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

The reference treatment for locally advanced (stage III) non-small cell lung cancer (NSCLC) is concomitant chemoradiotherapy (CRT) followed by durvalumab consolidation for 1 year. This strategy is based on the results of the PACIFIC trial, which compared, in a randomized fashion after CRT, the superiority of treatment with durvalumab at a dose of 1500 mg every 4 weeks for 12 months to placebo in patients with non-progressive disease. The coprimary endpoints of this trial were progression-free survival (PFS) and overall survival (OS). This study was positive and showed a benefit in PFS and OS. However, less than half of patients (49%) received the full 12 months of durvalumab in this study, one-third of these discontinuations being related to toxicity. Furthermore, the prescription of durvalumab in this setting is not currently guided by any companion biomarker. As a result, the systematic prescription of a 12-month consolidation immunotherapy after CRT, without any selection criteria, leads to a possible overtreatment of patients whose survival would have been prolonged without additional treatment. These patients are systematically exposed to a potentially high and serious risk of toxicity in the course of immunotherapy. It is therefore crucial to move towards a more individualized approach in the prescription of consolidation immunotherapy after CRT in stage III NSCLC. This would ensure that the most appropriate treatment is delivered to patients who are likely to derive significant clinical benefit, while concurrently minimizing the exposure of other patients to potentially severe clinical toxicities. Additionally, such an approach would help protect healthcare systems from unnecessary economic burden, preventing the allocation of resources to treatments that offer limited therapeutic value.

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 \ 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.