Clinical trial NCT03774732: PD-1 Inhibitor and Chemotherapy With Concurrent Irradiation at Varied Tumour Sites in Advanced Non-small Cell Lung Cancer
Official title: PD-1 Inhibitor and Chemotherapy With Concurrent Irradiation at Varied Tumour Sites in Advanced Non-small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Non Small Cell Lung Cancer
Non Small Cell Lung Cancer Metastatic
Non-Small Cell Carcinoma of Lung, TNM Stage 4
Keywords: NSCLC
radiotherapy
immunotherapy
PD(L)-1 blockage
Lead sponsor: UNICANCER
Sponsor class: OTHER
Collaborators: name: National Cancer Institute, France
First posted: 2018-12-13
Enrollment: 327
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: 1-year Overall Survival
timeFrame: 1 year
Secondary outcomes:
measure: Tumour response
timeFrame: 1 year
measure: Progression-free survival
timeFrame: 1 year
measure: Local and distant controls in irradiated patients
timeFrame: 6 months and 1 year
measure: Quality of life of the patients using EORTC-QLQ-C 30
timeFrame: up to 2 years
measure: Acute/Late toxicities
timeFrame: 1 year
measure: Non-small lung cancer specific survival
timeFrame: 1 year
measure: 2-year Overall survival
timeFrame: 2 years
Other outcomes:
Locations:
city: Angers
country: France
facility: Institut de Cancérologie de l'Ouest - Site Paul Papin
city: Arras
country: France
facility: Centre Marie Curie
city: Arras
country: France
facility: Hôpital Privé Arras Les Bonnettes
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Beuvry
country: France
facility: Centre Pierre Curie
city: Beuvry
country: France
facility: Clinique Ambroise Pare
city: Blois
country: France
facility: Hôpital Simone Veil Blois
city: Bordeaux
country: France
facility: Institut Bergonie
city: Brest
country: France
facility: CHRU de Brest
city: Caen
country: France
facility: Centre François Baclesse
city: Caen
country: France
facility: Centre Hospitalier Universitaire De Caen - Hôpital Cote De Nacre
city: Calais
country: France
facility: Centre Hospitalier Dr Jean-Eric TECHER
city: Cannes
country: France
facility: Centre hospitalier de Cannes Simone Veil
city: Chalon Sur Saone
country: France
facility: Centre Hospitalier William Morey
city: Chalon-sur-Saône
country: France
facility: Institut de Cancérologie de Bourgogne
city: Chambray-lès-Tours
country: France
facility: Pôle départemental de Cancérologie Libérale 37
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal De Creteil
city: Dijon
country: France
facility: Centre Georges Francois Leclerc
city: Dijon
country: France
facility: Institut de Cancérologie de Bourgogne
city: Dijon
country: France
facility: Polyclinique du Parc Drevon
city: Dunkerque
country: France
facility: Centre André DUTREIX
city: Dunkerque
country: France
facility: Centre Hospitalier de Dunkerque
city: La Chaussée-Saint-Victor
country: France
facility: Centre de radiothérapie et de cancérologie de Blois
city: La Réunion
country: France
facility: CHU Sud de la Réunion
city: Le Kremlin-Bicêtre
country: France
facility: Hôpital de Bicêtre
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: Clinique Chenieux
city: Marseille
country: France
facility: Hôpital Européen Marseille
city: Marseille
country: France
facility: Hôpital Privé Clairval
city: Montpellier
country: France
facility: Centre de cancérologie du grand Montpellier-Clinique Clementville
city: Montélimar
country: France
facility: Centre Hospitalier de Montelimar
city: Morlaix
country: France
facility: Centre Hospitalier des Pays de Morlaix
city: Mougins
country: France
facility: Centre Azuréen De Cancérologie
city: Mougins
country: France
facility: Hôpital Privé Arnault Tzanck
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nîmes
country: France
facility: CHU de Nîmes
city: Paris
country: France
facility: Fondation Hôpital Saint-Joseph
city: Paris
country: France
facility: Hopital Pitie Salpetriere
city: Paris
country: France
facility: Hopital Tenon
city: Perpignan
country: France
facility: Centre Catalan d'Oncologie
city: Reims
country: France
facility: Institut Jean Godinot
city: Rouen
country: France
facility: Centre Frédéric JOLIOT
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Rouen
country: France
facility: Clinique Saint-Hilaire
city: Rouen
country: France
facility: Hopital Charles Nicolle
city: Saint-Cloud
country: France
facility: Institut Curie - Hôpital René Huguenin
city: Saint-Martin-Boulogne
country: France
facility: Centre Joliot Curie
city: Saint-Étienne
country: France
facility: CHU St Etienne
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Tarbes
country: France
facility: Polyclinique de l'Ormeau
city: Toulouse
country: France
facility: CHU de Toulouse Hôpital Larrey
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Valence
country: France
facility: Centre Marie Curie
city: Valence
country: France
facility: Hôpital Privé Drôme Ardèche
city: Vandœuvre-lès-Nancy
country: France
facility: Institut De Cancerologie De Lorraine
city: Villejuif
country: France
facility: Gustave Roussy
city: Monaco
country: Monaco
facility: Centre Hospitalier Princesse Grace
Study officials:
affiliation: Centre Antoine Lacassagne
name: Jérôme DOYEN, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Antonin LEVY, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Benjamin BESSE, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.