A phase II randomised trial investigating the benefit of adjuvant immunotherapy after neoadjuvant chemoimmunotherapy for resectable NSCLC (ADIL)

Prior treatment

• Treatment with any investigational medicinal product (IMP) that may interfere with the study treatment, within 1 month or 5 half-lives prior to first study drug administration (whichever is longer) prior to first administration of study drug.
• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
• History of another primary malignancy except for: a)Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of IP and of low potential risk for recurrence b)Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease c)Adequately treated carcinoma in situ without evidence of disease d)Low-grade prostate cancer defined as observed with watchful waiting or treated with curative intent and Gleason ≤ 6.
• Participant has received a live vaccine within 30 days of planned start of study therapy. COVID-19 vaccines that do not contain live viruses are allowed. Note: mRNA and adenoviral-based COVID-19 vaccines are considered non-live.
• 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: a)Patients with vitiligo or alopecia b)Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement c)Any chronic skin condition that does not require systemic therapy d)Patients without active disease in the last 2 years may be included but only after consultation with the study physician e)Patients with celiac disease controlled by diet alone f)A rheumatologist is consulted and immunotherapy is not deemed a risk for the disease.
• Subjects with HBV infection, characterised by positive HBsAg and/or anti-HBcAb with undetectable HBV DNA (< 10 IU/ml or under the limit of detection per local lab standard) do not require antiviral therapy prior to randomisation. These subjects will be tested at every cycle to monitor HBV DNA levels; if HBV DNA is detected (≥ 10 IU/ml or above the limit of detection per local lab standard), antiviral therapy must be initiated, continued for the study duration and for 6 months after the last dose of IP.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. For biologics or other long-acting immunosuppressive agents a washout period of at least 28 days or 5 half-lives (whichever is longer) should be all allowed.The following are exceptions to this criterion: a)Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articularection) b)Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent c)Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• 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.

Other illness

• Uncontrolled intercurrent illness that would prevent the use of chemotherapy and/or immunotherapy, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea, 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.
• Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening. Participants with a past or resolved HBV infection (defined as the presence of anti HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Adjust wording as necessary and consider evaluating at screening for studies with known hepatotoxicity or other relevant requirements.
• Participants co-infected with HBV and HCV, or co-infected with HBV and HDV, namely: HBV positive (presence of HBsAg and/or anti HBcAb with detectable HBV DNA); AND a)HCV positive (presence of anti-HCV antibodies); OR b)HDV positive (presence of anti-HDV antibodies)..
• Hypersensitivity to durvalumab or any of its excipients.
• Participant has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal/gastric varices, or persistent jaundice. Note: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria.
• Clinically significant cardiovascular disease within 6 months of enrolment.

Lab values

• Patients with known targetable mutations in EGFR or ALK.
• Subjects with HBV infection, characterised by positive HBsAg and/or anti-HBcAb with detectable HBV DNA (≥ 10 IU/ml or above the limit of detection per local laboratory standard), must be treated with antiviral therapy, per institutional practice. Following antiviral therapy initiation, subjects must show adequate viral suppression (ie, HBV DNA ≤ 2000 IU/mL) as prior to randomisation. Participants will remain on antiviral therapy for the study duration and for 6 months after the last dose of IP.
• Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA load (below 50 or the limit of detection for 12 weeks, CD4+ count of ≥350 cells/mm3, no history of AIDS-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications.
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. a)Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. b)Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
• Participant has experienced any of the following with prior immunotherapy: any immune related AE (irAE) of Grade 3 or higher, immune-related severe neurologic events of any grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis, Guillain Barré syndrome, or transverse myelitis), exfoliative dermatitis of any grade (SJS, TEN, or DRESS syndrome), or myocarditis of any grade. Non–clinically significant laboratory abnormalities are not exclusionary.

Other

• Patients that are medically inoperable.
• Pregnancy or lactation.
• Any reason why, in the opinion of the investigator, the patient should not participate.
• Immunocompromised patients are not allowed.

• Participant must be 18 years of age or older, at the time of signing the informed consent.
  • Body weight >30kg.
  • 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.
  • Patients with stage II-III NSCLC evaluated at an MDT as having high risk of relapse.
  • Resectability: It should be deemed possible to obtain free margins after resection (R0) evaluated by the MDT-meeting.
  • ECOG performance status 0-1.
  • Known negative status of ALK and EGFR by approved assays (this includes a positive KRAS mutation status which is considered a surrogate marker for negative EGFR/ALK).
  • Operability: The patients should be deemed operable by an MDT according to national guidelines.
  • Women of childbearing potential (WOCBP) should use a highly effective method during the treatment period and for at least 5 months after the last dose of immunotherapy to avoid pregnancy. Methods considered as highly effective birth control methods include combined (oestrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of ovulation (oral, intravaginal, injectable, implantable or transdermal), intrauterine device (including hormone-releasing), bilateral tubal occlusion, vasectomised partner or sexual abstinence
  • 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 (eg, 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.
  • Participants should have adequate organ and bone marrow function defined as in protocol.