DIRECT

Key Outcome parameters

Primary endpoints:

• Safety defined as the percentage of patients with adverse events. Safety will be assessed throughout the study. The following possible immune related adverse events will be registered throughout the study: hyperthyroidism, hypothyroidism, adrenal insufficiency, hypophysitis, skin reactions, myositis, nephritis, pyrexia, pancreatitis, diabetes, increased transaminases, colitis, diarrhea, nausea, pleural effusion, dyspnea, pneumonia, pneumonitis. Other adverse events deemed related to the study medication will also be registered. The causal association will be determined by the investigators. The severity of adverse events will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. The following post-operative complications will be registered: air leakage >5 days, infection, fistula formation. Any complication leading to delay or canceling of surgery will be noted
• To assess major pathological response (MPR) and pathological complete response (pCR) rates in resected tumor-specimens.

Secondary endpoints:

• To assess tumor immune infiltration after durvalumab and RT in 4 categories
• To assess radiological response to durvalumab and RT using RECIST v1.1 criteria, and metabolic response based on 18F-FDG PET

Exploratory endpoints:

• Immuno-profiling of tumor micro-environment
• Blood samples obtained at baseline, after durvalumab and RT, and 3 months after surgery will be analyzed for immune sub-populations in peripheral blood by flowcytometry

Intervention

RT will be applied to the primary tumor in 1 fraction of 8Gy, concomitant with one dose of durvalumab..

Resection is planned approximately 6 weeks after the RT and durvalumab administration took place.

Key inclusion criteria

Inclusion criteria

• Histologically confirmed NSCLC
• T1c-3N0, here T3 tumors are based on size, but not based on invasion into the thoracic wall, mediastinum, vertebra or diaphragm or ipsilateral lung nodules
• Willing and able to provide written informed consent for the trial
• Above 18 years of age on day of signing informed consent
• Have measurable disease based on RECIST 1.1
• Have a ECOG performance status of 0-1, and are considered operable based on pulmonary function test and/or exercise testing
• Demonstrate adequate organ function, as deemed acceptable by the treating physician in the context of immunotherapy
• Body weight >30 kg

Key exclusion criteria

Exclusion criteria

• Prior surgery and/or radiotherapy on the ipsilateral thorax
• Patients deemed inoperable
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of day 0. Inhaled or topical steroids, and adrenal replacement steroid >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• Additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
• 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
• Uncontrolled intercurrent illness, including but not limited to symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 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
• Active infection requiring systemic therapy
• A history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
• Active infection including tuberculosis, hepatitis B, hepatitis C
• Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Has received prior therapy with an anti-PD-1, anti-PD-L1 including durvalumab, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• Patient is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the pre-screening or screening visit through 23 weeks after the last dose of trial treatment.