IFCT-2401 SPORADIC a multicenter randomized open label phase II study evaluating the efficacy and the tolerance of adding cemiplimab to Sequential hyPOfractionated chemoRADiotherapy in unfit or elderly patients with unresectable stage III non-small cell lung cancer

Prior treatment

• Immunotherapy or chemotherapy contra-indicated.
• Any immunosuppressive therapy received within 28 days and corticosteroids > 10mg/day of prednisone or equivalent received within 7 days prior the start of chemotherapy excepted hydrocortisone replacement for adrenal insufficiency or pituitary disease not considered immunosuppressive therapy.
• Severe infections (including covid-19 infection) within 4 weeks prior to initiation of study treatment, including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.
• Live attenuated vaccine received within 28 days of starting chemotherapy
• Patients eligible for treatment with concomitant radio-chemotherapy validated by multidisciplinary committee.
• Major surgery within 4 weeks of starting treatment.
• Previously received a treatment with anti-PD1/PDL1, anti-CTLA, or other antineoplastic immunotherapy or chemotherapy for NSCLC.
• Patients not eligible for curative radiotherapy (tumor extension, predictable dose constraints that cannot be met).

Other illness

• Active autoimmune pathology. History of autoimmune pathology including myasthenia, Guillain-Barre syndrome, lupus erythematosus, antiphospholipid syndrome, Wegener's granulomatosis, glomerulonephritis, inflammatory bowel disease, vasculitis, sarcoidosis, uveitis. Autoimmune thyroid pathologies under replacement therapy as well as type 1 diabetes under insulin are authorized.
• History of idiopathic pulmonary fibrosis, organized pneumopathy or signs of active interstitial pulmonary pathology on CT scan.
• Chronic active infection including tuberculosis, HIV, hepatitis B (HBsAg positive) or C. Patients with a history of cured hepatitis B (anti HBc and absence of negative HBs antigen) are eligible. In case of hepatitis C (anti HCV Ac) patients are eligible if the HCV PCR is negative.
• History of thoracic radiotherapy.
• History of organ or bone marrow transplantation.
• Histology other than primary non-small cell lung cancer.

Lab values

• Known activating EGFR mutation or ALK or ROS1 translocation.
• Severe uncontrolled comorbidities or severe intercurrent disease: acute coronary syndrome less than 3 months old, unstable angina, heart failure with LVEF ≤30%, uncontrolled hypertension, Child B or C cirrhosis, severe sepsis, myocarditis or any other active conditions that would contraindicate chemotherapy, immunotherapy, or radiotherapy in the opinion of the investigator.

Age

• History of neoplastic disease (other than NSCLC) less than 3 years old or progressive (except basal cell carcinoma of the skin and carcinoma in situ of the cervix).

Other

• Weight loss ≥15% of total body weight in the last 6 months.
• ECOG PS upper 2
• Patient already included in another therapeutic trial.
• Positive pregnancy test or breastfeeding woman.
• Protected adults (under guardianship or curatorship).
• Inability to undergo medical monitoring of the study (for geographical, social and/or physical reasons).
• Patients unable to understand the study.
• Stage I or II NSCLC.
• Metastatic NSCLC including brain metastasis.

• Patients must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care.
• Measurable disease according to RECIST 1.1 per investigator assessment. The radiological assessment has to be done within the timelines indicated
• Respiratory function: FEV1 ≥ 40% of theoretical value, DLCO ≥ 40%.
• Bone marrow function: absolute neutrophil count (ANC) ≥ 1.5.109/L, platelets ≥ 100.109/L, hemoglobin ≥ 9 g/dl.
• Expression of PD-L1 as assessed locally by the investigator center.
• Renal and hepatic function: estimated creatinine clearance ≥ 45 ml/min, bilirubin ≤1.5xULN, AST ALT ≤3xULN, Albumin ≥28g/dl.
• Participant has national health insurance coverage.
• Effective method of contraception during the treatment and during the 6 months following the last dose for patients of childbearing potential and for male subjects who are sexually active with a woman of childbearing potential.
• Patients must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing.
• Age ≥ 18 years.
• Histologically or cytologically confirmed treatment-naïve, locally advanced NSCLC stage IIIA non resectable, IIIB or IIIC accordingly to 8th classification TNM, UICC 2015.
• Unfit or elderly patients as defined below: ≥ 70 years ; PS 0 to 1 ; Charlson sccore : watever OR < 70 years ; PS 0 to 1 ; Charslon score ≥ 3 OR < 70 years ; PS 2 ; Charlson sccore : watever
• Patients eligible for treatment with sequential radio-chemotherapy validated by multidisciplinary committee.