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

NCT03774732 | Active Not Recruiting Phase 3 DMC

• 1 other identifier: UC-0107/1718
• Study Type: interventional
• Target: 327
• Locations: 2 countries
• Sites: 58

Brief Summary

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.

Conditions

Non Small Cell Lung Cancer; Non-Small Cell Carcinoma of Lung, TNM Stage 4; Non Small Cell Lung Cancer Metastatic

Keywords

NSCLC; radiotherapy; immunotherapy; PD(L)-1 blockage

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Tumour response

  1 year

• Progression-free survival

  1 year

• Local and distant controls in irradiated patients

  6 months and 1 year

• Quality of life of the patients using EORTC-QLQ-C 30

  up to 2 years

• Acute/Late toxicities

  1 year

Study Arms (2)

Pembrolizumab+ Chemotherapy + Radiotherapy

EXPERIMENTAL

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; Drug: Pembrolizumab; Drug: Chemotherapy

Pembrolizumab+ Chemotherapy

ACTIVE COMPARATOR

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; Drug: Chemotherapy

Interventions

Radiotherapy RADIATION

Irradiation technique (3D-CRT or SABR) will be at physician discretion.

Also known as: 3D-CRT or SABR

Pembrolizumab+ Chemotherapy + Radiotherapy

Pembrolizumab DRUG

pembrolizumab will be administered as per standard of care every 3 weeks until progression or toxicity

Pembrolizumab+ Chemotherapy; Pembrolizumab+ Chemotherapy + Radiotherapy

Chemotherapy DRUG

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

Also known as: Carboplatin, paclitaxel, nab-paclitaxel, cisplatin, pemetrexed

Pembrolizumab+ Chemotherapy; Pembrolizumab+ Chemotherapy + Radiotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must have signed a written informed consent form prior to any study specific procedures
• Histologically or cytologically confirmed advanced (stage IIIB/IIIC/IV), squamous or non-squamous NSCLC
• NSCLC patients eligible for treatment with pembrolizumab and chemotherapy according to the European Marketing Authorization:
• squamous: in combination with carboplatin and either paclitaxel or nab-paclitaxel
• non squamous with no EGFR or ALK positive mutations: in combination with pemetrexed and a platinum based chemotherapy
• Patient ≥18 of age
• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1
• Life expectancy \>3 months
• Measurable lesion as assessed by RECIST version 1.1
• 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)
• Patients must have adequate organ function defined by the following laboratory results obtained within 14 days prior to the first study treatment:
• absolute neutrophil count of ≥1 500 /mm³
• platelets ≥ 100 000/mm³
• haemoglobin \>9 g/dL (transfusions allowed)
• creatinine clearance \>60 mL/min

Sponsors & Collaborators

• UNICANCER: lead
• National Cancer Institute, France: collaborator

Study Sites (58)

Institut de Cancérologie de l'Ouest - Site Paul Papin

Angers, France

Location

Centre Marie Curie

Arras, France

Location

Hôpital Privé Arras Les Bonnettes

Arras, France

Location

Institut Sainte Catherine

Avignon, France

Location

Centre Pierre Curie

Beuvry, France

Location

Clinique Ambroise Pare

Beuvry, France

Location

Hôpital Simone Veil Blois

Blois, France

Location

Institut Bergonie

Bordeaux, France

Location

CHRU de Brest

Brest, France

Location

Centre François Baclesse

Caen, France

Location

Centre Hospitalier Universitaire De Caen - Hôpital Cote De Nacre

Caen, France

Location

Centre Hospitalier Dr Jean-Eric TECHER

Calais, France

Location

Centre hospitalier de Cannes Simone Veil

Cannes, France

Location

Centre Hospitalier William Morey

Chalon-sur-Saône, France

Location

Institut de Cancérologie de Bourgogne

Chalon-sur-Saône, France

Location

Pôle départemental de Cancérologie Libérale 37

Chambray-lès-Tours, France

Location

Centre Jean Perrin

Clermont-Ferrand, France

Location

Centre Hospitalier Intercommunal De Creteil

Créteil, France

Location

Centre Georges Francois Leclerc

Dijon, France

Location

Institut de Cancérologie de Bourgogne

Dijon, France

Location

Polyclinique du Parc Drevon

Dijon, France

Location

Centre André DUTREIX

Dunkirk, France

Location

Centre Hospitalier de Dunkerque

Dunkirk, France

Location

Centre de radiothérapie et de cancérologie de Blois

La Chaussée-Saint-Victor, France

Location

CHU Sud de la Réunion

La Réunion, France

Location

Hôpital de Bicêtre

Le Kremlin-Bicêtre, France

Location

Centre Oscar Lambret

Lille, France

Location

Clinique Chenieux

Limoges, 87039, France

Location

Hôpital Européen Marseille

Marseille, France

Location

Hôpital Privé Clairval

Marseille, France

Location

Centre Hospitalier de Montelimar

Montélimar, France

Location

Centre de cancérologie du grand Montpellier-Clinique Clementville

Montpellier, France

Location

Centre Hospitalier des Pays de Morlaix

Morlaix, France

Location

Centre Azuréen De Cancérologie

Mougins, France

Location

Hôpital Privé Arnault Tzanck

Mougins, France

Location

Centre Antoine Lacassagne

Nice, France

Location

CHU de Nîmes

Nîmes, France

Location

Fondation Hôpital Saint-Joseph

Paris, France

Location

Hopital Pitie Salpetriere

Paris, France

Location

Hopital Tenon

Paris, France

Location

Centre Catalan d'Oncologie

Perpignan, France

Location

Institut Jean Godinot

Reims, France

Location

Centre Frédéric JOLIOT

Rouen, France

Location

Centre Henri Becquerel

Rouen, France

Location

Clinique Saint-Hilaire

Rouen, France

Location

Hopital Charles Nicolle

Rouen, France

Location

Institut Curie - Hôpital René Huguenin

Saint-Cloud, France

Location

CHU St Etienne

Saint-Etienne, France

Location

Centre Joliot Curie

Saint-Martin-Boulogne, France

Location

Centre Paul Strauss

Strasbourg, France

Location

Polyclinique de l'Ormeau

Tarbes, France

Location

CHU de Toulouse Hôpital Larrey

Toulouse, France

Location

Institut Claudius Regaud

Toulouse, France

Location

Centre Marie Curie

Valence, France

Location

Hôpital Privé Drôme Ardèche

Valence, France

Location

Institut De Cancerologie De Lorraine

Vandœuvre-lès-Nancy, France

Location

Gustave Roussy

Villejuif, France

Location

Centre Hospitalier Princesse Grace

Monaco, Monaco

Location

Related Publications (1)

• 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.

  PMID: 34810130 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Radiotherapy; Radiotherapy, Conformal; Radiosurgery; pembrolizumab; Drug Therapy; Carboplatin; Paclitaxel; 130-nm albumin-bound paclitaxel; Cisplatin; Pemetrexed

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Radiotherapy, Computer-Assisted; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques; Coordination Complexes; Organic Chemicals; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 26, 2018
• First Posted: December 13, 2018
• Study Start: January 24, 2018
• Primary Completion (Estimated): December 22, 2026
• Study Completion (Estimated): December 22, 2026
• Last Updated: February 25, 2026

Record last verified: 2026-01

Locations

MO (1); FR (57)