Studio di fase 2 sull'immunoterapia di consolidamento dopo trattamento radicale del tumore del polmone oligometastatico

1. Registration phase

   Inclusion criteria
   * Histologic or cytologic confirmation of NSCLC. If small-cell elements present, participant will be ineligible.
   * Synchronous oligometastatic disease at diagnosis - and still oligometastatic at registration into the study - defined as maximum 5 metastases, in maximum 3 organs. Hilar, mediastinal and/or supraclavicular lymph nodes are not considered as metastases.
   * Age at registration ≥18 years
   * Eastern Cooperative Oncology Group performance status (ECOG PS)/ World Health Organization (WHO) 0-1.
   * Hepatic function:
   * Serum total bilirubin ≤1.5x upper limit of normal (ULN), or ≤3x ULN, if liver metastases or in patients with history of Gilbert syndrome
   * Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤3x ULN (or ≤5x ULN, if liver metastases)
   * Renal function:
   * Glomerular filtration rate (GFR) based on the modification of diet in renal disease (MDRD) equation ≥30 mL/min
   * Bone marrow function:
   * Hemoglobin ≥9.0 g/dL
   * Absolute neutrophil count (ANC) ≥1.5 x 109/L
   * Platelet count ≥100 x 109/L
   * Women of childbearing potential (WOCBP) must have a negative serum or highly sensitive urine pregnancy test within 7 days prior to the first dose of treatment.

   Note: Women of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e., females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrhoeic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression, or other reasons.
   * Patients of childbearing / reproductive potential should agree to use adequate birth control measures, as defined by the protocol, during the study treatment period and for:
   * At least 6 months after the last dose of pemetrexed-if pemetrexed was administered.
   * At least 6 months after the last dose of cemiplimab/placebo. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Such methods are detailed in Appendix Y.
   * Women who are breast feeding should discontinue nursing prior to the first dose of study treatment and until:
   * At least 6 months after the last dose of pemetrexed, if pemetrexed was administered.
   * At least 6 months after the last dose of cemiplimab/placebo.
   * 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.

   Exclusion criteria
   * Presence of malignant pleural, pericardial and/or peritoneal effusion.
   * Presence of leptomeningeal carcinomatosis.
   * Tumour known to be positive for EGFR exon 19 or 21 mutations, ALK translocations or ROS1 fusions.
   * Prior pneumonectomy, radiotherapy (including mediastinal radiotherapy), chemotherapy, immune-check inhibitors or targeted therapy for lung cancer within the last 3 years before registration.
   * Previously treated brain metastases that are radiologically non-stable.

   Notes:
   * Patients with previously treated brain metastases, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention, can participate. These treated brain metastasis will count as metastasis in the definition of oligometastatic disease.
   * Symptomatic brain metastases should be treated with surgery and/or stereotactic radiotherapy/ radiosurgery as soon as possible after diagnosis. If surgery is considered it must be applied before enrolment. Radiotherapy can be performed at any time.
   * History of any solid or hematological malignancy in the past 3 years before registration.

   Exceptions include patients who underwent successful definitive treatment of basal or squamous cell carcinoma of the skin, or any in-situ carcinoma(s).
   * Any uncontrolled, intercurrent illness or clinical situation that would, in the judgment of investigator, limit compliance with study requirements.
   * Any uncontrolled active infection, defined as an infection ≥ grade 3 according to CTCAE version 5.0.
   * Any autoimmune disease that has required systemic treatment in the past 2 years (defined as any use of disease modifying agents, corticosteroids or immunosuppressive drugs).

   Replacement therapy (e.g., thyroxine for hypothyroidism or insulin for type I diabetes) is not considered a form of systemic treatment.

   The following treatments are allowed:
   * Intranasal, inhaled and topical steroids as well as local steroid injections (e.g., intra articular injection).
   * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
   * Systemic corticosteroid replacement therapy for adrenal or pituitary insufficiency.
   * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

     * Known active hepatitis B or C, defined as a positive HBV surface antigen (HBsAg) result or positive HCV RNA.
     * Known active HIV infection, defined as >200 copies of HIV per ml of blood.
     * History of interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or history of non-infectious pneumonitis that required systemic glucocorticoids to assist with management.

   A history of radiation pneumonitis in the radiation field is permitted as long as pneumonitis resolved ≥12 months prior to registration.

   • Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 2 weeks prior to the first dose of cemiplimab.

   Patients who require brief courses of steroids (e.g., as prophylaxis for imaging studies due to hypersensitivity to contrast agents) can be included.
   * Participation in any other clinical study involving an investigational drug or device within 4 weeks before registration.
   * History of documented allergic reaction or acute hypersensitivity reaction attributed to antibody treatments.
   * Sensitivity to any of the study interventions, or components thereof, or other allergy that, in the opinion of the investigator, contraindicates participation in the study.
   * Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol, understanding and completion of questionnaires and follow-up schedule; those conditions should be assessed and discussed with the patient before the enrolment in the trial
2. At randomization Prior to treatment allocation for the consolidation phase an additional set of selection criteria need to be met and stratification factors provided.

Inclusion criteria

* Stable disease, partial or complete response according to RECIST v.1.1 after 4 cycles of induction treatment and radical treatment of all residual disease (if applicable). Patients with progressive disease will be excluded.
* Anticipated life expectancy >12 weeks
* Hepatic function:
* Serum total bilirubin ≤1.5x ULN (or ≤3x ULN, if liver metastases or in patients with history of Gilbert syndrome)
* AST and/or ALT ≤3x ULN (or ≤5x ULN, if liver metastases)
* Renal function:
* GFR based on MDRD equation ≥30 mL/min
* Bone marrow function:
* Hemoglobin ≥9.0 g/dL
* ANC ≥1.5 x 109/L
* Platelet count ≥100 x 109/L
* WOCBP must have a negative serum or highly negative urine pregnancy test within 7 days prior to the first dose of consolidation treatment.

Exclusion criteria

• Use of immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 2 weeks prior to the first dose of cemiplimab/placebo. Patients who require brief courses of steroids (e.g., as prophylaxis for imaging studies due to hypersensitivity to contrast agents) can be included.