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.

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