CHIO3 Trial: CHemotherapy Combined With Immune Checkpoint Inhibitor for Operable Stage IIIA/B Non-Small Cell Lung Cancer

Operability Criteria:

1. ECOG Performance Status 0-1.
2. Absence of major associated comorbidities that increase the surgery risk to anunacceptable level.
3. Pulmonary function capacity capable of tolerating the proposed lung resection. FEV1 atleast 2 L. If less than 2 L, the predicted postoperative forced expiratory volume in 1second (FEV1) must be >0.8 L or be >35% of the predicted value. Postoperativepredicted DLCO ≥35% is required. Inclusion Criteria:
4. Patients who are at least 18 years of age.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
6. Life expectancy of at least 12 weeks.
7. Patients with potentially resectable IIIA/B (T1-3, N2) NSCLC (per the 8thInternational Association for the Study of Lung Cancer classification) who arecandidates for surgery with intent of R0 resection. Invasive T3 disease (eg, phrenicnerve, pericardium, chest wall other than Pancoast superior sulcus) may be included ifthe surgeon and study team deem it to be resectable. T4 disease per AJCC 8th editionstaging system is excluded given the lack of benefit of surgery in T4N2.
8. Patients must be evaluated by a thoracic surgeon within 4 weeks of registration.
9. Operability is defined as having adequate pulmonary, cardiac, renal, nutritional,musculoskeletal, neurologic, and cognitive capacity to undergo major pulmonaryresection with acceptable morbidity and mortality.
10. N2 nodes must be discrete (ie, not invading surrounding structures) and less than 3 cmin maximum diameter.
11. Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
12. Pathologically proven N2 disease within 4 weeks of registration. PET/CT positivity inthe ipsilateral mediastinal nodes will not be sufficient to establish N2 nodal status.Mediastinal lymph node sampling biopsy is required pre-operatively by at least one ofthe following:

• Endobronchial Ultrasound Transbronchial Needle Aspiration (EBUS-TBNA);
• Mediastinoscopy;
• Mediastinotomy (Chamberlain procedure);
• Endoscopic ultrasound guided node aspiration (EUS);
• Video-assisted thoracoscopy; OR
• Fine needle aspiration by image guidance.
• Endobronchial ultrasound (EBUS) or mediastinoscopy or other tissue sampling (atleast 2 stations must be biopsied, with at least one station positive for N2disease). If there are any mediastinal nodes suspicious by CT (>1.5 cm) or PET inN3 stations, they must be biopsied. If biopsy proven involvement in an N3station, the patient is excluded.

10. Mediastinal nodal biopsy or aspiration can only be omitted in the special circumstancein which ALL of the following are true:

• The tumor is left sided;
• The only mediastinal nodal involvement is a node visible in the AP (level 5)region on CT scan;
• Distinct primary tumor separate from the nodes; AND
• Biopsy proven non-small cell histology from the primary tumor.

11. No prior history of thoracic radiation.
12. Organ and marrow function definitions (example below)

• leukocytes ≥3,000/mcL
• absolute neutrophil count ≥1,500/mcL
• platelets ≥100,000/mcL
• Hemoglobin >9.0 g/dL
• total bilirubin within normal institutional limits
• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
• creatinine within normal institutional limits OR
• creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levelsabove institutional normal.

13. Patients are capable of giving informed consent and/or have an acceptable surrogatecapable of giving consent on the subject's behalf.
14. Nonpregnant and non-nursing. The effect of durvalumab on the fetus is unknown.
15. Women of childbearing potential (WOCBP) must be willing to use 2 methods of birthcontrol or be surgically sterile, or abstain from heterosexual activity for the courseof the study through 3 months after the last dose of study medication. Patients ofchildbearing potential are those who have not been surgically sterilized or have notbeen free of menses >1 year.
16. Evidence of postmenopausal status or negative urinary or serum pregnancy test forfemale premenopausal patients. Women will be considered postmenopausal if they havebeen amenorrheic for 12 months without an alternative medical cause. The followingage-specific requirements apply:

• Women <50 years of age would be considered postmenopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulating hormonelevels in the postmenopausal range for the institution or underwent surgicalsterilization (bilateral oophorectomy or hysterectomy).
• Women ≥50 years of age would be considered postmenopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses >1 year ago, hadchemotherapy-induced menopause with last menses >1 year ago, or underwentsurgical sterilization (bilateral oophorectomy, bilateral salpingectomy, orhysterectomy).

17. Patient is willing and able to comply with the protocol for the duration of the studyincluding undergoing treatment and scheduled visits and examinations including followup.
18. Male patients must agree to use an adequate method of contraception starting with thefirst dose of study therapy through 12 weeks after the last dose of study therapy.

Exclusion Criteria:

1. Any prior treatment for NSCLC.
2. Prior thoracic radiation.
3. Patients with ≥Grade 2 peripheral neuropathy.
4. Any active or history of autoimmune disease (including any history of inflammatorybowel disease) or history of a syndrome that required systemic steroids orimmunosuppressive medications, except for patients with vitiligo or resolved childhoodasthma/atopy.
5. Patients requiring systemic treatment with either corticosteroids (>10 mg dailyprednisone equivalents) or other immunosuppressive medications within 14 days of studydrug administration. Inhaled or topical steroids and adrenal replacement doses <10 mgdaily prednisone equivalents are permitted in the absence of active autoimmunedisease.
6. Patients with previous malignancies (except nonmelanoma skin cancers, in situ bladder,gastric, breast, colon or cervical cancers/dysplasia) are excluded unless a completeremission was achieved at least 2 years prior to study entry and no additional therapyis required or anticipated to be required during the study period.
7. History of solid organ transplant.
8. N3 nodal disease.
9. Mixed small cell/NSCLC will be excluded.
10. Pregnant or breastfeeding.
11. History of allogenic organ transplantation.
12. Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [eg, colitis or Crohn's disease], active diverticulitiswith the exception of diverticulosis, systemic lupus erythematosus, Sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions tothis criterion:

• Patients with vitiligo or alopecia.
• Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormonereplacement.
• Any chronic skin condition that does not require systemic therapy.
• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician.
• Patients with celiac disease controlled by diet alone.

13. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantially increaserisk of incurring AEs or compromise the ability of the patient to give writteninformed consent.
14. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 mscalculated.