Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Bone Density Conservation Agents

Gemcitabine

Carboplatin

Pemetrexed

Cisplatin

Denosumab

Protective Agents

4 - 6 cycles of standard chemotherapy + best supportive care including any bone protective agent except denosumab.

Standard chemotherapy consis of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed.

4 - 6 cycles of standard chemotherapy + denosumab 120 mg, administered subcutaneously every 3-4 weeks until unacceptable toxicity, patient refusal, or patient's death. Denosumab should be administered on day 1 of each cycle, before or after the administration of chemotherapy. After stop of first-line chemotherapy, denosumab must be continued life-long, regardless of tumour progression and concomitantly with subsequent lines of systemic treatment, as long as tolerable for the patient.

Standard chemotherapy consis of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed.

Denosumab: 120 mg, s.c. every 3-4 weeks (in cycle 1 additional dose on day 8) until unacceptable toxicity, patient refusal or patient's death (max. 4 years 3 months).

Possible standard chemotherapies (3 weeks cycles, duration: 4 - 6 cycles):

Cisplatin 75 mg/m2 as an infusion on day 1 Gemcitabine 1250 mg/m2 as an infusion days 1 and 8 or Carboplatin AUC 5 as an infusion on day 1 Gemcitabine 1000 mg/m2 as an infusion days 1 and 8 or Cisplatin 75 mg/m2 as an infusion on day 1 Pemetrexed 500 mg/m2 as an infusion on day 1 or Carboplatin AUC 5 as an infusion on day 1 Pemetrexed 500 mg/m2 as an infusion on day 1

None, standard chemotherapy only

Solange Peters, MD, PhD

Mary O'Brien, MD

Sarah Danson, PhD

Rolf Stahel, MD

The purpose of this study is to investigate how well the standard treatment (platinum-based doublet chemotherapy) in combination with denosumab works compared with the standard treatment alone in patients with a type of lung cancer called "non small cell lung cancer" (NSCLC) that has spread to other parts of the body.

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.

Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy

A Randomised, Open-label Phase III Trial Evaluating the Addition of Denosumab to Standard First-line Anticancer Treatment in Advanced NSCLC

OS will be defined as the time from the date of randomization to the date of death, whatever the cause. The follow-up of participants still alive will be censored at the moment of last follow-up. OS will be reported for all participants in both treatment arms.

Progression-free survival (PFS) is defined as time from date of randomisation until objective disease progression or death, whichever occurs first. Disease progression and its evaluation are defined based on RECIST 1.1: Progressive disease (PD); \> 20% increase in the sum of the longest diameter of target lesions, new lesions or non-equivocal progression in non-target disease.

If neither event has been observed, then the patient is censored at the date of the last follow up examination.

Patients with new non-lung cancer malignancy must continue to be followed for progression of the original lung cancer.

Patients who discontinue treatment prior to documented disease progression, including those who initiate non-protocol therapy prior to progression, will be followed for disease progression and death.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

For more details to RECIST 1.1 criteria, see https://recist.eortc.org/

Number of patients with serious adverse events classified according to NCI CTCAE V4.

Overall survival is defined as time from the date of randomisation until death from any cause. Patients who are still alive at last contact are censored at the date of last follow up.

European Organisation for Research and Treatment of Cancer - EORTC

Amgen

ETOP IBCSG Partners Foundation

4 - 6 cycles of standard chemotherapy + best supportive care including any bone protective agent except denosumab.

Standard chemotherapy consis of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed.

None, standard chemotherapy only: Possible standard chemotherapies (3 weeks cycles, duration: 4 - 6 cycles):

Cisplatin 75 mg/m2 as an infusion on day 1 Gemcitabine 1250 mg/m2 as an infusion days 1 and 8 or Carboplatin AUC 5 as an infusion on day 1 Gemcitabine 1000 mg/m2 as an infusion days 1 and 8 or Cisplatin 75 mg/m2 as an infusion on day 1 Pemetrexed 500 mg/m2 as an infusion on day 1 or Carboplatin AUC 5 as an infusion on day 1 Pemetrexed 500 mg/m2 as an infusion on day 1

None, Standard Chemotherapy Only

4 - 6 cycles of standard chemotherapy + denosumab 120 mg, administered subcutaneously every 3-4 weeks until unacceptable toxicity, patient refusal, or patient's death. Denosumab should be administered on day 1 of each cycle, before or after the administration of chemotherapy. After stop of first-line chemotherapy, denosumab must be continued life-long, regardless of tumour progression and concomitantly with subsequent lines of systemic treatment, as long as tolerable for the patient.

Standard chemotherapy consis of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed.

Denosumab: Denosumab: 120 mg, s.c. every 3-4 weeks (in cycle 1 additional dose on day 8) until unacceptable toxicity, patient refusal or patient's death (max. 4 years 3 months).

Standard Chemotherapy + Denosumab

Total

Age, Categorical

Sex: Female, Male

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

Squamous

Non-squamous

Mixed

Histology

Bone metastasis

PS 0/1 (fully active or lightly restricted)

PS 2 (ambulatory and capable of selfcare but unable to carry out work activities)

This tool describes a patient's level of functioning in terms of their ability to care for themself, daily activity, and physical ability (walking, working, etc.).

PS 0: Fully active PS 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature PS 2: Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours

ECOG Performance status (PS)

Eastern Europe

Western Europe

Southern Europe

Region

The study steering committee decided to close the study prematurely due to poor accrual. The primary analysis is therefore underpowered.

European Thoracic Oncology Platform

Overall Survival

Progression-free Survival (PFS) Based on RECIST 1.1

Number of Participants With Response (CR+PR) Based on RECIST 1.1

Toxicity Profile of Denosumab

Membranous RANK(+) patients only, receiving

4 - 6 cycles of standard chemotherapy + best supportive care including any bone protective agent except denosumab.

Standard chemotherapy consis of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed.

None, standard chemotherapy only: Possible standard chemotherapies (3 weeks cycles, duration: 4 - 6 cycles):

Cisplatin 75 mg/m2 as an infusion on day 1 Gemcitabine 1250 mg/m2 as an infusion days 1 and 8 or Carboplatin AUC 5 as an infusion on day 1 Gemcitabine 1000 mg/m2 as an infusion days 1 and 8 or Cisplatin 75 mg/m2 as an infusion on day 1 Pemetrexed 500 mg/m2 as an infusion on day 1 or Carboplatin AUC 5 as an infusion on day 1 Pemetrexed 500 mg/m2 as an infusion on day 1

None, Standard Chemotherapy Only, RANK (+)

Membranous RANK(+) patients only, receiving

4 - 6 cycles of standard chemotherapy + denosumab 120 mg, administered subcutaneously every 3-4 weeks until unacceptable toxicity, patient refusal, or patient's death. Denosumab should be administered on day 1 of each cycle, before or after the administration of chemotherapy. After stop of first-line chemotherapy, denosumab must be continued life-long, regardless of tumour progression and concomitantly with subsequent lines of systemic treatment, as long as tolerable for the patient.

Standard chemotherapy consis of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed.

Denosumab: Denosumab: 120 mg, s.c. every 3-4 weeks (in cycle 1 additional dose on day 8) until unacceptable toxicity, patient refusal or patient's death (max. 4 years 3 months).

Standard Chemotherapy + Denosumab, RANK (+)

Membranous RANK (-) patients only, receiving 4 - 6 cycles of standard chemotherapy + best supportive care including any bone protective agent except denosumab.

Standard chemotherapy consis of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed.

None, standard chemotherapy only: Possible standard chemotherapies (3 weeks cycles, duration: 4 - 6 cycles):

Cisplatin 75 mg/m2 as an infusion on day 1 Gemcitabine 1250 mg/m2 as an infusion days 1 and 8 or Carboplatin AUC 5 as an infusion on day 1 Gemcitabine 1000 mg/m2 as an infusion days 1 and 8 or Cisplatin 75 mg/m2 as an infusion on day 1 Pemetrexed 500 mg/m2 as an infusion on day 1 or Carboplatin AUC 5 as an infusion on day 1 Pemetrexed 500 mg/m2 as an infusion on day 1

None, Standard Chemotherapy Only, RANK (-)

Membranous RANK(-) patients only, receiving

4 - 6 cycles of standard chemotherapy + denosumab 120 mg, administered subcutaneously every 3-4 weeks until unacceptable toxicity, patient refusal, or patient's death. Denosumab should be administered on day 1 of each cycle, before or after the administration of chemotherapy. After stop of first-line chemotherapy, denosumab must be continued life-long, regardless of tumour progression and concomitantly with subsequent lines of systemic treatment, as long as tolerable for the patient.

Standard chemotherapy consis of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed.

Denosumab: Denosumab: 120 mg, s.c. every 3-4 weeks (in cycle 1 additional dose on day 8) until unacceptable toxicity, patient refusal or patient's death (max. 4 years 3 months).

Standard Chemotherapy + Denosumab, RANK(-)

Information on RANK(L) measurements was available for 463 patients, 229 in chemotherapy alone and 234 in chemotherapy-denosumab arm, among the total 514 patients randomized in the SPLENDOUR trial.

Overall Survival by Membranous RANK Expression.

Cytoplasmic RANK(+) patients only, receiving

4 - 6 cycles of standard chemotherapy + best supportive care including any bone protective agent except denosumab.

Standard chemotherapy consis of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed.

None, standard chemotherapy only: Possible standard chemotherapies (3 weeks cycles, duration: 4 - 6 cycles):

Cisplatin 75 mg/m2 as an infusion on day 1 Gemcitabine 1250 mg/m2 as an infusion days 1 and 8 or Carboplatin AUC 5 as an infusion on day 1 Gemcitabine 1000 mg/m2 as an infusion days 1 and 8 or Cisplatin 75 mg/m2 as an infusion on day 1 Pemetrexed 500 mg/m2 as an infusion on day 1 or Carboplatin AUC 5 as an infusion on day 1 Pemetrexed 500 mg/m2 as an infusion on day 1

Cytoplasmic RANK(+) patients only receiving

4 - 6 cycles of standard chemotherapy + denosumab 120 mg, administered subcutaneously every 3-4 weeks until unacceptable toxicity, patient refusal, or patient's death. Denosumab should be administered on day 1 of each cycle, before or after the administration of chemotherapy. After stop of first-line chemotherapy, denosumab must be continued life-long, regardless of tumour progression and concomitantly with subsequent lines of systemic treatment, as long as tolerable for the patient.

Standard chemotherapy consis of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed.

Denosumab: Denosumab: 120 mg, s.c. every 3-4 weeks (in cycle 1 additional dose on day 8) until unacceptable toxicity, patient refusal or patient's death (max. 4 years 3 months).

Cytoplasmic RANK(-) patients only, receiving

4 - 6 cycles of standard chemotherapy + best supportive care including any bone protective agent except denosumab.

Standard chemotherapy consis of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed.

None, standard chemotherapy only: Possible standard chemotherapies (3 weeks cycles, duration: 4 - 6 cycles):

Cisplatin 75 mg/m2 as an infusion on day 1 Gemcitabine 1250 mg/m2 as an infusion days 1 and 8 or Carboplatin AUC 5 as an infusion on day 1 Gemcitabine 1000 mg/m2 as an infusion days 1 and 8 or Cisplatin 75 mg/m2 as an infusion on day 1 Pemetrexed 500 mg/m2 as an infusion on day 1 or Carboplatin AUC 5 as an infusion on day 1 Pemetrexed 500 mg/m2 as an infusion on day 1

Cytoplasmic RANK(-) patients only, receiving

4 - 6 cycles of standard chemotherapy + denosumab 120 mg, administered subcutaneously every 3-4 weeks until unacceptable toxicity, patient refusal, or patient's death. Denosumab should be administered on day 1 of each cycle, before or after the administration of chemotherapy. After stop of first-line chemotherapy, denosumab must be continued life-long, regardless of tumour progression and concomitantly with subsequent lines of systemic treatment, as long as tolerable for the patient.

Standard chemotherapy consis of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed.

Denosumab: Denosumab: 120 mg, s.c. every 3-4 weeks (in cycle 1 additional dose on day 8) until unacceptable toxicity, patient refusal or patient's death (max. 4 years 3 months).

Spots Global Cancer Trial Database for none, standard chemotherapy only