Multinational, randomized, controlled, open-label, multicenter phase II trial. Eligible patients will be randomized in a ratio of 1:1 to Experimental Arm (FDG-PET-based small volume accelerated radiotherapy with concurrent standard of care chemotherapy) or Conventional Arm (standard FDG-PET-based radiotherapy with concurrent standard of care chemotherapy). Patients showing complete response, partial response, or stable disease following chemoradiotherapy will receive standard of care consolidation therapy with durvalumab (fixed dose of 1500 mg q4w) for up to 12 months or until progression of disease, unacceptable toxicity, patient´s wish, or investigator´s decision, whichever comes first.

After end of durvalumab therapy, patients will undergo safety follow up for 90 (+7) days followed by survival follow up until overall end of study. Overall end of study will be reached 24 months after the last patient has started durvalumab therapy. Patients showing PD following chemoradiotherapy will be treated according to investigator´s decision but will be followed up until overall end of study.

Inclusion Criteria:

• Written informed consent

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

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

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

• Patients fit for simultaneous chemoradiotherapy and consolidation immunotherapy according to interdisciplinary consensus

• Histologically proven PD-L1-expression of ≥ 1% (tumor proportion score; TPS) in tumor sample as assessed in routine staging using a validated test such as Ventana SP236 assay

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

• 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% of predicted 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 as determined 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 for female pre-menopausal patients. Women will be considered post-menopausal if they are amenorrhoic for 12 months or more without an alternative medical cause. The following age-specific requirements apply:

  • Women <50 years old would be considered post-menopausal if they have been amenorrhoic for 12 months or more following cessation of exogenous hormonal treatments with luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
  • Women ≥50 years old would be considered post-menopausal if they have been amenorrhoic for 12 months or more following cessation of all exogenous hormonal treatments, radiation-induced oophorectomy with last menses >1 year ago, chemotherapy-induced menopause with >1 year interval since last menses, or surgical sterilization (bilateral oophorectomy or hysterectomy)

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

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 limited to, surgical resection, radiation therapy, investigational agents, chemotherapy, and monoclonal antibodies (mAbs). Exception: Prior surgical resection of limited metachronous 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 phase and up to 30 days end of treatment

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

• Prior exposure to immune-mediated therapy, including but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1 (including durvalumab), and anti-PD-L2 antibodies, including therapeutic anticancer vaccines

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

  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

• History of allogeneic organ transplantation

• Active or prior documented autoimmune or inflammatory disorders including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:

  • Patients with vitiligo or alopecia
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  • Any chronic skin condition that does not require systemic therapy
  • Patients without active disease in the last 5 years at randomization may be included 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 active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, ILD, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs, or compromise the ability of the patient to give written informed consent

• Patients with oxygen dependence

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

• History of another primary malignancy, except for

  • Basal cell carcinoma of the skin
  • Second malignancy diagnosed > 2 years prior to NSCLC diagnosis if after curative treatment without persistence or progression at baseline. 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 of disease
  • Adequately treated carcinoma in situ without evidence of disease

• History of leptomeningeal carcinomatosis

• Positive diagnostic test for hepatitis B (hepatitis B surface antigen) or hepatitis 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 or any of the excipients

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

• Patients who have disease considered for surgical treatment as part of their care 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 interventional study

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

• Pregnancy or breast-feeding