Neoadjuvant chemotherapy and dual immunotherapy with chemoradiation for unresectable stage III non-small cell lung cancer

Inclusion Criteria:

* Males or females aged 18 to 75 years or older;
* Patients must have histologically or cytologically confirmed locally advanced, unresectable (Stage III) non-small cell lung cancer (NSCLC);
* EGFR, ALK, and ROS1 wild-type;
* No prior chemotherapy, radiotherapy, surgery, targeted therapy, or immunotherapy;
* Expected survival ≥ 12 weeks;
* WHO Performance Status (PS) score of 0 or 1;
* Female subjects must not be breastfeeding;
* Women of childbearing potential (WOCBP) must agree to use contraception during the study treatment and for 5 months after the last dose of study drug (i.e., 30 days \[one ovulation cycle\] plus approximately five half-lives of the study drug);
* Adequate organ and bone marrow function as defined by the following criteria:
* Forced Expiratory Volume in 1 second (FEV1) ≥ 800 mL;
* Absolute neutrophil count ≥ 1.5 × 10⁹/L;
* Platelets ≥ 100 × 10⁹/L;
* Hemoglobin ≥ 9.0 g/dL;
* Creatinine clearance ≥ 50 mL/min as calculated by the Cockcroft-Gault formula (Cockcroft and Gault, 1976);
* Serum bilirubin ≤ 1.5 × upper limit of normal (ULN);
* AST and ALT ≤ 2.5 × ULN.

Exclusion Criteria:

1. Exclusion criteria for enrolment for neoadjuvant therapy. Patients should not enter the study if any of the following exclusion criteria are fulfilled:

   * Concurrent enrolment in another clinical study, unless it is an observational(non-interventional) clinical study;
   * Mixed small cell and non-small cell lung cancer histology;
   * Prior use of anti-PD-1, anti-PD-L1, or anti-CTLA4 antibodies;
   * Recent major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access;
   * Active or prior documented autoimmune disease within the past 2 years;
   * Active or prior documented inflammatory bowel disease (eg. Crohn's disease, ulcerative colitis);
   * History of primary immunodeficiency;
   * History of organ transplant that requires therapeutic immunosuppression;
   * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent;
   * Known history of tuberculosis;
   * History of another primary malignancy within 5 years prior to starting treatment, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ and the disease under study;
   * Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control.
2. Exclusion criteria for concurrent chemoradiation following neoadjuvant therapy. Patients should not enter the concurrent chemoradiation phase if any of the following exclusion criteria are fulfilled:

   * Patients who develop distant metastasis;
   * Patients who develop locoregional disease progression and the irradiation dose of normal tissue will exceed the limit.
   * World Health Organization (WHO) Performance Status of 2-4;
   * Inadequate organ and marrow function as defined below:

     * Forced expiratory volume in 1 second (FEV1) \<800ml
     * Absolute neutrophil count \<1.5 x 109/L (1500 per mm3)
     * Platelets \<100 x 109/L (100,000 per mm3)
     * Haemoglobin\<9.0 g/dL (5.59 mmol/L)
     * Serum creatinine CL \<50 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976)
     * Serum bilirubin \>1.5 x upper limit of normal (ULN).
     * Aspartate Transaminase(AST) and Alanine Transaminase(ALT) \>2.5 x ULN.
3. Further exclusion criteria for consolidation therapy. Patients should not enter the consolidation therapy if any of the following exclusion criteria are fulfilled:

   * Patients who have progressed whilst definitive platinum based, concurrent chemoradiation therapy;
   * Current or prior use of immunosuppressive medication within 28 days before the first dose of Iparomlimab and tuvonralimab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Systemic steroid administration required to manage toxicities arising from radiation therapy delivered as part of the chemoradiation therapy for locally advanced NSCLC is allowed.
   * Any unresolved toxicity CTCAE \>Grade 2 from the prior chemoradiation therapy will be excluded from randomization;
   * Patients with Grade ≥2 pneumonitis from prior chemoradiation therapy will be excluded from randomization;
   * Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE\>Grade 1.