Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy

The investigational medicinal product denosumab is a protein (monoclonal antibody) that works to slow down bone destruction caused by cancer spreading to the bone (bone metastasis). Denosumab is used in adults with cancer to prevent serious complications caused by bone metastasis (e.g., fracture, pressure on the spinal cord or the need to receive radiation therapy or surgery). Results from one study in lung cancer patients with bone metastasis suggested that adding denosumab to the standard chemotherapy may lead to a possible survival benefit.

All patients will receive standard chemotherapy consisting of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed, depending on the nature of the lung cancer, every 3 weeks for about 3-4 months:

Patients will be assigned to one of two groups, known as 'arms'.

The treatment for each arm will be as follows:

Arm A: 4 - 6 cycles of chemotherapy and best supportive care (including any bone protective agent except denosumab)

Arm B: 4 - 6 cycles of chemotherapy + denosumab 120 mg, administered subcutaneously every 3-4 weeks until unacceptable toxicity, patient refusal or patient's death. After stop of first-line chemotherapy, denosumab must be continued every 3-4 weeks lifelong, regardless of tumour progression and concomitantly with subsequent lines of systemic treatment, as long as tolerable for the patient.

Beyond primary analysis, all subjects randomised to ARM B and still benefitting from the drug will be offered denosumab at a dose of 120 mg s.c. until patient or physician elect to discontinue denosumab for any reason, and for a maximum of 2 years after the required number of events for the final analysis has been reached.

A total of 1000 patients from centers in Europe, Switzerland and Israel are expected to be enrolled in this study over a period of 37 months. The study will take approximately 56 months to be completed.

Inclusion criteria

• Histologically or cytologically confirmed advanced stage IV non-small cell lung carcinoma (NSCLC), according to 7th TNM classification
• Age ≥ 18 years
• ECOG performance status 0-2
• Measurable or evaluable disease (according to RECIST 1.1 criteria) assessed within 28 days from randomization.
• Availability of tumour tissue (as assessed by the local pathologist) for translational research:
• preferred: FFPE block from primary tumour or metastasis,
• alternatively: cell block
• if no block available: 10 freshly cut unstained slides.
• Adequate haematological function: neutrophils ≥ 1.5 ×109/L, platelets

≥ 100×109/L, and hemoglobin ≥ 9 g/dL

• Adequate liver function:
• ALT ≤ 3 × ULN ( ≤ 5 × ULN if liver metastasis are present)
• Total bilirubin < 2 x ULN
• Adequate renal function: calculated renal creatinine clearance (CrCl) ≥ 30 mL/min (according to the formula of Cockroft-Gault)
• Life expectancy of at least 3 months
• Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before enrollment. Pregnancy test has to be repeated within 14 days before treatment start.
• All sexually active men and women of childbearing potential must use an effective contraceptive method during the study treatment and for a period of at least 6 months following the last administration of trial treatment
• Written Informed Consent must be signed and dated by the patient and the investigator prior to any trial-related intervention for

• Trial treatment
• Submission of biomaterial for central testing

Exclusion criteria

• Patients with presence of documented sensitizing EGFR activating mutation or ALK rearrangements (screening following local standards is optional, but strongly encouraged in non-squamous histology)
• Patients with documented brain metastases (systematic screening of patients not mandatory; however, if the patient is symptomatic, brain metastases screening is recommended).
• Prior chemotherapy or molecular targeted therapy for metastatic disease.

Exceptions:

• Neoadjuvant or adjuvant chemotherapy or radio-chemotherapy are allowed if terminated more than 6 months before registration.
• Previous radical radiotherapy without systemic treatment is allowed.
• One previous line of systemic immunotherapy by checkpoint inhibitors is allowed and needs to be documented
• Concomitant treatment with immune checkpoint inhibitors
• Any investigational agent(s) within 30 days prior to randomisation
• Concurrent bisphosphonate administration
• Oral/ dental conditions (by visual inspection):
• Prior history or current evidence of osteomyelitis / osteonecrosis of the jaw
• Active dental or jaw condition which requires oral surgery
• Planned invasive dental procedure for the course of the trial
• Non-healed dental or oral surgery
• Evidence of any medical condition which would impair the ability of the patient to participate in the trial or might preclude therapy with trial drugs (e.g. unstable or uncompensated respiratory, cardiac, hepatic or renal disease, active infection, uncontrolled diabetes mellitus; uncontrolled arterial hypertension ≥ 160/100 mmHg, history of myocardial infarction in the last 3 months)
• Documented active infection with Hepatitis B virus or Hepatitis C virus, known infection with human immunodeficiency virus (HIV)
• Known hypersensitivity to any of the components of the treatment
• Severe, uncorrected hypocalcaemia or hypercalcaemia:
• hypercalcaemia: total calcium >3.1 mmol/l or corrected calcium (with albumin level) >3 mmol/l
• hypocalcaemia: total calcium <2 mmol/l or corrected calcium (with albumin level) < 1.9 mmol/l
• Legal incapacity or limited legal capacity
• Medical or psychological condition, including uncontrolled arterial hypertension (>160/110) despite adequate medication which in the opinion of the investigator would not permit the patient to complete the trial or sign meaningful informed consent
• Women who are pregnant or breastfeeding
• Any concurrent malignancy other than adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ breast carcinoma, or prostate cancer Gleason score < 6. (Patients with a previous malignancy but without evidence of disease for ≥ 2 years will be allowed to enter the trial)
• Any previous exposure to denosumab, with the exception of a maximum of 2 previous doses of denosumab (Prolia®) more than 6 month before enrolment for osteoporosis treatment/prevention.