Lung Cancer Non-small Cell Stage IV
Conditions
Keywords
NSCLC, stage IV
Brief summary
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.
Detailed description
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.
Interventions
DRUGDenosumab
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).
OTHERNone, 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
Sponsors
ETOP IBCSG Partners Foundation
European Organisation for Research and Treatment of Cancer - EORTC
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 1. Trial treatment 2. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Overall survival was measured from the date of randomization to the date of death, whatever the cause, up to a maximum of 56 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Based on RECIST 1.1 | Time from date of randomisation until objective disease progression or death, whichever occurs first, assessed up to a maximum of 56 months | 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. |
| Number of Participants With Response (CR+PR) Based on RECIST 1.1 | Response of the tumour is defined according to RECIST 1.1 criteria, assessed up to 56 months | 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/ |
| Toxicity Profile of Denosumab | Assessed up to 56 months | Number of patients with serious adverse events classified according to NCI CTCAE V4. |
| Overall Survival by Membranous RANK Expression. | Up to maximum of 56 months | 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. |
| Overall Survival by Cytoplasmic RANK Expression. | up to a maximum of 56 months | 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. |
Countries
Austria, Belgium, France, Germany, Ireland, Italy, Poland, Slovenia, Spain, Switzerland, United Kingdom
Contacts
STUDY_CHAIRSolange Peters, MD, PhD
Trial Chair, CHUV Lausanne, Switzerland
STUDY_CHAIRMary O'Brien, MD
EORTC Trial Co-Chair, Royal Marden Hospital, Sutton, UK
STUDY_CHAIRSarah Danson, PhD
EORTC Trial Co-Chair, University of Sheffield, Sheffield, UK
STUDY_CHAIRRolf Stahel, MD
Trial Co-Chair, University Hospital of Zuerich, Switzerland
Participant flow
Recruitment details
The first patient was screened on Jan 12, 2015. On Jan 31, 2018, when accrual to the study was closed, 595 patients were registered in the study by 55 sites in 10 countries. Of the 595 patients who were screened and registered, 514 (86%) were randomized.
Pre-assignment details
Age ≥ 18 years ECOG performance status 0-2 Histologically or cytologically confirmed advanced stage IV non-small cell lung carcinoma (NSCLC), according to 7th TNM classification Life expectancy of at least 3 months.
Participants by arm
| Arm | Count |
|---|---|
| None, Standard Chemotherapy Only 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 | 255 |
| Standard Chemotherapy + Denosumab 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). | 259 |
| Total | 514 |
Baseline characteristics
| Characteristic | None, Standard Chemotherapy Only | Standard Chemotherapy + Denosumab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 138 Participants | 152 Participants | 290 Participants |
| Age, Categorical Between 18 and 65 years | 117 Participants | 107 Participants | 224 Participants |
| Bone metastasis No | 118 participants | 121 participants | 239 participants |
| Bone metastasis Yes | 137 participants | 138 participants | 275 participants |
| ECOG Performance status (PS) PS 0/1 (fully active or lightly restricted) | 229 participants | 230 participants | 459 participants |
| ECOG Performance status (PS) PS 2 (ambulatory and capable of selfcare but unable to carry out work activities) | 26 participants | 29 participants | 55 participants |
| Histology Mixed | 3 participants | 6 participants | 9 participants |
| Histology Non-squamous | 187 participants | 183 participants | 370 participants |
| Histology Squamous | 65 participants | 70 participants | 135 participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region Eastern Europe | 18 participants | 10 participants | 28 participants |
| Region Southern Europe | 84 participants | 87 participants | 171 participants |
| Region Western Europe | 153 participants | 162 participants | 315 participants |
| Sex: Female, Male Female | 187 Participants | 179 Participants | 366 Participants |
| Sex: Female, Male Male | 68 Participants | 80 Participants | 148 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 178 / 255 | 177 / 259 |
| other Total, other adverse events | 235 / 255 | 246 / 259 |
| serious Total, serious adverse events | 97 / 255 | 138 / 259 |
Outcome results
Primary
Overall Survival
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.
Time frame: Overall survival was measured from the date of randomization to the date of death, whatever the cause, up to a maximum of 56 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| None, Standard Chemotherapy Only | Overall Survival | 0.73 years |
| Standard Chemotherapy + Denosumab | Overall Survival | 0.68 years |
p-value: 0.35595% CI: [0.78, 1.19]Regression, Cox
Secondary
Number of Participants With Response (CR+PR) Based on RECIST 1.1
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/
Time frame: Response of the tumour is defined according to RECIST 1.1 criteria, assessed up to 56 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| None, Standard Chemotherapy Only | Number of Participants With Response (CR+PR) Based on RECIST 1.1 | Complete response | 1 Participants |
| None, Standard Chemotherapy Only | Number of Participants With Response (CR+PR) Based on RECIST 1.1 | Partial response | 74 Participants |
| None, Standard Chemotherapy Only | Number of Participants With Response (CR+PR) Based on RECIST 1.1 | Stable disease | 101 Participants |
| None, Standard Chemotherapy Only | Number of Participants With Response (CR+PR) Based on RECIST 1.1 | Progressive disease | 51 Participants |
| None, Standard Chemotherapy Only | Number of Participants With Response (CR+PR) Based on RECIST 1.1 | Not evaluable | 27 Participants |
| None, Standard Chemotherapy Only | Number of Participants With Response (CR+PR) Based on RECIST 1.1 | Missing | 1 Participants |
| Standard Chemotherapy + Denosumab | Number of Participants With Response (CR+PR) Based on RECIST 1.1 | Not evaluable | 23 Participants |
| Standard Chemotherapy + Denosumab | Number of Participants With Response (CR+PR) Based on RECIST 1.1 | Complete response | 1 Participants |
| Standard Chemotherapy + Denosumab | Number of Participants With Response (CR+PR) Based on RECIST 1.1 | Progressive disease | 70 Participants |
| Standard Chemotherapy + Denosumab | Number of Participants With Response (CR+PR) Based on RECIST 1.1 | Partial response | 78 Participants |
| Standard Chemotherapy + Denosumab | Number of Participants With Response (CR+PR) Based on RECIST 1.1 | Missing | 0 Participants |
| Standard Chemotherapy + Denosumab | Number of Participants With Response (CR+PR) Based on RECIST 1.1 | Stable disease | 87 Participants |
Secondary
Overall Survival by Cytoplasmic RANK Expression.
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.
Time frame: up to a maximum of 56 months
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| None, Standard Chemotherapy Only | Overall Survival by Cytoplasmic RANK Expression. | 10.1 Months |
| Standard Chemotherapy + Denosumab | Overall Survival by Cytoplasmic RANK Expression. | 8.5 Months |
| None, Standard Chemotherapy Only, RANK (-) | Overall Survival by Cytoplasmic RANK Expression. | 7.8 Months |
| Standard Chemotherapy + Denosumab, RANK(-) | Overall Survival by Cytoplasmic RANK Expression. | 7.9 Months |
Secondary
Overall Survival by Membranous RANK Expression.
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.
Time frame: Up to maximum of 56 months
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| None, Standard Chemotherapy Only | Overall Survival by Membranous RANK Expression. | 7.1 Months |
| Standard Chemotherapy + Denosumab | Overall Survival by Membranous RANK Expression. | 8.2 Months |
| None, Standard Chemotherapy Only, RANK (-) | Overall Survival by Membranous RANK Expression. | 9.1 Months |
| Standard Chemotherapy + Denosumab, RANK(-) | Overall Survival by Membranous RANK Expression. | 7.9 Months |
Secondary
Progression-free Survival (PFS) Based on RECIST 1.1
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.
Time frame: Time from date of randomisation until objective disease progression or death, whichever occurs first, assessed up to a maximum of 56 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| None, Standard Chemotherapy Only | Progression-free Survival (PFS) Based on RECIST 1.1 | .39 years |
| Standard Chemotherapy + Denosumab | Progression-free Survival (PFS) Based on RECIST 1.1 | .39 years |
p-value: 0.45995% CI: [0.82, 1.19]Regression, Cox
Secondary
Toxicity Profile of Denosumab
Number of patients with serious adverse events classified according to NCI CTCAE V4.
Time frame: Assessed up to 56 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| None, Standard Chemotherapy Only | Toxicity Profile of Denosumab | Patients with serious adverse events | 97 Participants |
| None, Standard Chemotherapy Only | Toxicity Profile of Denosumab | Patients without serious adverse events | 158 Participants |
| Standard Chemotherapy + Denosumab | Toxicity Profile of Denosumab | Patients with serious adverse events | 138 Participants |
| Standard Chemotherapy + Denosumab | Toxicity Profile of Denosumab | Patients without serious adverse events | 121 Participants |