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

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