Overview

This is a multi-center, double-blind, placebo-controlled randomized phase II study to assess whether continuation of cemiplimab treatment (for up to 12 months) increases progression-free survival (PFS) as compared to placebo in patients with a stage IV, synchronous, oligometastatic non-small cell lung cancer (NSCLC) who have not progressed following 4 cycles of cemiplimab with our without platinum-based chemotherapy and radical treatment.

Eligible patients are randomized with a 1:1 ratio to either the cemiplimab or placebo group and will undergo disease assessment (e.g. imaging, blood tests) at regular follow-up visits.

Eligibility

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.