PORT was associated with a non-statistically signi
ficant 15% increase in DFS
among stage IIIAN2 pts.
Clinical trial identi
fication:
NCT00410683.
Legal entity responsible for the study:
Gustave Roussy.
Funding:
French National Cancer Institute (INCa), French Health Ministry (PHRC),
Gustave Roussy and CRUK grant (A13969).
Disclosure:
C. Le Pechoux: Honoraria (institution): Amgen; Honoraria (institution), Advisory/Con-sultancy: AstraZeneca; Honoraria (institution): Lilly; Honoraria (self): PrimeOncology; Honoraria (institution): Medscape; Honoraria (institution), Advisory/Consultancy: Roche; Honoraria (institution), Advisory/Consultancy: Nanobiotix. F. Barlesi: Honoraria (self), Personal fees: AstraZeneca; Honoraria (self): Bayer; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Boehringer-Ingelheim; Honoraria (self): Eli Lilly Oncology; Honoraria (self): F. Hoffmann-La Roche Ltd.; Honoraria (self): Novartis; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Takeda. C. Faivre-Finn: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Elekta. G. Zalcman: Research grant/Funding (insti-tution): Fondation Roche; Honoraria (self), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: BMS; Honoraria (self): MSD; Honoraria (self), Advisory/Con-sultancy: Inventiva; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Abb-Vie; Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Da Volterra. J. Madelaine: Honoraria (self), Dr JM received support: AstraZeneca; Honoraria (self): Chugai Pharma; Honoraria (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): MSD France; Honoraria (self): Roche SAS; Honoraria (self): Actelion; Honoraria (self): GSK; Honoraria (self): Bristol-Myers Squibb. A. Bardet: Advisory/Consultancy: Roche. All other authors have declared no conflicts of interest.https://doi.org/10.1016/j.annonc.2020.08.2280
LBA49
Durvalumab after chemoradiotherapy in stage III NSCLC: 4-year
survival update from the phase III PACIFIC trial
C. Faivre-Finn
1, D. Vicente
2, T. Kurata
3, D. Planchard
4, L. Paz-Ares
5,
J.F. Vansteenkiste
6, D.R. Spigel
7, M.C. Garassino
8, M. Reck
9, S. Senan
10,
J. Naidoo
11,12, A. Rimner
12, Y-L. Wu
13, J.E. Gray
14, M. Özgüro
glu
15, K.H. Lee
16,
M. Newton
17, L. Wang
17, P. Thiyagarajah
18, S.J. Antonia
141
The University of Manchester and The Christie NHS Foundation Trust, Manchester,
UK;
2Hospital Universitario Virgen Macarena, Seville, Spain;
3Kansai Medical
Univer-sity Hospital, Hirakata, Japan;
4Department of Medical Oncology, Thoracic Unit,
Gustave Roussy, Villejuif, France;
5Hospital Universitario 12 de Octubre, CiberOnc,
Universidad Complutense and CNIO, Madrid, Spain;
6Department of Respiratory
Oncology, University Hospitals KU Leuven, Leuven, Belgium;
7Sarah Cannon Research
Institute/Tennessee Oncology, Nashville, TN, USA;
8Fondazione IRCCS Istituto
Nazio-nale dei Tumori, Milan, Italy;
9Lung Clinic Grosshansdorf, Airway Research Center
North, German Center for Lung Research, Grosshansdorf, Germany;
10Department of
Radiation Oncology, Amsterdam University Medical Centers, Vrije Universiteit
Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands;
11Sidney Kimmel
Comprehensive Cancer Center and Bloomberg-Kimmel Institute for Cancer
Immuno-therapy, Johns Hopkins University, Baltimore, MD, USA;
12Department of Radiation
Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA;
13Department
of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General
Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China;
14H. Lee
Mof
fitt Cancer Center and Research Institute, Tampa, FL, USA;
15Istanbul
University-Cerrahpas¸a, Cerrahpas¸a School of Medicine, Istanbul, Turkey;
16Chungbuk National
University Hospital, Chungbuk National University College of Medicine, Cheongju,
Republic of Korea;
17AstraZeneca, Gaithersburg, MD, USA;
18AstraZeneca, Cambridge,
UK
Background:
In the phase III PACIFIC trial of patients (pts) with unresectable Stage III
NSCLC without disease progression after concurrent chemoradiotherapy (cCRT),
durvalumab signi
ficantly improved progression-free survival (PFS; stratified HR 0.52,
95% CI 0.42
e0.65; P<0.0001; median 16.8 vs 5.6 months; data cutoff [DCO], 13 Feb
2017) and overall survival (OS; strati
fied HR 0.68, 95% CI 0.53e0.87; P¼0.0025;
median not reached vs 28.7 months; DCO, 22 Mar 2018) vs placebo (pbo), with
manageable safety. We report updated, exploratory analyses of survival outcomes at
4 years, including the
first estimate of median OS for the durvalumab arm.
Methods:
Pts with WHO PS 0/1 (any tumour PD-L1 status) who had received
2
cycles of platinum-based cCRT (RT dosage typically 60
e66 Gy in 30e33 fractions)
were enrolled and randomised (2:1), 1
e42 days post-cCRT, to IV durvalumab 10 mg/
kg or pbo (q2w for
12 months), stratified by age, sex, and smoking history. Primary
endpoints were PFS (blinded independent central review; RECIST v1.1) and OS (both
measured from the time of randomisation). HRs and 95% CIs were estimated using a
strati
fied log-rank test in the ITT population. Medians and OS/PFS rates at 48 months
were estimated by Kaplan
eMeier method.
Results:
In total, 709/713 randomised patients received durvalumab (n/N
¼473/476)
and pbo (n/N
¼236/237). The last pt had completed study treatment in May 2017,
almost 3 years prior to the current DCO. As of 20 Mar 2020 (current DCO; median
follow up, 34.2 months [range, 0.2
e64.9]), updated PFS (stratified HR 0.55, 95% CI
0.44
e0.67; median 17.2 vs 5.6 months) and OS (stratified HR 0.71, 95% CI 0.57e0.88)
remained consistent with previous reports. Median OS for the durvalumab arm was
determined for the
first time: 47.5 months (pbo, 29.1 months). The 48-month OS
rates were 49.6% vs 36.3% for durvalumab vs pbo, and PFS rates were 35.3% vs 19.5%
respectively. Updates to treatment effects for pt subgroups will be reported.
Conclusions:
These updated analyses of PFS and OS demonstrate durable bene
fit with
durvalumab after cCRT. Approximately half of patients randomised to durvalumab in
PACIFIC remain alive at 4 years, and about a third remain both alive and progression
free, almost 3 years after the last pt completed study treatment.
Clinical trial identi
fication:
NCT02125461.
Editorial acknowledgement:
Medical writing support, which was in accordance with
Good Publication Practice (GPP3) guidelines, was provided by Aaron Korpal, PhD, of
Cirrus Communications (Manchester, UK), an Ash
field company, and was funded by
AstraZeneca.
Legal entity responsible for the study:
AstraZeneca.
Funding:
AstraZeneca.
Disclosure:
C. Faivre-Finn: Advisory/Consultancy, Research grant/Funding (institution), Travel/Ac-commodation/Expenses: AstraZeneca; Research grant/Funding (institution), Travel/Accommodation/ Expenses: Elekta. D. Vicente: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/ Funding (institution): Roche. T. Kurata: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self): Ono; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant/ Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (institution): Chugai; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Takeda. D. Planchard: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Celgene; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Merck; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: prIME Oncology; Advisory/Consul-tancy: Peer CME; Advisory/ConsulAdvisory/Consul-tancy: Roche; Advisory/ConsulAdvisory/Consul-tancy: Samsung. L. Paz-Ares: Advi-sory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: MSD;Annals of Oncology
abstracts
Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommo-dation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accom-modation/Expenses: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eli Lilly; Advisory/Consultancy: Merck; Advisory/Consultancy: Novartis; Advisory/Consultancy: Angem; Advisory/Consultancy: Incyte; Advisory/Consultancy: Takeda; Advisory/Consultancy: Blueprint; Advisory/Consultancy: Bayer; Leadership role: Altum Sequencing; Leadership role: Genomica; Advisory/Consultancy: PharmaMar; Advisory/Consultancy: Ipsen. J.F. Vansteenkiste: Advisory/Con-sultancy: Boehringer Ingelheim; Advisory/ConAdvisory/Con-sultancy: AstraZeneca; Advisory/ConAdvisory/Con-sultancy: MSD; Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche; Advisory/Consultancy: Pfizer; Advi-sory/Consultancy: Bristol-Myers Squibb. D.R. Spigel: Honoraria (institution), Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Aeglea Biotherapeutics; Research grant/Funding (institution): Agios; Research grant/Funding (institution): Astellas Pharma; Research grant/Funding (institution): Bind Therapeutics; Honoraria (institution), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (institution), Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Celldex Therapeutics; Research grant/Funding (institution): Clovis; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Eli Lilly; Honoraria (institution), Research grant/Funding (institution): EMD Serono; Honoraria (institution), Research grant/Funding tion): Roche/Genentech; Research grant/Funding (institution): G1 Therapeutics; Honoraria (institu-tion), Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Grail; Research grant/Funding (institution): ImClone Systems; Honoraria (institution), Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Janssen; Research grant/ Funding (institution): Merck; Research grant/Funding (institution): Nektar Therapeutics; Research grant/Funding (institution): Neon Therapeutics; Honoraria (institution), Research grant/Funding (institution): Novartis; Honoraria (institution), Research grant/Funding (institution): Takeda Phar-maceuticals; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): Transgene; Research grant/Funding (institution): UT Southwestern; Research grant/Funding (insti-tution): Cyteir Therapeutics; Research grant/Funding (insti(insti-tution): Apollomics; Research grant/ Funding (institution): Elevation Oncology; Honoraria (institution): Aptitude Health; Honoraria (institution): Bayer; Honoraria (institution): Dracen Pharmaceuticals; Honoraria (institution): Exelixis; Honoraria (institution): Iksuda Therapeutics; Honoraria (institution): Intellisphere; Honoraria (insti-tution): Jazz Pharmaceuticals; Honoraria (insti(insti-tution): Mirati Therapeutics; Honoraria (insti(insti-tution): Molecular Templates; Honoraria (institution): Puma Biotechnology. M.C. Garassino: Advisory/Con-sultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Non-remunerated activity/ies: Eli Lilly; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Otsuka Pharma; Advisory/Consul-tancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca; Advi-sory/Consultancy, Research grant/Funding (institution): Novartis; AdviAdvi-sory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Bristol-Myers Squibb; Advisory/Consul-tancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche; Advisory/ Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies: Pfizer; Advisory/ Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Celgene; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Incyte; Advisory/Consultancy: Inivata; Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Research grant/Funding (institution): Tiziana Sciences; Research grant/Funding (institution): Clovis; Research grant/Funding (institution): Merck Serono; Advisory/Consultancy, Research grant/ Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution),
Non-remunerated activity/ies: MSD; Advisory/Consultancy, Research grant/Funding (institution): Glax-oSmithKline S.p.A.; Advisory/Consultancy: Sanofi-Aventis; Advisory/Consultancy, Research grant/ Funding (institution): Spectrum Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicine; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Daiichi Sankyo; Research grant/Funding (institution): United Therapeutics Corporation; Research grant/Funding (institution): Merck KGaA; Advisory/Consultancy: Janssen. M. Reck: Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: Eli Lilly; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Samsung. S. Senan: Honoraria (self), Research grant/ Funding (institution): AstraZeneca; Research grant/Funding (institution): ViewRay Inc.; Honoraria (self): Celgene; Honoraria (self): MSD; Honoraria (self), Research grant/Funding (institution): Varian Medical Systems. J. Naidoo: Honoraria (self), Advisory/Consultancy, Research grant/Funding (insti-tution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Research grant/ Funding (institution): Roche/Genentech; Honoraria (self), Advisory/Consultancy, Travel/Accommo-dation/Expenses: Bristol-Myers Squibb; Research grant/Funding (institution): Merck. A. Rimner: Research grant/Funding (institution): Varian Medical Systems; Honoraria (self), Research grant/ Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Merck; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Pfizer; Honoraria (self): Research to Practice; Honoraria (self): Cybrexa; Honoraria (self): More Health; Non-remunerated activity/ies: Philips/Elektra. Y-L. Wu: Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca; Speaker Bureau/Expert testimony: Boehringer Ingelheim; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bristol-Myers Squibb; Speaker Bureau/Expert testimony: Eli Lilly; Speaker Bureau/Expert testimony: MSD; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer; Speaker Bureau/Expert tes-timony: Sanofi. J.E. Gray: Advisory/Consultancy: AstraZeneca; Research grant/Funding (institution): Genentech; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consul-tancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/ConsulAdvisory/Consul-tancy, Research grant/Funding (institution): Merck KGaA; Advisory/Consultancy, Research grant/Funding (institu-tion): Novartis; Research grant/Funding (institu(institu-tion): Boehringer Ingelheim. M. Özgüroglu: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Honoraria (self), Advisory/ Consultancy: Sanofi; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Speaker Bureau/ Expert testimony: Astellas; Honoraria (self): Novartis; Honoraria (self): Roche; Travel/Accommoda-tion/Expenses: Bristol-Myers Squibb. K.H. Lee: Advisory/Consultancy: Bristol-Myers Squibb; Advi-sory/Consultancy: MSD; AdviAdvi-sory/Consultancy: AstraZeneca; AdviAdvi-sory/Consultancy: Pfizer. M. Newton: Full/Part-time employment: AstraZeneca. L. Wang: Full/Part-time employment: AstraZe-neca. P. Thiyagarajah: Shareholder/Stockholder/Stock options, Full/Part-time employment: Astra-Zeneca. S.J. Antonia: Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy: CBMG; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Memgen; Advisory/Consultancy, Travel/Accommodation/Expenses: RAPT; Advisory/Consultancy: Venn; Advi-sory/Consultancy, Travel/Accommodation/Expenses: Achilles Therapeutics; AdviAdvi-sory/Consultancy, Travel/Accommodation/Expenses: Celsius; Advisory/Consultancy: Samyang Biopharma; Advisory/ Consultancy, Travel/Accommodation/Expenses: GlaxoSmithKline; Advisory/Consultancy, Travel/Ac-commodation/Expenses: Amgen; Travel/AcTravel/Ac-commodation/Expenses: Merck; Research grant/Funding (institution): Novartis.
