Prospective Phase-II Trial of induction chemotherapy and chemoradiotherapy plus/minus the PD-L1 antibody durvalumab followed by surgery or definitive chemoradiation boost and consolidation durvalumab in resectable stage III NSCLC

Prior treatment

• previous administration of chemotherapy and/or radiotherapy within five years prior to randomization
• previous immunotherapy within five years prior to randomization
• Participation in another clinical study with an investigational product during the last 12 months
• Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study
• Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable
• 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, or 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 may be included but only after consultation with the study physician – Patients with celiac disease controlled by diet alone
• History of another primary malignancy except for – Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence – Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease – Adequately treated carcinoma in situ without evidence of disease
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. 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)
• Current or prior use of immunostimulatory agents within 14 days before the first dose of durvalumab
• Receipt of live attenuated vaccine within 90 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 90 days after the last dose of IP

Other illness

• clinically symptomatic vena cava superior syndrome
• invasion of the heart (except left atrium – T4 – heart)
• lung or heart function not allowing at the time of inclusion the intended surgical procedure
• insufficient patients compliance (e.g. symptomatic psychiatric disorder)
• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan
• History of allogenic organ transplantation
• (full blown) Pancoast-syndrome in tumors of the superior sulcus (T3-4 Nx)
• History of a stem cell transplantation
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled diabetes, cardiac arrhythmia, interstitial lung disease, 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
• History of active primary immunodeficiency
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV-1 or HIV-2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
• malignant (positive) pericardial effusion (M1a – pericardial effusion)
• Known allergy or hypersensitivity to durvalumab or any excipient
• malignant (positive) pleural effusion (M1a – pleural effusion)
• unresectable disease pre-treatment

Other

• resectable IIB or selected IIIA (T3N0; T3N1)
• diffuse mediastinal involvement
• patients with T3N3 and T4N3 tumors (IIIC IASLC/UICC 8)
• invasion of the thoracic aorta (T4 – aorta)
• invasion of the esophagus (T4 – esophagus)
• ipsi- or contralateral supraclavicular nodes (N3 – supraclavicular nodes)
• invasion of spine (T4 – spine)
• loss of weight > 10 % in the last six months
• missing written informed consent or definitive refusal for participation
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy
• involvement of the contralateral hilar nodes (if any data available)
• endobronchial tumor extension to the contralateral main stem bronchus
• mixed histology with areas of small cell carcinoma (neuroendocrine markers)

• Body weight >30 kg
• Must have a life expectancy of > 12 weeks
• Adequate normal organ and marrow function as defined below: o Haemoglobin ≥ 9.0 g/dL o Absolute neutrophil count (ANC) > 1.5 x 109/L (> 1500 per mm3) o Platelet count ≥ 100 x 109/L (≥ 100.000 per mm3) o Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician. o AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal o Measured creatinine clearance (CL) > 40 mL/min or Calculated creatinine CL > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24- hour urine collection for determination of creatinine clearance: Males: Creatinine CL (mL/min) = Weight (kg) x (140 – Age) 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = Weight (kg) x (140 – Age) x 0.85 72 x serum creatinine (mg/dL)
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female premenopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: o Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy) o Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
• Stable cardiac function (no Myocardial infarction (MI) within 6 months, no heart failure NYHA III-IV)
• Age ≥ 18 years and ≤ 75 years
• Male or female patients. Female (as well as male) patients have to take care of effective measures of anticonception
• Histologically proven non-small cell lung cancer
• Selected patients with non-small cell lung cancer stages IIIA and IIIB:  IIIA: one or more lymph node levels involved at EBUS/mediastinoscopy  IIIA: bulky N2-disease histologically proven at EBUS/cervical mediastinoscopy/parasternal mediastinotomy, not diffuse mediastinal involvement  selected IIIB: N3-disease with contralateral mediastinal nodes involved at EBUS/mediastinoscopy  potentially resectable T4-disease: o involvement of the pulmonary artery (angiogr.-CT/MRI/TEE), o involvement of the carina (histologically proven), o involvement of the left atrium (angiogr.-CT/MRI/TEE), o involvement of the vena cava (angiogr.-CT/MRI/TEE), o involvement of ipsilateral intrapulmonary satellite nodules, o mediastinal involvement (not diffuse)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Resectable disease at the time of inclusion
• Fulfillment of adequate criteria for functional and medical resectability as described in the ERS/ESTS guidelines [Brunelli et al 2009] and acceptable general clinical condition for multimodality treatment (interdisciplinary committee)
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations