PD-1 Inhibitor and Chemotherapy With Concurrent Irradiation at Varied Tumour Sites in Advanced Non-small Cell Lung Cancer (NIRVANA-LUNG)

Overall survival (OS) of patients with advanced (stage IIIB/IV) non-small-cell lung cancer (NSCLC) remains short after the first line of treatment with a median OS of 12.2 months in non squamous NSCLC and 9.2 months in squamous NSCLC . In this setting the programmed death 1/ligand 1 (PD-1/-L1) were targeted with nivolumab (IgG4) in advanced squamous and nonsquamous NSCLC leading to an increase of the 1-year OS rate of approximately 10-15% in both histologies. Nivolumab, pembrolizumab and atezolizumab are now considered a standard of care in 2nd line advanced NSCLC and in 1st line for pembrolizumab but but prognosis still remains poor in advanced NSCLC. Overall survival (OS) of patients with advanced (stage III/IV) NSCLC remains limited with a median OS of 12.2 months in non-squamous NSCLC and 9.2 months in squamous NSCLC if anti-PD1 alone. It is of around 16 months if pembrolizumab is combined with chemotherapy.

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.

Study Overview

• Status: Recruiting
• Conditions: Non Small Cell Lung Cancer; Non Small Cell Lung Cancer Metastatic; Non-Small Cell Carcinoma of Lung, TNM Stage 4
• Intervention / Treatment: Radiation: Radiotherapy; Drug: Pembrolizumab; Drug: Chemotherapy

• Study Type: Interventional
• Enrollment (Estimated): 327
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Assia LAMRANI-GHAOUTI, PhD; Email: a-lamrani-ghaouti@unicancer.fr
• Study Contact Backup: Name: Saliha GHANEM, PhD; Phone Number: 01 80 50 12 98; Email: s-ghanem@unicancer.fr

Study Locations

• France
  • Angers, France
    • Recruiting
    • Institut de cancérologie de l'Ouest - Site Paul Papin
    • Contact: Amaury PAUMIER, MD
  • Arras, France
    • Active, not recruiting
    • Centre Marie Curie
  • Arras, France
    • Recruiting
    • Hôpital privé Arras les Bonnettes
    • Contact: Alexandre HENNI, MD
  • Avignon, France
    • Recruiting
    • Institut Sainte Catherine
    • Contact: Nicolas POUREL, MD
  • Beuvry, France
    • Active, not recruiting
    • centre Pierre Curie
  • Beuvry, France
    • Recruiting
    • Clinique Ambroise Paré
    • Contact: Jean-Briac PREVOST, MD
  • Blois, France
    • Active, not recruiting
    • Hôpital Simone Veil Blois
  • Bordeaux, France
    • Recruiting
    • Institut Bergonié
    • Contact: Sophie COUSIN, MD
  • Brest, France
    • Not yet recruiting
    • CHRU de Brest
    • Contact: Vincent BOURBONNE, MD
  • Caen, France
    • Recruiting
    • Centre francois Baclesse
    • Contact: Radj GERVAIS, MD
  • Caen, France
    • Active, not recruiting
    • Centre Hospitalier Universitaire de Caen - Hôpital Côte de Nacre
  • Calais, France
    • Recruiting
    • CENTRE HOSPITALIER Dr Jean-Eric TECHER
    • Contact: Fatima MENIAI, MD
  • Cannes, France
    • Recruiting
    • Centre hospitalier de Cannes Simone Veil
    • Contact: Yannick DUVAL, MD
  • Chalon Sur Saone, France
    • Active, not recruiting
    • Centre Hospitalier William Morey
  • Chalon-sur-Saône, France
    • Active, not recruiting
    • Institut de Cancérologie de Bourgogne
  • Chambray-lès-Tours, France
    • Recruiting
    • Pôle départemental de Cancérologie Libérale 37
    • Contact: Thomas BOISSERIE, MD
  • Clermont-Ferrand, France
    • Recruiting
    • Centre Jean Perrin
    • Contact: Pascale Dubray Longeras
  • Créteil, France
    • Recruiting
    • Centre hospitalier intercommunal de Créteil
    • Contact: Isabelle MONNET, MD
  • Dijon, France
    • Recruiting
    • Centre Georges François Leclerc
    • Contact: Aurélie LAGRANGE, MD
  • Dijon, France
    • Active, not recruiting
    • Institut de Cancérologie de Bourgogne
  • Dijon, France
    • Active, not recruiting
    • Polyclinique du Parc Drevon
  • Dunkerque, France
    • Recruiting
    • Centre André DUTREIX
    • Contact: Fatima MENIAI
  • Dunkerque, France
    • Active, not recruiting
    • Centre Hospitalier de Dunkerque
  • La Chaussée-Saint-Victor, France
    • Active, not recruiting
    • Centre de radiothérapie et de cancérologie de Blois
  • La Réunion, France
    • Recruiting
    • CHU Sud de la Réunion
    • Contact: Shakeel SUMODHEE, MD
  • Le Kremlin-Bicêtre, France
    • Recruiting
    • Hopital de Bicetre
    • Contact: Andrei SEFERIAN, MD
  • Lille, France
    • Recruiting
    • Centre Oscar Lambret
    • Contact: Florence LE TINIER, MD
  • Limoges, France, 87039
    • Recruiting
    • Clinique Chenieux
    • Contact: Xavier ZASADNY, MD
  • Marseille, France
    • Recruiting
    • Hôpital Européen Marseille
    • Contact: Jacques LE TREUT, MD
  • Marseille, France
    • Active, not recruiting
    • Hôpital Privé Clairval
  • Montpellier, France
    • Recruiting
    • Centre de Cancerologie du Grand Montpellier-Clinique Clementville
    • Contact: Emmanuel BEGUIER, MD
  • Montélimar, France
    • Active, not recruiting
    • Centre Hospitalier de Montélimar
  • Morlaix, France
    • Not yet recruiting
    • Centre hospitalier des pays de Morlaix
    • Contact: Karim AMRANE, MD
  • Mougins, France
    • Active, not recruiting
    • Centre Azuréen de Cancérologie
  • Mougins, France
    • Active, not recruiting
    • Hopital prive Arnault Tzanck
  • Nice, France
    • Recruiting
    • Centre Antoine Lacassagne
    • Contact: Jérôme DOYEN, MD
  • Nîmes, France
    • Recruiting
    • CHU de Nimes
    • Contact: Sylvie VAN HULST, MD
  • Paris, France
    • Recruiting
    • Hôpital Pitié Salpêtrière
    • Contact: Nicolas MEILLAN, MD
  • Paris, France
    • Recruiting
    • Fondation Hôpital Saint-Joseph
    • Contact: Charles NALTET, MD
  • Paris, France
    • Active, not recruiting
    • Hopital Tenon
  • Perpignan, France
    • Not yet recruiting
    • Centre Catalan d'Oncologie
    • Contact: Sabine VIEILLOT, MD
  • Reims, France
    • Active, not recruiting
    • Institut Jean Godinot
  • Rouen, France
    • Active, not recruiting
    • Centre Henri Becquerel
  • Rouen, France
    • Active, not recruiting
    • Centre Frédéric JOLIOT
  • Rouen, France
    • Active, not recruiting
    • Clinique Saint-Hilaire
  • Rouen, France
    • Active, not recruiting
    • Hopital Charles Nicolle
  • Saint-Cloud, France
    • Recruiting
    • Institut Curie - Hopital Rene Huguenin
    • Contact: Joelle OTZ, MD
  • Saint-Martin-Boulogne, France
    • Recruiting
    • Centre Joliot Curie
    • Contact: Anne-Catherine COURTECUISSE-DEGRENDEL, MD
  • Saint-Étienne, France
    • Active, not recruiting
    • CHU St Etienne
  • Strasbourg, France
    • Recruiting
    • Centre Paul Strauss
    • Contact: Roland SCHOTT, MD
  • Tarbes, France
    • Active, not recruiting
    • Polyclinique de l'Ormeau
  • Toulouse, France
    • Recruiting
    • Institut Claudius Regaud
    • Contact: Jonathan KHALIFA, M.D
  • Toulouse, France
    • Active, not recruiting
    • CHU de Toulouse Hopital Larrey
  • Valence, France
    • Recruiting
    • Centre Marie Curie
    • Contact: Emilie BONNET, MD
  • Valence, France
    • Recruiting
    • Hôpital Privé Drôme Ardèche
    • Contact: Mathieu BOSSET, MD
  • Vandœuvre-lès-Nancy, France
    • Active, not recruiting
    • Institut de Cancerologie de Lorraine
  • Villejuif, France
    • Recruiting
    • Gustave Roussy
    • Contact: Antonin LEVY, MD, PhD
• Monaco
  • Monaco, Monaco
    • Recruiting
    • Centre Hospitalier Princesse Grace
    • Contact: Cécile ORTHOLAN, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

INCLUSION CRITERIA:

1. Patient must have signed a written informed consent form prior to any study specific procedures
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

NON-INCLUSION CRITERIA:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Radiation: Radiotherapy; Irradiation technique (3D-CRT or SABR) will be at physician discretion.; Other Names: 3D-CRT or SABR; Drug: Pembrolizumab; pembrolizumab will be administered as per standard of care every 3 weeks until progression or toxicity; Drug: 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 Names: Carboplatin, paclitaxel, nab-paclitaxel, cisplatin, pemetrexed
Active Comparator: 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.	Drug: Pembrolizumab; pembrolizumab will be administered as per standard of care every 3 weeks until progression or toxicity; Drug: 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 Names: Carboplatin, paclitaxel, nab-paclitaxel, cisplatin, pemetrexed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1-year Overall Survival	The primary endpoint of this trial is overall survival (OS) defined as the time from randomization to the date of documented death from any cause or last follow-up.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life of the patients using EORTC-QLQ-C 30	Quality of life will be assessed using QLQ-C 30 questionnaire from the European Organization for Research and Treatment of Cancer (EORTC). It is a 30-item self-reporting questionnaire developed to assess the quality of life of cancer patients. It is grouped into five functional subscales (role, physical, cognitive, emotional and social functioning). In addition, there are three multi-item symptom scales (fatigue, pain, and nausea and vomiting), individual questions concerning common symptoms in cancer patients,and two questions assessing overall Quality of Life	up to 2 years
Tumour response	Tumour response is defined as the percentage of patients with a complete response (CR) or partial response (PR), according to RECIST 1.1 and iRECIST (centralized response evaluation).	1 year
Progression-free survival	Progression-free survival (PFS) is defined as the time from randomization until documented disease progression (PD) according to RECIST 1.1 and iRECIST (centralized response evaluation for both arms), or death, whichever occurs first.	1 year
Local and distant controls in irradiated patients	Local and distant controls in irradiated patients are defined as the time from randomization to the first documented local event or distant event.	6 months and 1 year
Acute/Late toxicities	Acute/ late toxicity will be assessed according to the flowchart and graded by CTCAE v5	1 year
Non-small lung cancer specific survival	To evaluate, compared to standard of care, whether the addition of radiotherapy improves survival of patients until death from non-small lung cancer	1 year
2-year Overall survival	Overall survival (OS) is defined as the time from randomization to the date of documented death from any cause or last follow-up.	2 years

Collaborators and Investigators

• Sponsor: UNICANCER
• Collaborators: National Cancer Institute, France
• Investigators: Principal Investigator: Jérôme DOYEN, MD, Centre Antoine Lacassagne; Principal Investigator: Antonin LEVY, MD, Gustave Roussy, Cancer Campus, Grand Paris; Principal Investigator: Benjamin BESSE, MD, Gustave Roussy, Cancer Campus, Grand Paris

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2019
• Primary Completion (Estimated): September 21, 2026
• Study Completion (Estimated): September 21, 2026

Study Registration Dates

• First Submitted: September 26, 2018
• First Submitted That Met QC Criteria: December 12, 2018
• First Posted (Actual): December 13, 2018

Study Record Updates

• Last Update Posted (Actual): December 18, 2023
• Last Update Submitted That Met QC Criteria: December 11, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: immunotherapy; NSCLC; radiotherapy; PD(L)-1 blockage
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Folic Acid Antagonists; Carboplatin; Paclitaxel; Cisplatin; Pembrolizumab; Pemetrexed
• Other Study ID Numbers: UC-0107/1718

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No