PACCELIO - FDG-PET Based Small Volume Accelerated Immuno Chemoradiotherapy in Locally Advanced NSCLC

Inclusion Criteria:

• Written informed consent

• Patients irrespective of sex and gender, aged 18 years or older at the time ofsigning the ICF

• Patients must be willing and able to comply with scheduled visits, treatmentschedule, laboratory testing, and other requirements of the study as determined bythe investigator

• Patients with histologically or cytologically documented NSCLC who present withlocally advanced, unresectable (Stage III) disease (according to version 8 of theInternational Association for the Study of Lung Cancer Staging Manual in ThoracicOncology (IASLC Staging Manual in Thoracic Oncology 2016))

• Patients fit for simultaneous chemoradiotherapy and consolidation immunotherapyaccording to interdisciplinary consensus

• Histologically proven PD-L1-expression of ≥ 1% (tumor proportion score; TPS) intumor sample as assessed in routine staging using a validated test such as VentanaSP236 assay

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 atenrolment

• Tumor assessment by FDG-PET CT within 21 days prior to start of chemoradiotherapy.

• Adequate pulmonary function test results

• Pre- or post-bronchodilator forced expiratory volume 1 of 1.0 L or >40% ofpredicted AND

• Diffusing capacity of the lung for carbon monoxide (DLCO) >30% of predicted

• Adequate bone marrow and organ function at enrolment

• Hemoglobin ≥9.0 g/dL

• Absolute neutrophil count >1.5 × 109/L

• Platelet count >100 × 109/L

• Serum bilirubin ≤1.5 × upper limit of normal (ULN)

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN

• Measured creatinine clearance (CrCl) >40 mL/min or calculated CL >40 mL/min asdetermined by Cockcroft-Gault (using actual body weight)

• Body weight of >30 kg at enrolment

• Evidence of post-menopausal status, or negative urinary or serum pregnancy test forfemale pre-menopausal patients. Women will be considered post-menopausal if they areamenorrhoic for 12 months or more without an alternative medical cause. Thefollowing age-specific requirements apply:

• Women <50 years old would be considered post-menopausal if they have beenamenorrhoic for 12 months or more following cessation of exogenous hormonaltreatments with luteinizing hormone and follicle-stimulating hormone levels inthe post-menopausal range for the institution

• Women ≥50 years old would be considered post-menopausal if they have beenamenorrhoic for 12 months or more following cessation of all exogenous hormonaltreatments, radiation-induced oophorectomy with last menses >1 year ago,chemotherapyinduced menopause with >1 year interval since last menses, orsurgical sterilization (bilateral oophorectomy or hysterectomy)

• Women of childbearing potential (WOCBP) and male patients with partners ofchildbearing potential must agree to always use a highly effective form ofcontraception according to the Clinical Trials Facilitation and Coordination Groupduring the treatment phase of this study and for at least 90 days after the lastdose durvalumab or 6 months after the last dose of chemotherapy, whichever occurslast

Exclusion Criteria:

• Mixed small cell and NSCLC histology

• Neuroendocrine tumor

• Distant metastases

• Malignant pleural effusion or pericardial effusion

• Acute superior vena cava obstruction

• Receipt of prior or current cancer treatment for NSCLC, including but not limitedto, surgical resection, radiation therapy, investigational agents, chemotherapy, andmonoclonal antibodies (mAbs). Exception: Prior surgical resection of limitedmetachronous NSCLC (i.e., stage I or II) is permitted.

• Receipt of live attenuated vaccine within 30 days prior to the start of therapy.Note: Patients, if enrolled, should not receive live vaccine during treatment phaseand up to 30 days end of treatment

• Major surgical procedure (as defined by the Investigator) within 28 days prior startof treatment.

• Prior exposure to immune-mediated therapy, including but not limited to, otheranti-CTLA-4, anti-PD-1, anti-PD-L1 (including durvalumab), and anti-PD-L2antibodies, including therapeutic anticancer vaccines

• Current use of ongoing long-term immunosuppressive medication. The following areexceptions to this criterion

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)

• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent

• Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication)

• History of allogeneic organ transplantation

• Active or prior documented autoimmune or inflammatory disorders includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosissyndrome, 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 (e.g., following Hashimoto syndrome) stable onhormone replacement

• Any chronic skin condition that does not require systemic therapy

• Patients without active disease in the last 5 years at randomization may beincluded but only after consultation with the local study physician

• Patients with celiac disease controlled by diet alone

• Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, ILD, serious chronic gastrointestinalconditions associated with diarrhea, or psychiatric illness/social situations thatwould limit compliance with study requirement, substantially increase risk ofincurring AEs, or compromise the ability of the patient to give written informedconsent

• Patients with oxygen dependence

• Acute inflammation of mediastinal lymph nodes/mediastinal lymphadenopathy in thecontext of active pneumoconiosis, sarcoidosis or tuberculosis

• History of another primary malignancy except for o Diagnosis of second malignancy (except basal cell carcinoma) < 2 years prior to NSCLC diagnosis, or persistence orprogression of previously diagnosed malignancy.

Patients with a previous history of radiation therapy are eligible provided field overlap is minimal and the risk of toxicity to tissues in the overlapping region(s) is deemed to be acceptable by treating radiation oncologist.

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence ofdisease

• Adequately treated carcinoma in situ without evidence of disease

• History of leptomeningeal carcinomatosis

• Positive diagnostic test for hepatitis B (hepatitis B surface antigen) orhepatitis C (hepatitis C antibody or hepatitis C RNA)

• Known active infection of tuberculosis or human immunodeficiency virus

• Known allergy or hypersensitivity to concomitant chemotherapy and durvalumab orany of the excipients

• Any medical contraindication to treatment with platinum-based doubletchemotherapy as listed in the applying SmPCs

• Patients who have disease considered for surgical treatment as part of theircare plan, such as Pancoast or superior sulcus tumors.

• Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or the follow-up period of an interventionalstudy

• Participation in another clinical study with an investigational product duringthe 4 weeks prior to enrolment

• Pregnancy or breast-feeding