PD-1 Inhibitor and Chemotherapy With Concurrent Irradiation at Varied Tumour Sites in Advanced Non-small Cell Lung Cancer
- Conditions
- Non Small Cell Lung CancerNon Small Cell Lung Cancer MetastaticNon-Small Cell Carcinoma of Lung, TNM Stage 4
- Interventions
- Registration Number
- NCT03774732
- Lead Sponsor
- UNICANCER
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 327
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Pembrolizumab+ Chemotherapy + Radiotherapy Chemotherapy 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. Pembrolizumab+ Chemotherapy 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+ Chemotherapy + Radiotherapy 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. Pembrolizumab+ Chemotherapy + Radiotherapy Pembrolizumab 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. Pembrolizumab+ Chemotherapy Pembrolizumab 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.
- Primary Outcome Measures
Name Time Method 1-year Overall Survival 1 year 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.
- Secondary Outcome Measures
Name Time Method Non-small lung cancer specific survival 1 year To evaluate, compared to standard of care, whether the addition of radiotherapy improves survival of patients until death from non-small lung cancer
Local and distant controls in irradiated patients 6 months and 1 year Local and distant controls in irradiated patients are defined as the time from randomization to the first documented local event or distant event.
Quality of life of the patients using EORTC-QLQ-C 30 up to 2 years 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
Acute/Late toxicities 1 year Acute/ late toxicity will be assessed according to the flowchart and graded by CTCAE v5
Tumour response 1 year 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).
Progression-free survival 1 year 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.
2-year Overall survival 2 years Overall survival (OS) is defined as the time from randomization to the date of documented death from any cause or last follow-up.
Trial Locations
- Locations (56)
Hôpital Simone Veil Blois
🇫🇷Blois, France
Centre Hospitalier Dr Jean-Eric TECHER
🇫🇷Calais, France
CHRU de Brest
🇫🇷Brest, France
Centre Jean Perrin
🇫🇷Clermont-Ferrand, France
Institut de Cancérologie de Bourgogne
🇫🇷Dijon, France
Pôle départemental de Cancérologie Libérale 37
🇫🇷Chambray-lès-Tours, France
Centre Azuréen De Cancérologie
🇫🇷Mougins, France
Institut de Cancérologie de l'Ouest - Site Paul Papin
🇫🇷Angers, France
Centre Marie Curie
🇫🇷Valence, France
Hôpital Privé Arras Les Bonnettes
🇫🇷Arras, France
Institut Sainte Catherine
🇫🇷Avignon, France
Centre Pierre Curie
🇫🇷Beuvry, France
Clinique Ambroise Pare
🇫🇷Beuvry, France
Institut Bergonie
🇫🇷Bordeaux, France
Centre François Baclesse
🇫🇷Caen, France
Centre Hospitalier Universitaire De Caen - Hôpital Cote De Nacre
🇫🇷Caen, France
Clinique Chenieux
🇫🇷Limoges, France
Hôpital Européen Marseille
🇫🇷Marseille, France
Hôpital Privé Clairval
🇫🇷Marseille, France
Centre de cancérologie du grand Montpellier-Clinique Clementville
🇫🇷Montpellier, France
Centre Hospitalier de Montelimar
🇫🇷Montélimar, France
Centre Hospitalier des Pays de Morlaix
🇫🇷Morlaix, 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
Centre hospitalier de Cannes Simone Veil
🇫🇷Cannes, France
Centre Hospitalier William Morey
🇫🇷Chalon Sur Saone, France
Centre Hospitalier Intercommunal De Creteil
🇫🇷Créteil, France
Centre Georges Francois Leclerc
🇫🇷Dijon, France
Polyclinique du Parc Drevon
🇫🇷Dijon, France
Centre André DUTREIX
🇫🇷Dunkerque, France
Centre Hospitalier de Dunkerque
🇫🇷Dunkerque, 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
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
Centre Joliot Curie
🇫🇷Saint-Martin-Boulogne, France
CHU St Etienne
🇫🇷Saint-Étienne, France
Centre Paul Strauss
🇫🇷Strasbourg, France
Polyclinique de l'Ormeau
🇫🇷Tarbes, France
CHU de Toulouse Hôpital Larrey
🇫🇷Toulouse, France
Institut Claudius Regaud
🇫🇷Toulouse, 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