New Adjuvant Trial of Chemotherapy vs Chemo-immunotherapy

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

210 stage IB-IIIA, completely resected, non-small cell lung cancer patients will be enrolled in this trial to evaluate the disease free survival between experimental arm (Adjuvant Chemotherapy-Immunotherapy + maintenance adjuvant Immunotherapy) and control arm (Adjuvant Chemotherapy)

This is an open-label, randomised, two-arm, phase III, multicentre clinical trial.The total sample size is 210 and 105 per arm. The population to be included are stage IB-IIIA, completely resected, non-small cell lung cancer patients.

Patients randomised to the experimental arm will receive Nivolumab 360mg + Paclitaxel 200mg/m2 + Carboplatin AUC5 for 4 cycles every 21 days (+/- 3 days) as adjuvant treatment followed by maintenance adjuvant treatment for 6 cycles with Nivolumab 480 mg Q4W (+/- 3 days).

Patients randomized to the control arm will receive Paclitaxel 200mg/m2 + Carboplatin AUC5 for 4 cycles every 21 days (+/- 3 days) followed by 2 observation visits.

The primary objective is to evaluate the disease-free survival (DFS): defined as the length of time from randomization to the earliest event defined as disease recurrence, any new lung cancer (even in the opposite lung), or death from any cause at any known point in time.

Patient accrual is expected to be completed within 3.5 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 observation phase. The study will end once survival follow-up has concluded.

Eligibility Criteria:
Inclusion Criteria:

* 1. Patients diagnosed of primary non-small cell lung cancer, histologically confirmed
* 2. Patients should be classified postoperatively in stage IB (=4 cm), II or IIIA according to pathological criteria and according to 8th version of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology.
* 3. Complete surgical resection of the primary NSCLC is also essential. Surgeons are strongly advised to dissect or obtain samples of all accessible lymph node levels, as established in the European Society of Thoracic Surgeons guide . Consequently, at the end of the surgical intervention it is recommended to have obtained samples of a minimum of 3 (three) specific mediastinal ganglionic lobe stations (N2), one of which should include station 7, and at least one N1 station (including those resected with the tumor piece).
* 4. The surgical intervention may consist of a lobectomy, sleeve resection, bilobectomy or pneumonectomy, as determined by the responsible surgeon based on intraoperative findings. Patients who have had only segmentectomies or wedge resections are not considered eligible for participation in this study.
* 5. Preoperative (neoadjuvant) use of platinum-based chemotherapy or other types of chemotherapy are not accepted.
* 6. Preoperative, postoperative, or scheduled radiation therapy is not accepted for a later time. Patients with only N2 disease, who have to receive post-operative adjuvant radiotherapy will not be eligible.
* 7. A minimum of 3 weeks must have elapsed between the surgical intervention performed for the NSCLC and the randomization. Adjuvant treatment must start between the 3rd and the 10th week from surgery.
* 8. ECOG 0-1
* 9. Patients aged ≥ 18 years
* 10. Correct hematological, hepatic and renal function i. Neutrophils ≥ 1500×109/L ii. Platelets ≥ 100 ×109/L iii. Hemoglobin \> 9.0 g/dL iv. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault).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 x ULN) vii. The patients need to have a forced expiratory volume (FEV1) ≥ 1.2 liters or \>40% predicted value viii. INR/APTT within normal limits.
* 11. Patient consent must be obtained in the appropriate manner as established in the applicable local and regulatory requirements
* 12. Patients must be accessible for treatment and follow-up
* 13. 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 3 days before randomization.
* 14. All sexually active men and women of childbearing potential must use a highly 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 5 months for females and 7 months for males following the last administration of trial drugs.

Exclusion Criteria:

* 1. Patients with a history of other malignant diseases, with the exception of the following:

  * or properly treated non-melanotic skin cancer
  * or cancer in situ treated with curative intent
  * or other malignancies treated with curative intent and without signs of disease for a period of\> 3 years after the end of the treatment and which, in the opinion of the doctor in charge of their treatment, do not present a substantial risk of relapse of the previous malignant disease.
* 2. Patients with ALK, STKB11 o KEAP1 known mutations before inclusion in this trial.
* 3. Patients with adenocarcinoma NSCLC must be tested for the common EGFR mutations before inclusion. Patients with any known EGFR mutation cannot be enrolled in the study.
* 4. Patients with a combination of microcytic and non-small cell lung cancer, a carcinoid lung tumor or large cell neuroendocrine carcinoma.
* 5. Patients that received live attenuated vaccines within 30 days prior to randomization.
* 6. History of a primary immunodeficiency, history of organ allogeneic transplantation, use of immunosuppressive drugs within 28 days before randomization or previous history of toxicity of severe immune mechanism (grade 3 or 4) with other immunological treatments
* 7. Patients with active or uncontrolled infections or with serious medical conditions or disorders that may not allow patient management as established in the protocol
* 8. Patients who have suffered untreated and / or uncontrolled cardiovascular disorders and / or who have symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial infarction in the previous year or ventricular cardiac arrhythmias that require medication, history of atrioventricular conduction of second or third degree). Patients with relevant cardiac history, even when well controlled, should have an LVEF\> 50% in the 12 weeks prior to randomization
* 9. Pregnant or breastfeeding women
* 10. Patients in whom R0 resection cannot be confirmed
* 11. Patients with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
* 12. 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
* 13. Any positive test result for hepatitis B virus or hepatitis C virus, indicating presence of virus, e.g. Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative)
* 14. History of allergy or hypersensitivity to any of the study drug components
* 15. Prior anti-PD1/L1 treatment