Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
This study will evaluate the efficacy, safety, and pharmacokinetics of immunotherapy-based treatment combinations in participants with metastatic non-small cell lung cancer (NSCLC). Two cohorts will be enrolled in parallel in this study: Cohort 1 will consist of participants with tumor PD-L1 expression who have received no prior systemic therapy for metastatic NSCLC, and Cohort 2 will consist of participants who experienced disease progression during or following treatment with a platinum-containing regimen and a PD-L1/PD-1 checkpoint inhibitor, given in combination as one line of therapy or as two separate lines of therapy, regardless of PD-L1 expression. In each cohort, eligible participants will initially be assigned to one of several treatment arms (Stage 1). Participants who experience disease progression, loss of clinical benefit, or unacceptable toxicity during Stage 1 may be eligible to continue treatment with a different treatment regimen (Stage 2).
Interventions
DRUGRO6958688
Cycle 1: RO6958688 is administered by IV infusion on Days 1, 8, and 15 of a 21 day cycle at increasing dosage. Subsequent cycles: RO6958688 is administered by IV infusion on Days 1, 8, and 15 of a 21 day cycle.
DRUGAtezolizumab
Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.
DRUGCobimetinib
Cobimetinib is administered orally on Days 1-21 of a 28 day cycle.
DRUGDocetaxel
Docetaxel is administered by IV on Day 1 of each 21 day cycle.
DRUGCPI-444
CPI-444 is administered orally twice daily on Days 1- 21, of a 21 day cycle.
DRUGPemetrexed
Pemetrexed is administered by IV on Day 1 of a 21 day cycle.
DRUGCarboplatin
Carboplatin is administered by IV on day 1 of the first 4 or 6 cycles out of a 21 day cycle.
DRUGGemcitabine
Gemcitabine is administered by IV on Days 1 and 8 of the first 4 or 6 cycles out of a 21 day cycle.
DRUGLinagliptin
Linagliptin is administered orally once daily on Days 1 to 21 out of a 21 day cycle.
DRUGTocilizumab
Tocilizumab is administered for the management of cytokine-release syndrome in the RO6958688-containing arms.
DRUGIpatasertib
Ipatasertib will be administered orally once a day on Days 1-21 of each 28-day cycle.
DRUGBevacizumab
Bevacizumab is administered by IV on Day 1 of each 21-day cycle.
DRUGSacituzumab Govitecan
Sacituzumab Govitecan is administered by IV on Day 1 and 8 of each 21-day cycle.
OTHERRadiation
Radiotherapy up to 21 days
DRUGEvolocumab
Evolocumab is administered subcutaneously at a dose of 140 mg on Days 1 and 15 of each 28-day cycle.
DRUGTiragolumab
Tiragolumab is administered on Day 1 of each 21 day cycle.
DRUGXL092
XL092 is administered orally once a day on Day 1 to Day 21 of a 21 day cycle.
DRUGCamonsertib
Camonsertib is administered orally on Days 1-3, Days 8-10 of a 21 day cycle.
Sponsors
Hoffmann-La Roche
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
General Inclusion Criteria * Eastern Cooperative Oncology Group (ECOG) performance Status of 0 or 1 * Life expectancy greater than or equal to 3 months * Histologically or cytologically confirmed metastatic, non-squamous or squamous Non-Small Cell Lung Cancer (NSCLC) * Measurable disease (at least one target lesion) * Adequate hematologic and end-organ function * Tumor accessible for biopsy * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating eggs as outlined for each specific treatment arm * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as outlined for each specific treatment arm Inclusion Criteria for Cohort 1 * No prior systemic therapy for metastatic NSCLC * High tumor PD-L1 expression, defined as Tumor Proportion Score (TPS) or TCs \>= 50% or TC3 Inclusion Criteria for Cohort 2 \- Disease progression during or following treatment for metastatic or locally advanced, inoperable NSCLC
Exclusion criteria
* Prior allogeneic stem cell or solid organ transplantation * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) * Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases * History of leptomeningeal disease * Active or history of autoimmune disease or immune deficiency * History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan * History of malignancy other than NSCLC within 2 years prior to screening * Active tuberculosis * Severe infection within 4 weeks prior to initiation of study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1: Percentage of Participants With Objective Response (OR) as Determined by Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST V1.1) | Up to 50.4 months | OR was defined as a complete response (CR) or partial response (PR) on two consecutive occasions, ≥4 weeks apart, during Stage 1 as determined by the investigator using RECIST v.1.1. Objective response rate (ORR) was defined as the percentage of participants with OR. CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) have a reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of all target lesions, taking as reference the baseline SOD, in the absence of CR. 95% confidence intervals (CI) for rates were constructed using Clopper-Pearson method. Percentages have been rounded off. The participant in the 'Stage 1 Cohort 2 (S1C2): Idasanutlin + Docetaxel' arm did not receive study treatment and was therefore excluded from the efficacy analyses. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1: Progression-free Survival (PFS) as Determined by Investigator According to RECIST V1.1 | From randomization to the first occurrence of PD or death (Up to 48.6 months) | PFS was defined as the time from study treatment initiation to the first occurrence of documented PD, as determined by the investigator according to RECIST v1.1 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 sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm or unequivocal progression of existing non-target lesions. Participants who did not have documented PD or death, PFS was censored at the day of the last tumor assessment. Kaplan-Meier (K-M) method was used to estimate PFS. The participant in the 'Stage 1 Cohort 2: Idasanutlin + Docetaxel' arm did not receive study treatment and was therefore excluded from the efficacy analyses. |
| Stage 1: PFS Rate at Month 6 | At Month 6 | PFS was defined as the time from study treatment initiation to the first occurrence of documented PD, as determined by the investigator according to RECIST v1.1 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 sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm or unequivocal progression of existing non-target lesions. Participants who did not have documented PD or death, PFS was censored at the day of the last tumor assessment. The KM approach was used to estimate the percentage of participants who were event-free for PFS at Month 6. Percentages have been rounded off. The participant in the 'Stage 1 Cohort 2: Idasanutlin + Docetaxel' arm did not receive study treatment and was therefore excluded from the efficacy analyses. |
| Stage 1: Overall Survival (OS) | From randomization to death (Up to 67 months) | OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. K-M method was used to estimate OS. The participant in the 'Stage 1 Cohort 2: Idasanutlin + Docetaxel' arm did not receive study treatment and was therefore excluded from the efficacy analyses. |
| Stage 1: OS Rate at Month 6 | At Month 6 | OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. The Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for OS at Month 6. Percentages have been rounded off. The participant in the 'Stage 1 Cohort 2: Idasanutlin + Docetaxel' arm did not receive study treatment and was therefore excluded from the efficacy analyses. |
| Stage 1: Duration of Response (DOR), as Determined by Investigator According to RECIST V1.1 | From first occurrence of a documented OR until the time of documented PD or death (Up to 50.4 months) | DOR was defined as the time from the first occurrence of a documented OR until the time of documented PD or death from any cause, whichever occurred first as per investigator assessment using RECIST v1.1. DOR was calculated for participants who had a best confirmed OR of CR/PR. CR and PR were defined as outlined in the description for ORR outcome measure. PD=at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on the study including baseline (nadir). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm or unequivocal progression of existing non-target lesions. Participants who did not have documented PD or death, DOR was censored at the day of the last tumor assessment. K-M method was used to estimate DOR. The participant in the 'S1C2: Idasanutlin + Docetaxel' arm did not receive study treatment and was therefore excluded from the efficacy analyses. |
| Stage 1: Percentage of Participants With Disease Control (DC), as Determined by Investigator According to RECIST V1.1 | Up to 50.4 months | DC was defined as stable disease (SD) for ≥ 12 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1 Disease control rate (DCR) was defined as the percentage of participants with DC. CR was defined as the disappearance of all target \& non-target lesions. Any pathological lymph nodes (whether target or non-target) have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD=at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on the study including baseline (nadir). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm or unequivocal progression of existing non-target lesions. Percentages have been rounded off. |
| Stages 1 and 2: Number of Participants With Adverse Events (AEs) | From baseline until 30 days (for AEs) or 135 days (for SAEs & AESIs) after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurred first (Stage 1: up to 54.8 months; Stage 2: up to 43.1 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. SAEs = Serious AEs; AESIs = Adverse Events of Special Interest. |
Countries
Australia, France, Israel, South Korea, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 314 participants with metastatic non-small cell lung cancer (NSCLC) took part in the study from 27 Dec 2017 to 25 Nov 2025. The study had 2 cohorts: Cohort 1: participants with no prior systemic therapy for metastatic NSCLC & Cohort 2: participants with 1 prior line of systemic therapy for NSCLC. Multiple combination therapies were compared against common control(s) in Cohorts 1 and 2.
Pre-assignment details
Eligible participants were assigned to 1 of several treatment arms in Stage 1. Participants with PD, loss of clinical benefit, or unacceptable toxicity in Stage 1 were eligible for a different treatment combination in Stage 2. Participants in Stage 1 who did not enter Stage 2 & those who completed Stage 2 treatment entered the long-term survival follow-up. Results include only those cohorts that enrolled participants; planned cohorts that were never opened for enrollment are not presented.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical Stage 1 <=18 years | 0 Participants |
| Age, Categorical Stage 1 >=65 years | 160 Participants |
| Age, Categorical Stage 1 Between 18 and 65 years | 11 Participants |
| Age, Categorical Stage 2 <=18 years | 0 Participants |
| Age, Categorical Stage 2 >=65 years | 13 Participants |
| Age, Categorical Stage 2 Between 18 and 65 years | 32 Participants |
| Ethnicity (NIH/OMB) Stage 1 Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Stage 1 Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Stage 1 Unknown or Not Reported | 2 Participants |
| Ethnicity (NIH/OMB) Stage 2 Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Stage 2 Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Stage 2 Unknown or Not Reported | 10 Participants |
| Race (NIH/OMB) Stage 1 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Stage 1 Asian | 4 Participants |
| Race (NIH/OMB) Stage 1 Black or African American | 2 Participants |
| Race (NIH/OMB) Stage 1 More than one race | 0 Participants |
| Race (NIH/OMB) Stage 1 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Stage 1 Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) Stage 1 White | 0 Participants |
| Race (NIH/OMB) Stage 2 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Stage 2 Asian | 1 Participants |
| Race (NIH/OMB) Stage 2 Black or African American | 0 Participants |
| Race (NIH/OMB) Stage 2 More than one race | 0 Participants |
| Race (NIH/OMB) Stage 2 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Stage 2 Unknown or Not Reported | 11 Participants |
| Race (NIH/OMB) Stage 2 White | 43 Participants |
| Sex: Female, Male Stage 1 Female | 1 Participants |
| Sex: Female, Male Stage 1 Male | 23 Participants |
| Sex: Female, Male Stage 2 Female | 15 Participants |
| Sex: Female, Male Stage 2 Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 5 | 0 / 1 | 1 / 1 | 36 / 66 | 10 / 15 | 1 / 1 | 10 / 16 | 10 / 18 | 14 / 31 | 22 / 41 | 23 / 45 | 19 / 30 | 25 / 32 | 4 / 8 | 0 / 2 | 29 / 33 | 19 / 22 |
| other Total, other adverse events | 3 / 3 | 5 / 5 | 1 / 1 | 1 / 1 | 58 / 61 | 13 / 15 | 1 / 1 | 14 / 15 | 16 / 16 | 30 / 30 | 36 / 40 | 41 / 43 | 30 / 30 | 29 / 31 | 8 / 8 | 2 / 2 | 30 / 32 | 18 / 20 |
| serious Total, serious adverse events | 2 / 3 | 4 / 5 | 1 / 1 | 1 / 1 | 20 / 61 | 8 / 15 | 1 / 1 | 8 / 15 | 5 / 16 | 13 / 30 | 13 / 40 | 17 / 43 | 14 / 30 | 10 / 31 | 4 / 8 | 1 / 2 | 13 / 32 | 6 / 20 |
Outcome results
None listed