Lung Cancer, Non-Small Cell
Conditions
Keywords
Niraparib, Pembrolizumab, Maintenance therapy, Chemotherapy, Platinum-based
Brief summary
This is a multicenter, randomized, double-blind, placebo-controlled study of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy in participants with advanced or metastatic non-small cell lung cancer (NSCLC) who have achieved stable disease (SD), partial response (PR), or complete response (CR) following completion of standard of care first-line (SoC 1L) platinum-based induction chemotherapy with pembrolizumab. The primary hypotheses are: participants with confirmed diagnosis of NSCLC could benefit from niraparib plus pembrolizumab versus placebo plus pembrolizumab with respect to Progression-free survival (PFS) and Overall survival (OS).
Interventions
DRUGNiraparib
Niraparib will be administered.
BIOLOGICALPembrolizumab
Pembrolizumab will be administered
DRUGPlacebo
Matching placebo will be administered
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
The participant Investigator study staff and the Sponsor study team will be blinded.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must be \>=18 years of age. * Has a histologically or cytologically confirmed diagnosis of NSCLC without known targetable driver alteration (either non-squamous or squamous histology; mixed histology is allowed for which an approved targeted therapy is available in the 1L induction/maintenance therapy setting). * Has advanced (Stage IIIB or Stage IIIC, not amenable to definitive chemoradiotherapy) or metastatic (Stage IV) or metastatic (Stage IV) NSCLC. * Has completed at least 4 but no more than 6 cycles of SoC 1L platinum-based induction chemotherapy with pembrolizumab. * Has SD, PR, or CR of the NSCLC per Investigator's assessment after completion of 4 to 6 cycles of SoC 1L platinum-based induction chemotherapy with pembrolizumab. * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Has a life expectancy of at least 12 weeks. * Has adequate organ and bone marrow function. * Must submit tumor specimens. * Must be able to swallow and retain orally administered study treatment. * A female is eligible to participate if she is not pregnant or breastfeeding and must follow contraceptive guidance during the treatment period and 180 days afterwards. * A male is eligible to participate if he agrees to contraceptive guidance and refrains from sperm donation during the intervention period and for at least 90 days after the last dose of study treatment. * Is able to understand the study procedures and agrees to participate in the study by providing written informed consent. Participants must be informed that their participation is voluntary. Participants will be required to sign a statement of informed consent to participate in the study.
Exclusion criteria
* Has mixed small cell lung cancer or sarcomatoid variant NSCLC. * Has received prior Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor(s) in prior lines of treatment. * Has systolic blood pressure (BP) \>140 millimeters of mercury (mmHg) or diastolic BP \>90 mmHg. * Has any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels. * Has leptomeningeal disease, carcinomatous meningitis, symptomatic brain metastases, or radiographic signs of CNS hemorrhage. * Has received colony-stimulating factors (granulocyte macrophage colony-stimulating factor or recombinant erythropoietin) within 4 weeks prior to the first dose of study treatment. * Has an active or previously documented autoimmune or inflammatory disorder. * Is receiving chronic systemic steroids (prednisone \>20 mg per day) other than intermittent use of bronchodilators, inhaled steroids, or local steroid. * Has other active concomitant malignancy that warrants systemic, biologic, or hormonal therapy. * Is pregnant, breastfeeding, or expecting to conceive children while receiving study treatment and/or for up to 180 days after the last dose of study treatment. * Has a known history of Myelodysplastic syndrome (MDS) or Acute myeloid leukemia (AML). * Has a known history of active tuberculosis. * Has current active pneumonitis within 90 days of planned start of the study or a known history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis requiring steroid treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Assessed by Blinded Independent Central Review (BICR) - Complete and Partial Response (CR/PR) Population | Up to 52 months | PFS is defined as the time from the date of randomization to the date of first objectively documented disease progression (PD) as determined by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) or death from any cause in the absence of progression, whichever occurs first. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Assessed by BICR - Intent-to-Treat (ITT) Population | Up to 52 months | PFS is defined as the time from the date of randomization to the date of first objectively documented PD as determined by BICR using RECIST v1.1 or death from any cause in the absence of progression, whichever occurs first. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). |
| Overall Survival (OS) - CR/PR Population | Up to 52 months | OS is defined as the interval of time from the date of randomization to the date of death due to any cause. |
| Overall Survival (OS) - ITT Population | Up to 52 months | OS is defined as the interval of time from the date of randomization to the date of death due to any cause. |
| Time to Progression (TTP) in the Central Nervous System (CNS) Assessed by BICR Using RANO-BM Criteria | At Month 6, 12, 18, 24, 30, 36, 42 and 48 | TTP in the CNS is defined as the time from the date of randomization until the earliest date of documented PD in the CNS as assessed by BICR using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. This endpoint was analysed using a cumulative incidence competing-risk analysis, and the cumulative incidence rate was reported. |
| Progression-free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1 | Up to 52 months | PFS is defined as the time from the date of randomization to the date of first objectively documented PD as determined by investigators using RECIST v1.1 or death from any cause in the absence of progression, whichever occurs first. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). |
| CNS-PFS as Assessed by BICR Using RANO-BM Criteria | At Month 6, 12, 18, 24, 30, 36, 42 and 48 | PFS is defined as the time from the date of randomization to the date of first radiographic progression in the CNS as determined by BICR using RANO-BM criteria or until death due to any cause (whichever occurs first). This endpoint was analysed using a cumulative incidence competing-risk analysis, and the cumulative incidence rate was reported. |
| Progression-free Survival (PFS) by Programmed Cell Death-ligand 1 (PD-L1) Status | Up to 52 months | PFS is defined as the time from the date of randomization to the date of first objectively documented PD as determined by BICR using RECIST v1.1 or death from any cause in the absence of progression, whichever occurs first. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Participants were evaluated by PD-L1 status: Tumor Cells (TCs) ≥1% and TCs \<1%/Not Evaluable. |
| Overall Survival by Programmed Cell Death-ligand 1 (PD-L1) Status | Up to 52 months | OS is defined as the interval of time from the date of randomization to the date of death due to any cause. Participants were evaluated by PD-L1 status: Tumor Cells (TCs) ≥1% and TCs \<1%/Not Evaluable. |
| Number of Participants With Minimally Clinically Important Difference (MCID) Status in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC-QLQ-C30) | Baseline (Predose); Day (D) 1 of Cycle (C)2, C3, C4, C5-C67 (odd cycles only); End of Treatment (EoT, up to approx 49 months); Safety follow-up (SFU) 1 & 2 (up to approx 50 & 52 months) | The EORTC QLQ-C30 includes 30-items with single and multi-item scales. These included five functional scales (physical functioning \[PF\], role functioning \[RF\], cognitive functioning \[CF\], emotional functioning \[EF\] and social functioning \[SF\]), three symptom scales (fatigue, pain and nausea/vomiting \[N/V\]), a global health status (GHS)/ Quality-of-Life (QoL) scale, and six single items (constipation, diarrhoea, insomnia, dyspnoea, appetite loss \[AL\] and financial difficulties \[FD\]). Response options are 1 to 4. Scores were averaged and transformed to 0 to 100, a high score for functional scales/ GHS/QoL represent better functioning ability or health-related quality-of-life (HRQoL), whereas a high score for symptom scales/ single items represent significant symptomatology. MCID status: Functional scales \& GHS/QoL (Improved: ≥ +10; Stable: \> -10 and \< +10; Worsened: ≤ -10) and Symptom scales (Improved: ≤ -10; Stable: \> -10 and \< +10; Worsened: ≥ +10) |
| Changes From Baseline (CFB) in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 13-item Lung Cancer-specific Module (EORTC QLQ-LC13) | Baseline (Predose); Day (D) 1 of Cycle (C)2, C3, C4, C5-C67 (odd cycles only); EoT (up to approx 49 months); Safety follow-up (SFU) 1 & 2 (up to approx 50 & 52 months) | EORTC QLQ-LC13 is a 13-items questionnaire used in clinical research to assess health-related quality of life in lung cancer patients. The QLQ-LC13 includes questions assessing lung cancer-associated symptoms (Coughing, hemoptysis, dyspnea and site specific pain), treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy and alopecia) and pain medication. Scores are calculated and transformed to range from 0 to 100. For the disease symptoms and side-effects of treatment scales a higher score represents a higher level of symptoms/problems and a negative change from baseline value indicates reduction (i.e. improvement) in symptoms. |
| Time to Deterioration (TTD) in EORTC Cancer Quality of Life Questionnaire LC13 (EORTC QLQ-LC13) | Up to 52 months | TTD in lung symptoms is defined as the time from randomization to first onset of ≥10 point increase from baseline with confirmation by a second adjacent ≥10 point increase in the same symptom domain for any of the three symptoms: dyspnea, chest pain, and cough, on the EORTC QLQ-LC13 were scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0-100. A lower score indicates a better outcome. A longer TTD indicates a better outcome. |
| Number of Participants With Treatment Emergent (TE) Adverse Events (AEs), Serious TEAEs and Adverse Events of Special Interest (AESIs) | Up to 52 months | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, is life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, is a congenital anomaly/birth defect, other situations and is associated with liver injury or impaired liver function. SAEs are subsets of AEs. TEAE is an event that emerged during treatment having been absent pretreatment or worsened relative to the pretreatment state. AESI is any AE (serious or nonserious) that is of scientific and medical concern specific to niraparib for which ongoing monitoring and rapid communication by the Investigator to the Sponsor is warranted. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding system. |
| Plasma Concentrations of Niraparib | Cycle 1 Day 1 (pre-dose, 3 h), Cycle 1 Day 15 (pre-dose, 3 h), Cycle 2 Day 1 (pre-dose, 3 h), Cycle 4 Day 1 (pre-dose), Cycle 7 Day 1 (pre-dose), and End of Treatment (pre-dose); up to approximately 49 months | Blood samples were collected for plasma concentrations of niraparib. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Chile, Colombia, France, Germany, Greece, Hungary, Ireland, Italy, Mexico, Netherlands, Norway, Peru, Poland, Romania, Russia, South Korea, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORGSK Clinical Trials
GlaxoSmithKline
Participant flow
Pre-assignment details
The results presented are until the primary completion date. Additional safety results will be submitted within a year of study completion.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 65.2 YEARS STANDARD_DEVIATION 8.91 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 5 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants |
| Race/Ethnicity, Customized White | 322 Participants |
| Sex: Female, Male Female | 106 Participants |
| Sex: Female, Male Male | 448 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 196 / 329 | 177 / 329 |
| other Total, other adverse events | 293 / 329 | 261 / 329 |
| serious Total, serious adverse events | 97 / 329 | 81 / 329 |
Outcome results
None listed