Personnalized Immunotherapy in Patients With Stage III Non-small Cell Lung Cancer

Inclusion Criteria:

1. 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 patient care. Patients must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing.
2. Age ≥18 years.
3. ECOG Performance Status of 0 or 1.
4. Histologically proven unresectable locally advanced stage III NSCLC.
5. Diagnostic tumor tissue sample available for molecular biology analysis.
6. Measurable tumor according to RECIST1.1.
7. Patient eligible for concomitant curative CRT with authorization of two course of induction chemotherapy before the start of CRT. The minimum dose of radiotherapy is 60 Gy over 95% of tumor volumes.
8. FEV1≥40% of theoretical and PaO2≥60mmHg.
9. Hematological criteria: PNN ≥ 1.5x109/L and platelets ≥ 100x109/L, Hemoglobin ≥ 9 g/dL.
10. Creatinine clearance (according to the institution's standard method) ≥ 45 mL/min.
11. For women of childbearing potential (including women who have had a tubal ligation), serum pregnancy test must be performed and documented as negative within 14 days prior to C1D1.
12. Women of childbearing potential must remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of \< 1% per year during the treatment period and for at least 7 months after the last dose of study drugs. Women must refrain from donating eggs during this same period. A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries or uterus). Examples of contraceptive methods with a failure rate of \<1% per year include bilateral tubal ligation, male sterilization, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Hormonal contraceptive methods must be supplemented by a barrier method plus spermicide. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
13. Men with female partners of childbearing potential or pregnant female partners, must remain abstinent or use a condom during the treatment period and for at least 6 months after the last dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
14. Patient has national health insurance coverage.

Exclusion Criteria:

1. Known EGFR activating tumor mutation (deletion LREA in exon 19, L858R or L861X mutations in exon 21, G719A/S mutation in exon 18, exon 20 insertion) or HER2 exon 20 insertion (either tissue or plasma cfDNA mutation).
2. Known ALK, ROS1, gene rearrangement as assessed by immunohistochemistry, FISH or NGS (ADN or ARN) sequencing by local genetics and/or pathology laboratory.
3. Sequential CRT, defined as the start of thoracic irradiation after the administration of the third course of chemotherapy.
4. Pleural involvement or extra-thoracic tumor lesions.
5. Comorbidity contraindicating CRT.
6. Significant lesions of interstitial lung disease on chest CT or proven interstitial lung disease.
7. History of cancer in the last 3 years, or active cancer (with the exception of basal cell carcinoma of the skin and carcinoma in situ of the uterine cervix).
8. Previous thoracic radiotherapy.
9. Previous chemotherapy in the last 3 years.
10. Pregnant or breast-feeding woman.
11. Patient under legal protection.
12. Patient unable to follow the constraints of the trial.
13. Systemic corticosteroid therapy \> 10mg/day of prednisone or equivalent and immunosuppressive treatment (with the exception of supplementary hydrocortisone treatment).
14. History of autoimmune disease, with the exception of:

    * Stable substituted hypothyroidism
    * Balanced type 1 diabetes
    * Vitiligo, psoriasis, lichen, without extra-dermatological involvement
15. History of anti-cancer treatment with immune checkpoint inhibitor.

Randomisation Criteria:

1. Patient without immediate progression after CRT.
2. Patient with a comprehensive CAPP-Seq profile established on tumor tissue and/or ctDNA before CRT.
3. PS 0-1
4. Patient without contra-indication to immunotherapy.
5. Completion of CRT at a total dose of at least 60 Gy over 95% of tumour volumes and with at least two cycles of concurrent chemotherapy.