NADIM II: Neo-Adjuvant Immunotherapy

This is an open-label, randomised, two-arm, phase II, multi-centre clinical trial.

90 patients will be enrolled in this trial to examine the pathological Complete Response defined as the absence of residual tumor in lung and lymph nodes comparing patients treated with chemo-immunotherapy versus chemotherapy alone.

This is an open-label, randomised, two-arm, phase II, multi-centre clinical trial.

Patients randomised to the experimental arm will receive Nivolumab 360mg + Paclitaxel 200mg/m2 + Carboplatin AUC5 for 3 cycles every 21 days as neoadjuvant treatment followed by surgery and 6 months of adjuvant treatment with Nivolumab 480 mg Q4W. Patients randomized to the control arm will receive Paclitaxel 200mg/m2 + Carboplatin AUC5 for 3 cycles every 21 days followed by surgery.

The primary objective is pathological Complete Response (pCR) defined as the absence of residual tumor in lung and lymph nodes comparing patients treated with chemo-immunotherapy versus chemotherapy alone.

Patient accrual is expected to be completed within 3 years excluding a run-in-period of 3 months. Treatment and follow-up are expected to extend the study duration to a total of 8.5 years. Patients will be followed 5 years after adjuvant treatment or surgery. The study will end once survival follow-up has concluded.

Eligibility Criteria:
Inclusion Criteria:

1. Previously untreated patients with histologically- or cytologically- documented NSCLC who present stage IIIA disease (according to 8th version of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology) and also, potentially resectable locally advanced NSCLC patients' stage IIIB with T3N2 disease according to 8th edition can be included.

   * PET/CT including IV contrast (CT of diagnostic quality) will be performed at baseline (28 days +10 before randomization)
2. Tumor should be considered resectable before study entry by a multidisciplinary team
3. ECOG (Performance status) 0-1
4. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization.

   i. Neutrophils ≥ 1500×109/L ii. Platelets ≥ 100 x×109/L iii. Hemoglobin \> 9.0 g/dL iv. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min v. AST/ALT ≤ 3 x ULN vi. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL) vii. The patients need to have a forced expiratory volume (FEV1) ≥ 1.2 liters or \>40% predicted value viii. INR/APTT within normal limits
5. All patients are notified of the investigational nature of this study and signed a written informed consent in accordance with institutional and national guidelines, including the Declaration of Helsinki prior to any trial-related intervention
6. Patients aged \> 18 years
7. Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before randomization.
8. All sexually active men and women of childbearing potential must use an effective contraceptive method (two barrier methods or a barrier method plus a hormonal method) during the study treatment and for a period of at least 12 months following the last administration of trial drugs
9. Patient capable of proper therapeutic compliance and accessible for correct follow-up
10. Measurable or evaluable disease (according to RECIST 1.1 criteria)

Exclusion Criteria:

1. All patients carrying activating mutations in the TK domain of EGFR or any variety of alterations in the ALK gene.
2. Patients with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement or unexpected conditions of recurrence in the absence of an external trigger are allowed to be included.
3. Patients with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses \> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
4. Patients with a history of interstitial lung disease cannot be included if they have symptomatic ILD (Grade 3-4) and/or poor lung function. In case of doubt please contact trial team.
5. Patients with other active malignancy requiring concurrent intervention and/or concurrent treatment with other investigational drugs or anti-cancer therapy
6. Patients with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period.
7. Any medical, mental or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or understand the patient information
8. Patients who have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways
9. Patients with positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
10. Patients with known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
11. Patients with history of allergy to study drug components excipients
12. Women who are pregnant or in the period of breastfeeding
13. Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study