Non-small Cell Lung Cancer (NSCLC)
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of tiragolumab in combination with atezolizumab plus pemetrexed and carboplatin/cisplatin (Arm A) compared with placebo in combination with pembrolizumab plus pemetrexed and carboplatin/cisplatin (Arm B) in participants with previously untreated, locally advanced unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC). Eligible participants will be randomized in a 1:1 ratio to receive one of the following treatment regimens during the induction phase: * Arm A: Tiragolumab plus atezolizumab plus pemetrexed and carboplatin or cisplatin * Arm B: Placebo plus pembrolizumab plus pemetrexed and carboplatin or cisplatin Following the induction phase, participants will continue maintenance therapy with either tiragolumab in combination with atezolizumab and pemetrexed (Arm A) or placebo in combination with pembrolizumab and pemetrexed (Arm B).
Interventions
DRUGTiragolumab
Tiragolumab at a fixed dose of 600 milligrams (mg), administered by intravenous (IV) infusion, every 3 weeks (Q3W) on Day 1 of each 21-day cycle.
DRUGAtezolizumab
Atezolizumab at a fixed dose of 1200 mg, administered by IV infusion, Q3W on Day 1 of each 21-day cycle.
DRUGPemetrexed
Pemetrexed 500 milligrams per square meter (mg/m\^2), administered by IV infusion, Q3W on Day 1 of each 21-day cycle.
DRUGCarboplatin
Carboplatin at dose of area under the concentration-time curve (AUC) of 5, administered by IV infusion, Q3W on Day 1 of each 21-day cycle for 4 cycles.
DRUGCisplatin
Cisplatin 75 mg/m\^2, administered by IV infusion, Q3W on Day 1 of each 21-day cycle for 4 cycles.
Matching placebo, administered by IV infusion, Q3W on Day 1 of each 21-day cycle.
DRUGPembrolizumab
Pembrolizumab at a fixed dose of 200 mg, administered by IV infusion, Q3W, on Day 1 of each 21-day cycle.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Histologically or cytologically documented locally advanced unresectable or metastatic non-squamous NSCLC that is not eligible for curative surgery and/or definitive chemoradiotherapy * No prior systemic treatment for metastatic non-squamous NSCLC * Known tumor programmed death-ligand 1 (PD-L1) status * Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) * Life expectancy \>= 12 weeks * Adequate hematologic and end-organ function * Negative human immunodeficiency virus (HIV) test at screening * Serology test negative for active hepatitis B virus or active hepatitis C virus at screening. Key
Exclusion criteria
* Mutations in epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) fusion oncogene * Pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC * Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases * Active or history of autoimmune disease or immune deficiency * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis * History of malignancy other than NSCLC within 5 years prior to randomization, with the exception of malignancies with a negligible risk of metastasis or death * Severe infection within 4 weeks prior to initiation of study treatment or any active infection that, in the opinion of the investigator, could impact patient safety * Treatment with investigational therapy within 28 days prior to initiation of study treatment * Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T lymphocyte-associated protein 4, anti-TIGIT, anti-PD-1, and anti-PD-L1 therapeutic antibodies * Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment * Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment * Known allergy or hypersensitivity or other contraindication to any component of the chemotherapy regimen the participant may receive during the study * Women who are pregnant, or breastfeeding * Known targetable c-ROS oncogene 1 (ROS1) or BRAFV600E genomic aberration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) as Determined by the Investigator | From randomization to first occurrence of PD or death from any cause (up to approximately 40 months) | PFS was defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) criteria, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters (SOD) of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline), in addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥5 mm or unequivocal progression of existing non-target lesions. Kaplan-Meier (KM) methodology was used to estimate the median PFS. |
| Overall Survival (OS) | From randomization to death from any cause (up to approximately 40 months) | OS was defined as the time from randomization to death from any cause. KM methodology was used to estimate the median OS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS as Determined by the Independent Review Facility (IRF) | From randomization to first occurrence of PD or death from any cause (up to approximately 40 months) | PFS was defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to RECIST v1.1 criteria, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline), in addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥5 mm or unequivocal progression of existing non-target lesions. KM methodology was used to estimate the median PFS. |
| Investigator Assessed PFS in Participants With PD-L1 Expression at TPS/TC >=1% | From randomization to first occurrence of PD or death from any cause (up to approximately 40 months) | PFS was defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to RECIST v1.1 criteria, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline), in addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥5 mm or unequivocal progression of existing non-target lesions. KM methodology was used to estimate the median PFS. |
| Investigator Assessed PFS in Participants With PD-L1 Expression at TPS/TC >=50% | From randomization to first occurrence of PD or death from any cause (up to approximately 40 months) | PFS was defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) criteria, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline), in addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥5 mm or unequivocal progression of existing non-target lesions. KM methodology was used to estimate the median PFS. |
| OS in Participants With PD-L1 Expression at TPS/TC >=1% | From randomization to death from any cause (up to approximately 40 months) | OS was defined as the time from randomization to death from any cause. KM methodology was used to estimate the median OS. |
| OS in Participants With PD-L1 Expression at TPS/TC >= 50% | From randomization to death from any cause (up to approximately 40 months) | OS was defined as the time from randomization to death from any cause. KM methodology was used to estimate the median OS. |
| PFS Rate at Month 6 and Month 12 | At Month 6 and Month 12 | PFS at 6 months and 12 months was defined as the percentage of participants who have not experienced PD as determined by the investigator according to RECIST v1.1 or death from any cause at 6 months and at 12 months, respectively. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline), in addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥5 mm or unequivocal progression of existing non-target lesions. |
| OS Rate at Month 12 and Month 24 | At Month 12 and Month 24 | OS rate at 12 months and 24 months was defined as the percentage of participants who have not experienced death from any cause at 12 and 24 months, respectively. |
| Duration of Response (DOR) | Up to approximately 40 months | DOR was defined as the time from the first occurrence of a documented objective response (OR) to PD, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurred first. Complete response (CR) was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target lesions) must have a reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. Partial response (PR) was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline) or unequivocal progression of existing non-target lesions. In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥5 mm. KM methodology was used to estimate the median DOR. |
| Objective Response Rate (ORR) | Up to approximately 40 months | ORR was defined as a percentage of participants with a CR or PR on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1. CR was defined as disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target lesions) must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off. |
| Time to Confirmed Deterioration (TTCD) in Participant-Reported Physical Functioning (PF) as Measured by European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC-QLQ-C30) | Up to approximately 40 months | EORTC QLQ-C30=self-reported measure, with 30 questions assessing 5 aspects of subjects functioning (physical, emotional, role, cognitive \& social), 3 symptom scales (fatigue, nausea \& vomiting, \& pain), global health status (GHS) \& Quality of Life (QoL), \& 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea \& financial difficulties) within the previous week. Functioning \& symptoms items were scored on a 4-point scale: 1=not at all to 4=very much. Scores were linearly transformed to a range of 0 to 100, with higher scores reflecting better functioning. TTCD was defined time from the date of randomization until the first confirmed clinically meaningful deterioration. Confirmed clinically meaningful deterioration was defined as score decrease of ≥10 from baseline in PF scale score that were held for at least two consecutive assessments or an initial ≥10 decrease from baseline followed by death from any cause within 3 weeks. |
| TTCD in Participant-Reported Global Health Status (GHS)/Quality of Life (QoL) as Measured by EORTC QLQ-C30 | Up to approximately 40 months | EORTC QLQ-C30=self-reported measure, with 30 questions assessing 5 aspects of subjects functioning (physical, emotional, role, cognitive \& social), 3 symptom scales (fatigue, nausea \& vomiting, \& pain), global health status (GHS) \& Quality of Life (QoL), \& 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea \& financial difficulties) within the previous week . GHS and QoL items were scored on a 7-point scale (1=very poor 7=excellent). Scores were linearly transformed to a range of 0 to 100, with higher scores reflecting better GHS/QoL. TTCD was defined as time from the date of randomization until the first confirmed clinically meaningful deterioration. Confirmed clinically meaningful deterioration was defined as score decrease of ≥10 from baseline in GHS/QoL scale score that were held for at least two consecutive assessments or an initial ≥10 decrease from baseline followed by death from any cause within 3 weeks. |
| TTCD in Participant-Reported Dyspnoea as Measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 13 (EORTC QLQ-LC13) | Up to approximately 40 months | The EORTC QLQ-LC13 is comprised of 13 lung cancer-specific items and includes 11 disease-specific scales/items (dyspnea, coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, pain in chest, pain in arm or shoulder, pain in other parts, pain medication). Symptoms were scored on a 4-point scale: 1=not at all to 4=very much. Scores are linearly transformed to a range of 0 to 100. A higher score indicates a worse level of dyspnoea. TTCD was defined as time from the date of randomization until the first confirmed clinically meaningful deterioration. Confirmed clinically meaningful deterioration in symptoms was defined as a score increase of ≥ 10-point from baseline in a symptom score that must be held for at least two consecutive assessments or an initial increase ≥ 10-point from baseline followed by death from any cause within 3 weeks. |
| TTCD in Participant-Reported Chest Pain, as Measured by EORTC QLQ-LC13 | Up to approximately 40 months | The EORTC QLQ-LC13 is comprised of 13 lung cancer-specific items and includes 11 disease-specific scales/items (dyspnea, coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, pain in chest, pain in arm or shoulder, pain in other parts, pain medication). Chest pain were scored on a 4-point scale: 1=not at all to 4=very much. Scores are linearly transformed to a range of 0 to 100. A higher score indicates a worse level of chest pain. TTCD was defined as time from the date of randomization until the first confirmed clinically meaningful deterioration. Confirmed clinically meaningful deterioration in symptoms was defined as a score increase of ≥ 10-point from baseline in a symptom score that must be held for at least two consecutive assessments or an initial increase ≥ 10-point from baseline followed by death from any cause within 3 weeks. |
| TTCD in Participant-Reported Cough, as Measured by EORTC QLQ-LC13 | Up to approximately 40 months | The EORTC QLQ-LC13 is comprised of 13 lung cancer-specific items and includes 11 disease-specific scales/items (dyspnea, coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, pain in chest, pain in arm or shoulder, pain in other parts, pain medication). Cough were scored on a 4-point scale: 1=not at all to 4=very much. Scores are linearly transformed to a range of 0 to 100. A higher score indicates a worse level of cough. TTCD was defined as time from the date of randomization until the first confirmed clinically meaningful deterioration. Confirmed clinically meaningful deterioration in symptoms was defined as a score increase of ≥ 10-point from baseline in a symptom score that must be held for at least two consecutive assessments or an initial increase ≥ 10-point from baseline followed by death from any cause within 3 weeks. |
| Number of Participants With Adverse Events (AEs) | From study start up to 90 days after last dose (up to approximately 40.8 months) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptoms, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. |
| Number of Participants With Response to Side Effects of Treatment as Assessed by European Organisation for Research and Treatment of Cancer Item List 46 (EORTC IL46) | Baseline, Day 1 of Cycles 2, 3, 4, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57 and treatment discontinuation visit (each cycle=21 days) (Up to 40 months) | The EORTC IL46 is a validated single-item question that assesses overall side effect impact, i.e. "To what extent have you been troubled with side-effects from your treatment ". Each item is scored on a 4-point scale (1= Not at all, 2= A Little, 3= Quite a Bit, and 4= Very Much). |
| Serum Concentration of Atezolizumab | Predose Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 and at treatment completion (TC)/early discontinuation (ED); and 0.5 hour (h) postdose Day 1 of Cycle 1 (each cycle=21 days) (Up to 40 months) | — |
| Serum Concentration of Tiragolumab | Predose Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 and at TC/ED; and 0.5 hour (h) postdose Day 1 of Cycle 1 (each cycle=21 days) (Up to 40 months) | — |
| Number of Participants With Treatment-Emergent Anti-drug Antibodies (ADAs) to Atezolizumab | Up to approximately 40 months | Participants who received atezolizumab were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following atezolizumab exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units (t.u.) greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants with a positive post-baseline sample has been reported here. |
| Number of Participants With Treatment-Emergent ADAs to Tiragolumab | Up to approximately 40 months | Participants who received tiragolumab were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following tiragolumab exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 t.u. greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants with a positive post-baseline sample has been reported here. |
Countries
Belgium, Brazil, Canada, China, Denmark, France, Germany, Hong Kong, Italy, Japan, Mexico, New Zealand, Poland, South Korea, Spain, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 542 participants with previously untreated, locally advanced unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) took part in the study at 129 investigative sites across 21 countries from 15 December 2020 to 20 November 2025.
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive either tiragolumab + atezolizumab + chemotherapy or placebo + pembrolizumab + chemotherapy. The study is considered "Completed" because all the pre-planned study activities and analyses have been performed.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 63.4 years STANDARD_DEVIATION 9.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 237 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 22 Participants |
| Race (NIH/OMB) Asian | 176 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 4 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 328 Participants |
| Sex: Female, Male Female | 189 Participants |
| Sex: Female, Male Male | 169 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 117 / 273 | 146 / 269 |
| other Total, other adverse events | 262 / 272 | 251 / 267 |
| serious Total, serious adverse events | 142 / 272 | 147 / 267 |
Outcome results
None listed