PD-1 Inhibitor and Chemotherapy With Concurrent Irradiation at Varied Tumour Sites in Advanced Non-small Cell Lung Cancer
NCT ID: NCT03774732
Last Updated: 2025-11-26
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE3
327 participants
INTERVENTIONAL
2018-01-24
2026-12-22
Brief Summary
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Preclinical data indicates that anti-tumor efficacy is increased when anti-PD-1/-L1 are combined with irradiation (IR). Radiotherapy alone can elicit tumor cell death which can increase tumor antigen in the blood stream, favoring recognition by the immune system and its activation against tumor cells outside of the radiation field (="abscopal effect").
IR may also reverse acquired resistance to PD-1 blockade immunotherapy by limiting T-cell exhaustion.
Because of these preclinical and clinical data several studies analysing the combination of IR and anti-PD1 in NSCLC are ongoing. Among them, two studies are testing the administration of IR and nivolumab in stage III NSCLC: the NCT02768558 phase III trial (RTOG), and the NCT02434081 phase II trial (ETOP). Antonia et al \[2017\] tested the use of anti-PD-L1 after chemoradiotherapy in unresectable stage III NSCLC. Median time to distant metastasis was increased (23.2 months vs. 14.6 months, p\<0.001). An increase of OS is consequently expected.
However, no study involving concurrent RT and pembrolizumab combined with chemotherapy in advanced NSCLC is ongoing, which is the purpose of the present study, NIRVANA-Lung.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Pembrolizumab+ Chemotherapy + Radiotherapy
In the experimental arm, patients will receive the same treatment as the control arm (chemotherapy plus pembrolizumab) in addition with conformal 3D radiotherapy (3D-CRT) or stereotactic ablative radiotherapy (SABR) that will be delivered at C2D1, 21 days after the beginning of pembrolizumab using photons/electrons with standard field encompassing tumour.
Irradiation technique (3D-CRT or SABR) will be at physician discretion. Ideally, oligometastatic patient (defined by the presence of less than 6 metastases) should be treated with SABR and those with non-oligometastatic disease should be treated with 3D-CRT.
Radiotherapy will be delivered a dose of at least 18 Gy in 3 X 6 Gy for 3D-CRT (cf. protocol for possible schemes and volumes restriction).
Irradiated tumor size will be ≤5 cm (GTV \<65 mL sphere); partial tumor irradiation should be delivered if larger tumor size while respecting dose constraints.
Radiotherapy
Irradiation technique (3D-CRT or SABR) will be at physician discretion.
Pembrolizumab
pembrolizumab will be administered as per standard of care every 3 weeks until progression or toxicity
Chemotherapy
for squamous NSCLC carboplatin AUC6, paclitaxel 200 mg/m² every 3 weeks for 4 cycles; for non-squamous NSCLC carboplatin AUC5 or cisplatin 75 mg/m² every 3 weeks for 4 cycles, and pemetrexed 500 mg/m² every 3 weeks until progression or toxicity
Pembrolizumab+ Chemotherapy
Squamous-cell lung carcinoma:
Pembrolizumab every 3 weeks and carboplatin + paclitaxel or nab paclitaxel every 3 weeks for 4 cycles then pembrolizumab every 3 or 6 weeks (according to the current version of the SmPC )
Non squamous-cell lung carcinoma:
Pembrolizumab every 3 weeks and carboplatin or cisplatin + pemetrexed every 3 weeks for 4 cycles, and then pemetrexed plus pembrolizumab every 3 weeks (according to the current version of the SmPC)
Pembrolizumab treatment may be continued as long as patient is experiencing clinical benefit, as assessed by an investigator, in the absence of unacceptable toxicity or symptomatic deterioration attributed to disease progression after an integrated assessment of radiographic data, biopsy results (if available) and clinical status.
Pembrolizumab
pembrolizumab will be administered as per standard of care every 3 weeks until progression or toxicity
Chemotherapy
for squamous NSCLC carboplatin AUC6, paclitaxel 200 mg/m² every 3 weeks for 4 cycles; for non-squamous NSCLC carboplatin AUC5 or cisplatin 75 mg/m² every 3 weeks for 4 cycles, and pemetrexed 500 mg/m² every 3 weeks until progression or toxicity
Interventions
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Radiotherapy
Irradiation technique (3D-CRT or SABR) will be at physician discretion.
Pembrolizumab
pembrolizumab will be administered as per standard of care every 3 weeks until progression or toxicity
Chemotherapy
for squamous NSCLC carboplatin AUC6, paclitaxel 200 mg/m² every 3 weeks for 4 cycles; for non-squamous NSCLC carboplatin AUC5 or cisplatin 75 mg/m² every 3 weeks for 4 cycles, and pemetrexed 500 mg/m² every 3 weeks until progression or toxicity
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Histologically or cytologically confirmed advanced (stage IIIB/IIIC/IV), squamous or non-squamous NSCLC
3. NSCLC patients eligible for treatment with pembrolizumab and chemotherapy according to the European Marketing Authorization:
1. squamous: in combination with carboplatin and either paclitaxel or nab-paclitaxel
2. non squamous with no EGFR or ALK positive mutations: in combination with pemetrexed and a platinum based chemotherapy
4. Patient ≥18 of age
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1
6. Life expectancy \>3 months
7. Measurable lesion as assessed by RECIST version 1.1
8. Metastases and/or primary tumour eligible for 3 dimensional conventional radiotherapy (3D-CRT) or stereotactic ablative radiotherapy (SABR) in terms of dose constraints at organ at risk (according to QUANTEC review)
9. Patients must have adequate organ function defined by the following laboratory results obtained within 14 days prior to the first study treatment:
1. absolute neutrophil count of ≥1 500 /mm³
2. platelets ≥ 100 000/mm³
3. haemoglobin \>9 g/dL (transfusions allowed)
4. creatinine clearance \>60 mL/min
5. bilirubin ≤1.5 X upper limit of normal (ULN) (unless Gilbert's syndrome where 3 X ULN is permitted)
6. serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 X ULN (unless documented liver metastasis where ≤5 X ULN is permitted)
7. Alkaline phosphatase (ALP) ≤2.5 X ULN (unless documented bone or liver metastasis where ≤5 X ULN is permitted)
8. International normalized ratio (INR), prothrombin (PT), and prothrombin time (PTT) ≤1.5 X ULN (unless the subject is receiving anticoagulant therapy)
10. Woman of childbearing potential and male patients must agree to use adequate contraception for the duration of study participation and up to 6 months after completing treatment/therapy
11. Patients affiliated to the social security system (or equivalent)
12. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits, and examinations including follow-up
1. Non-squamous NSCLC with targetable tumor mutations, activating EGFR mutations or ALK translocation Note: documentation of these mutation for non-squamous histology is mandatory as standard of care
2. Stage IIIB/IIIC NSCLC patient eligible to curative (thoracic radiotherapy or surgery) treatments in first line treatment
3. Prior therapy with T-cell costimulation or checkpoint-targeted agents Note: Stage I-III NSCLC who previously received single-agent anti-PD(L)1 immunotherapy and ultimately develop metastases remain eligible (minimal immunotherapy washout period of 3 months)
4. Clinical need of radiotherapy (e.g.: whole brain irradiation, painful metastasis, bleeding, compressive metastases)
5. Irradiation within 2 months before inclusion
6. Leptomeningeal carcinomatosis, or metastases with indistinct borders making targeting not feasible
7. Patient with evidence of active (presence of symptoms or requiring steroid treatment) central nervous system (CNS) metastases and/or carcinomatous meningitis. Patient with brain metastasis can be included if asymptomatic and not requiring steroids
8. Metastases located within 3 cm of the previously irradiated structures (EQD2doses):
1. Spinal cord previously irradiated to \>40 Gy;
2. Brachial plexus previously irradiated to \>50 Gy;
3. Small intestine, large intestine, or stomach previously irradiated to \>45 Gy;
4. Brainstem previously irradiated to \>50 Gy;
5. Lung previously irradiated with prior V20Gy \>30%
9. Active autoimmune disease except vitiligo, type-1 diabetes, hypothyroid stabilized with hormonal substitution, psoriasis
10. Symptomatic interstitial lung disease
11. Systemic immunosuppression or systemic immunosuppressive medicinal products within 2 weeks prior to study entry
12. Concomitant treatment with steroids \> 10 mg Note1: higher dose of steroids can be prescribed in case of occurrence of toxicities during radiotherapy; prophylactic dose of maximum 1 mg per kg during 2 weeks are authorized during the delivery of more than 6 Gy per fraction Note2: temporary use of steroid (less than 4 weeks) at a dose of 1 mg/kg is accepted
13. Prior invasive malignancy within the past 2 years (except non-melanomatous skin cancer non-invasive carcinoma in-situ of the breast, oral cavity, bladder or cervix)
14. Known Acquired Immune Deficiency Syndrome (AIDS) or severe uncontrolled co-morbidity
15. Known currently active infection including hepatitis B and hepatitis C
16. Patient who was administered a live, attenuated vaccine within 28 days prior to enrolment
17. Patient with any other disease or illness that requires hospitalisation or is incompatible with the study treatment are not eligible. Patient unable to comply with study obligations for geographic, social, or physical reasons, or who is unable to understand the purpose and procedures of the study
18. Patient who have taken any investigational medicinal product or have used an investigational device within 30 days of inclusion
19. Pregnant or breast feeding woman
20. Person deprived of their liberty or under protective custody or guardianship
21. If pemetrexed: patient is unable or unwilling to take folic acid or vitamin B12 supplementation
22. Pre-existing peripheral neuropathy of a severity of grade ≥ 2 by NCI CTCAE v5.0
23. Known hypersensitivity to one of the compounds or substances used in this protocol
24. Major surgery within the 28 days before initiating study treatment
18 Years
ALL
No
Sponsors
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UNICANCER
OTHER
National Cancer Institute, France
OTHER_GOV
Responsible Party
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Principal Investigators
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Jérôme DOYEN, MD
Role: PRINCIPAL_INVESTIGATOR
Centre Antoine Lacassagne
Antonin LEVY, MD
Role: PRINCIPAL_INVESTIGATOR
Gustave Roussy, Cancer Campus, Grand Paris
Benjamin BESSE, MD
Role: PRINCIPAL_INVESTIGATOR
Gustave Roussy, Cancer Campus, Grand Paris
Locations
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Institut de Cancérologie de l'Ouest - Site Paul Papin
Angers, , France
Centre Marie Curie
Arras, , France
Hôpital Privé Arras Les Bonnettes
Arras, , France
Institut Sainte Catherine
Avignon, , France
Centre Pierre Curie
Beuvry, , France
Clinique Ambroise Pare
Beuvry, , France
Hôpital Simone Veil Blois
Blois, , France
Institut Bergonie
Bordeaux, , France
CHRU de Brest
Brest, , France
Centre François Baclesse
Caen, , France
Centre Hospitalier Universitaire De Caen - Hôpital Cote De Nacre
Caen, , France
Centre Hospitalier Dr Jean-Eric TECHER
Calais, , France
Centre hospitalier de Cannes Simone Veil
Cannes, , France
Centre Hospitalier William Morey
Chalon-sur-Saône, , France
Institut de Cancérologie de Bourgogne
Chalon-sur-Saône, , France
Pôle départemental de Cancérologie Libérale 37
Chambray-lès-Tours, , France
Centre Jean Perrin
Clermont-Ferrand, , France
Centre Hospitalier Intercommunal De Creteil
Créteil, , France
Centre Georges Francois Leclerc
Dijon, , France
Institut de Cancérologie de Bourgogne
Dijon, , France
Polyclinique du Parc Drevon
Dijon, , France
Centre André DUTREIX
Dunkirk, , France
Centre Hospitalier de Dunkerque
Dunkirk, , France
Centre de radiothérapie et de cancérologie de Blois
La Chaussée-Saint-Victor, , France
CHU Sud de la Réunion
La Réunion, , France
Hôpital de Bicêtre
Le Kremlin-Bicêtre, , France
Centre Oscar Lambret
Lille, , France
Clinique Chenieux
Limoges, , France
Hôpital Européen Marseille
Marseille, , France
Hôpital Privé Clairval
Marseille, , France
Centre Hospitalier de Montelimar
Montélimar, , France
Centre de cancérologie du grand Montpellier-Clinique Clementville
Montpellier, , France
Centre Hospitalier des Pays de Morlaix
Morlaix, , France
Centre Azuréen De Cancérologie
Mougins, , France
Hôpital Privé Arnault Tzanck
Mougins, , France
Centre Antoine Lacassagne
Nice, , France
CHU de Nîmes
Nîmes, , France
Fondation Hôpital Saint-Joseph
Paris, , France
Hopital Pitie Salpetriere
Paris, , France
Hopital Tenon
Paris, , France
Centre Catalan d'Oncologie
Perpignan, , France
Institut Jean Godinot
Reims, , France
Centre Frédéric JOLIOT
Rouen, , France
Centre Henri Becquerel
Rouen, , France
Clinique Saint-Hilaire
Rouen, , France
Hopital Charles Nicolle
Rouen, , France
Institut Curie - Hôpital René Huguenin
Saint-Cloud, , France
CHU St Etienne
Saint-Etienne, , France
Centre Joliot Curie
Saint-Martin-Boulogne, , France
Centre Paul Strauss
Strasbourg, , France
Polyclinique de l'Ormeau
Tarbes, , France
CHU de Toulouse Hôpital Larrey
Toulouse, , France
Institut Claudius Regaud
Toulouse, , France
Centre Marie Curie
Valence, , France
Hôpital Privé Drôme Ardèche
Valence, , France
Institut De Cancerologie De Lorraine
Vandœuvre-lès-Nancy, , France
Gustave Roussy
Villejuif, , France
Centre Hospitalier Princesse Grace
Monaco, , Monaco
Countries
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Central Contacts
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Facility Contacts
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Amaury PAUMIER, MD
Role: primary
Alexandre HENNI, MD
Role: primary
Nicolas POUREL, MD
Role: primary
Jean-Briac PREVOST, MD
Role: primary
Sophie COUSIN, MD
Role: primary
Vincent BOURBONNE, MD
Role: primary
Radj GERVAIS, MD
Role: primary
Fatima MENIAI, MD
Role: primary
Yannick DUVAL, MD
Role: primary
Thomas BOISSERIE, MD
Role: primary
Pascale DUBRAY LONGERAS
Role: primary
Isabelle MONNET, MD
Role: primary
Aurélie LAGRANGE, MD
Role: primary
Fatima MENIAI
Role: primary
Shakeel SUMODHEE, MD
Role: primary
Andrei SEFERIAN, MD
Role: primary
Florence LE TINIER, MD
Role: primary
Xavier ZASADNY, MD
Role: primary
Jacques LE TREUT, MD
Role: primary
Emmanuel BEGUIER, MD
Role: primary
Karim AMRANE, MD
Role: primary
Jérôme DOYEN, MD
Role: primary
Sylvie VAN HULST, MD
Role: primary
Charles NALTET, MD
Role: primary
Nicolas MEILLAN, MD
Role: primary
Sabine VIEILLOT, MD
Role: primary
Joelle OTZ, MD
Role: primary
Anne-Catherine COURTECUISSE-DEGRENDEL, MD
Role: primary
Roland SCHOTT, MD
Role: primary
Jonathan KHALIFA, M.D
Role: primary
Emilie BONNET, MD
Role: primary
Mathieu BOSSET, MD
Role: primary
Antonin LEVY, MD, PhD
Role: primary
Cécile ORTHOLAN, MD
Role: primary
References
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Doyen J, Besse B, Texier M, Bonnet N, Levy A. PD-1 iNhibitor and chemotherapy with concurrent IRradiation at VAried tumor sites in advanced Non-small cell lung cAncer: the Prospective Randomized Phase 3 NIRVANA-Lung Trial. Clin Lung Cancer. 2022 May;23(3):e252-e256. doi: 10.1016/j.cllc.2021.10.008. Epub 2021 Oct 24.
Other Identifiers
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UC-0107/1718
Identifier Type: -
Identifier Source: org_study_id
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