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
• •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