Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the efficacy, safety, and pharmacokinetics of atezolizumab given in combination with cabozantinib compared with docetaxel monotherapy in patients with metastatic NSCLC, with no sensitizing EGFR mutation or ALK translocation, who have progressed following treatment with platinum-containing chemotherapy and anti-PD-L1/PD-1 antibody, administered concurrently or sequentially.
Interventions
DRUGCabozantinib
Cabozantinib will be administered orally, once daily at a dose of 40 mg on Days 1-21 of each cycle.
DRUGAtezolizumab
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.
DRUGDocetaxel
Docetaxel will be administered by IV infusion at a starting dose of 75mg/m2 on Day 1 of each 21-day cycle.
Sponsors
Exelixis
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
* Histologically or cytologically confirmed metastatic NSCLC * Documented radiographic disease progression during or following treatment with platinum-containing chemotherapy and anti-PD-L1/PD-1 antibody, administered concurrently or sequentially for metastatic NSCLC * Measurable disease per RECIST v1.1 outside CNS as assessed by investigator * Known PD-L1 status or availability of tumor tissue for central PD-L1 testing * ECOG Performance Status score of 0 or 1 * Recovery to baseline or Grade \<=1 NCI CTCAE v5.0 from toxicities related to any prior treatments, unless adverse events are clinically nonsignificant and/or stable on supportive therapy in the opinion of the investigator * Adequate hematologic and end-organ function * Negative HIV test at screening * Negative hepatitis B surface antigen (HBsAg) test at screening * Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening * Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm.
Exclusion criteria
* Prior therapy with the following agents for NSCLC: Cabozantinib, Docetaxel, Combination of an anti-PD-L1/PD-1 antibody concurrently with a vascular endothelial growth factor (VEGF)R targeting tyrosine kinase inhibitor (TKI) * Treatment with investigational therapy within 28 days prior to initiation of study treatment * Documentation of known sensitizing mutation in the EGFR gene or ALK fusion oncogene * Patients with known ROS1 rearrangements, BRAF V600E mutations, or other actionable oncogenes with approved therapies if available * Symptomatic, untreated, or actively progressing CNS metastases * History of leptomeningeal disease * Uncontrolled tumor-related pain * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (more frequently than once monthly) * Severe hepatic impairment * Uncontrolled or symptomatic hypercalcemia * Any other active malignancy at the time of initiation of study treatment or diagnosis of another malignancy within 3 years prior to initiation of study treatment that requires active treatment, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, incidental prostate cancer, or carcinoma in situ of the prostate, cervix, or breast * Stroke, transient ischemic attack, myocardial infarction or other symptomatic ischemic events within 6 months of initiation of study treatment * Significant vascular disease within 6 months of initiation of study treatment * Significant cardiovascular disease within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina * Active tuberculosis * Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that, in the opinion on the investigator, could impact patient safety * Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment * Current treatment with anti-viral therapy for HBV * Major surgical procedure, other than for diagnosis within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study * Pregnant or lactating females, or intention of becoming pregnant during the treatment with atezolizumab in combination with cabozantinib in the experimental arm or during the treatment with docetaxel in the control arm, or within 5 months after the final dose of atezolizumab and/or 4 months after the final dose of cabozantinib, whichever is later. * Ongoing Grade \>= 2 sensory or motor neuropathy * Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, granulomatosis with polyangiitis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis with the following exceptions: Patients with a history of autoimmune-mediated hypothyroidism who are on thyroid replacement hormone are eligible for the study. Patients with controlled Type 1 diabetes mellitus are eligible for the study. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only are eligible for the study provided all of following conditions are met: Rash must cover \< 10% of body surface area. * Pharmacologically uncompensated, symptomatic hypothyroidism * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan * Prior allogeneic stem cell or solid organ transplantation * Administration of a live, attenuated vaccine within 4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab * Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2) 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, with the following exceptions: Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication are eligible for the study after Medical Monitor confirmation has been obtained. Patients who received mineralocorticoids, inhaled or low-dose systemic corticosteroids for COPD or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study. * History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins * Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation * Known allergy or hypersensitivity to any component of the cabozantinib formulation * History of severe hypersensitivity to docetaxel or to other drugs formulated with polysorbate 80 * Concomitant anticoagulation with coumarin agents, direct thrombin inhibitor dabigatran, direct factor Xa inhibitor betrixaban, or platelet inhibitors * History of risk factors for torsades de pointes * Corrected QT interval corrected through use of Fridericia's formula (QTcF) \> 480 ms per ECG within 14 days before initiation of study treatment * Uncontrolled hypertension defined as systolic blood pressure \> 150 mm Hg or diastolic BP \> 90 mm Hg despite optimal antihypertensive treatment * Tumors invading the GI-tract, active peptic ulcer disease, acute pancreatitis, acute obstruction of the pancreatic or biliary duct, appendicitis, cholangitis, cholecystitis, diverticulitis, gastric outlet obstruction, or inflammatory bowel disease * Abdominal fistula, bowel obstruction, GI perforation, or intra-abdominal abscess within 6 months before initiation of study treatment * Known cavitating pulmonary lesion(s) or known endobronchial disease manifestation * Lesions invading major pulmonary blood vessels * Clinically significant hematuria, hematemesis, hemoptysis of \> 0.5 teaspoon (2.5 mL) of red blood, coagulopathy, or other history of significant bleeding within 3 months before initiation of study treatment * Serious non-healing wound/ulcer/bone fracture * Malabsorption syndrome * Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption are also excluded. * Requirement for hemodialysis or peritoneal dialysis * Inability to swallow tablets
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 24 months | OS was defined as the time from randomization to death from any cause. Participants alive at the time of the analysis were censored at the date when they were last known to be alive as documented by the investigator. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Objective Response Rate (ORR) as Determined by Investigator | Up to approximately 24 months | Confirmed ORR was defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to RECIST v1.1. CR= disappearance of all target lesions. In addition, any pathological lymph nodes must have a reduction in short axis to \< 10 mm. PR= at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters. 95% CIs for rates were constructed using the Clopper-Pearson method. Percentages have been rounded off. |
| Duration of Response (DOR) as Determined by Investigator | Up to approximately 24 months | DOR for participants with confirmed ORR=time from first documented objective response to PD, as determined by investigator per RECIST v1.1, or death from any cause (whichever occurred first). PD=≥ 20% increase in sum of longest diameters of target lesions, taking as reference smallest sum of longest diameters of target lesions recorded since treatment started, including screening, or appearance of new lesions. In addition, sum of diameters also demonstrated an absolute increase of ≥ 5 mm. Confirmed ORR=percentage of participants with a CR or PR on two consecutive occasions ≥4 weeks apart, as determined by investigator per RECIST v1.1. CR= disappearance of all target lesions. PR=≥ 30% decrease in sum of diameters of all target lesions. Participants who had not progressed and who did not die at the time of analysis were censored at the time of last tumor assessment date. Kaplan-Meier method was used to estimate median. 95% CI for median was computed using Brookmeyer and Crowley method. |
| Time to Confirmed Deterioration (TTCD) in Patient-reported Physical Functioning (PF) | Up to approximately 24 months | TTCD analyses was performed for patient-reported PF (items 1 to 5) of European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30). The PF was measured on 4-point scale (1='Not at all' to 4='Very much'). TTCD for PF was defined as time from date of randomization to first confirmed clinically meaningful decrease from baseline in PF score held for at least 2 consecutive assessments or initial clinically meaningful decrease from baseline followed by death from any cause within 21 days or until next tumor assessment, whichever occurs first. A score change of ≥ of 10-point on EORTC QLQ-C30 PF scale was determined as being clinically meaningful. Scores were averaged, transformed to 0-100 scale; where higher score represented high/healthy level of functioning. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley. |
| TTCD in Patient-reported Global Health Status (GHS) | Up to approximately 24 months | TTCD analyses was performed for GHS and quality of life (QoL) (items 29 and 30) of EORTC QLQ-C30. GHS/ QoL items were scored on a 7-point scale that ranges from very poor to excellent. TTCD for GHS/QoL was defined as the time from the date of randomization to the first confirmed clinically meaningful decrease from baseline in GHS/QoL score held for at least two consecutive assessments or an initial clinically meaningful decrease from baseline followed by death from any cause within 21 days or until the next tumor assessment, whichever occurs first. A score change of ≥ 10-point on the EORTC QLQ-C30 GHS/QoL scale was determined as being clinically meaningful. Scores were averaged, transformed to 0-100 scale; where higher score for GHS/QoL= better health-related QoL. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley. |
| PFS Rates Assessed by Investigator | 6 months and 1 year | PFS rates were defined as the percentage of participants alive and without PD as assessed by the investigator according to RECIST v1.1 at 6 months and 1 year after randomization. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints, including baseline. In addition, the sum of diameters also demonstrated an absolute increase of ≥ 5 mm. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley. Percentages have been rounded off. |
| OS Rates | 1 and 2 years | OS rates were defined as the percentage of participants who were alive at 1 and 2 years. Participants alive at the time of the analysis were censored at the date when they were last known to be alive as documented by the investigator. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley. Percentages have been rounded off. |
| Progression-Free Survival (PFS) as Determined by Investigator | Up to approximately 24 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), or death from any cause (whichever occurred first). PD was defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum of the longest diameters of the target lesions recorded since the treatment started, including screening, or the appearance of one or more new lesions. In addition, the sum of diameters also demonstrated an absolute increase of ≥ 5 millimeters (mm). Participants who were alive and did not experience PD at the time of analysis, were censored on the date of last tumor assessment. Participants with no post-baseline tumor assessment were censored at the date of randomization. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley. |
| Minimum Serum Concentration (Cmin) of Atezolizumab | Predose on Day 1 of Cycles 1, 2, 3, 4, 8, 12 and 16 (Cycle= 21 days) | — |
| Maximum Serum Concentration (Cmax) of Atezolizumab | 30 minutes (min) postdose on Day 1 of Cycle 1 (Cycle= 21 days) | — |
| Minimum Plasma Concentration (Cmin) of Cabozantinib | Predose on Day 1 of Cycles 1, 2, 3, 4, and 5 (Cycle= 21 days) | — |
| Maximum Plasma Concentration (Cmax) of Cabozantinib | Predose on Day 1 of Cycles 1, 2, 3, 4, and 5 (Cycle= 21 days) | — |
| Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | Pre-dose on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 and post-treatment follow-up (≤ 30 days after final dose) (Cycle= 21 days) | Participants were considered to be ADA positive if they were ADA negative or had missing data at baseline but developed an ADA response following study drug 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 unit greater than the titer of the baseline sample (treatment-enhanced ADA response). The total number of participants who developed ADAs to atezolizumab was determined by summing the ADA-positive participants across all timepoints. |
| Percentage of Participants With Adverse Events (AEs) | Up to approximately 41.4 months | An AE was defined as any untoward medical occurrence in a clinical investigation patient administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any of the following: unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product; any new disease or exacerbation of an existing disease; recurrence of an intermittent medical condition not present at baseline; any deterioration in a laboratory value or other clinical test; AEs related to a protocol-mandated intervention. AEs were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE, v5.0). Percentages have been rounded off. |
Countries
Australia, Austria, Belgium, France, Germany, Greece, Italy, Japan, Poland, Portugal, Russia, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 366 participants with metastatic non-small cell lung cancer (NSCLC) previously treated with anti-programmed death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) antibody and platinum-containing chemotherapy took part in the study at 97 investigative sites across 15 countries from 01 October 2020 to 17 January 2025.
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive either docetaxel monotherapy or atezolizumab & cabozantinib combination therapy. A total of 14 participants did not receive any study treatment and were therefore excluded from the safety analysis.
Participants by arm
| Arm | Count |
|---|---|
| Docetaxel Monotherapy Participants received docetaxel, 75 mg/m\^2, IV on Day 1 of each 21-day cycle until unacceptable toxicity or PD or loss of clinical benefit as determined by the investigator. | 180 |
| Atezolizumab + Cabozantinib Participants received atezolizumab, 1200 mg, IV, on Day 1 of each 21-day cycle along with cabozantinib, 40 mg, orally, given QD on Days 1-21 of each cycle until unacceptable toxicity, PD, or loss of clinical benefit as determined by the investigator. | 186 |
| Total | 366 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 131 | 147 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Reason Not Specified | 0 | 2 |
| Overall Study | Study Terminated by Sponsor | 20 | 29 |
| Overall Study | Withdrawal by Subject | 29 | 4 |
Baseline characteristics
| Characteristic | Atezolizumab + Cabozantinib | Total | Docetaxel Monotherapy |
|---|---|---|---|
| Age, Continuous | 63.8 years STANDARD_DEVIATION 9.5 | 64.1 years STANDARD_DEVIATION 9.4 | 64.4 years STANDARD_DEVIATION 9.4 |
| Race/Ethnicity, Customized Hispanic or Latino | 4 Participants | 11 Participants | 7 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 164 Participants | 322 Participants | 158 Participants |
| Race/Ethnicity, Customized Not Stated | 15 Participants | 27 Participants | 12 Participants |
| Race/Ethnicity, Customized Unknown | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 41 Participants | 94 Participants | 53 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 13 Participants | 28 Participants | 15 Participants |
| Race (NIH/OMB) White | 130 Participants | 241 Participants | 111 Participants |
| Sex: Female, Male Female | 52 Participants | 105 Participants | 53 Participants |
| Sex: Female, Male Male | 134 Participants | 261 Participants | 127 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 131 / 180 | 147 / 186 |
| other Total, other adverse events | 148 / 167 | 173 / 185 |
| serious Total, serious adverse events | 58 / 167 | 76 / 185 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from randomization to death from any cause. Participants alive at the time of the analysis were censored at the date when they were last known to be alive as documented by the investigator. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley.
Time frame: Up to approximately 24 months
Population: The ITT population included all randomized participants, whether or not the participant received the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel Monotherapy | Overall Survival (OS) | 10.5 months |
| Atezolizumab + Cabozantinib | Overall Survival (OS) | 10.7 months |
p-value: 0.366895% CI: [0.676, 1.156]Log Rank
Comparison: Unstratified Analysisp-value: 0.470995% CI: [0.696, 1.182]Log Rank
Secondary
Confirmed Objective Response Rate (ORR) as Determined by Investigator
Confirmed ORR was defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to RECIST v1.1. CR= disappearance of all target lesions. In addition, any pathological lymph nodes must have a reduction in short axis to \< 10 mm. PR= at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters. 95% CIs for rates were constructed using the Clopper-Pearson method. Percentages have been rounded off.
Time frame: Up to approximately 24 months
Population: The ITT population included all randomized participants, whether or not the participant received the assigned treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Docetaxel Monotherapy | Confirmed Objective Response Rate (ORR) as Determined by Investigator | 13.3 percentage of participants |
| Atezolizumab + Cabozantinib | Confirmed Objective Response Rate (ORR) as Determined by Investigator | 11.8 percentage of participants |
Comparison: Stratified analysis; stratification factors- histology, prior NSCLC treatment regimensp-value: 0.684695% CI: [-8.85, 5.84]Cochran-Mantel-Haenszel
Comparison: Stratified analysis; stratification factors- histology, prior NSCLC treatment regimens95% CI: [0.47, 1.63]
Comparison: Unstratified Analysisp-value: 0.721695% CI: [-8.85, 5.84]Chi-squared, Corrected
Comparison: Unstratified Analysis95% CI: [0.47, 1.62]
Secondary
Duration of Response (DOR) as Determined by Investigator
DOR for participants with confirmed ORR=time from first documented objective response to PD, as determined by investigator per RECIST v1.1, or death from any cause (whichever occurred first). PD=≥ 20% increase in sum of longest diameters of target lesions, taking as reference smallest sum of longest diameters of target lesions recorded since treatment started, including screening, or appearance of new lesions. In addition, sum of diameters also demonstrated an absolute increase of ≥ 5 mm. Confirmed ORR=percentage of participants with a CR or PR on two consecutive occasions ≥4 weeks apart, as determined by investigator per RECIST v1.1. CR= disappearance of all target lesions. PR=≥ 30% decrease in sum of diameters of all target lesions. Participants who had not progressed and who did not die at the time of analysis were censored at the time of last tumor assessment date. Kaplan-Meier method was used to estimate median. 95% CI for median was computed using Brookmeyer and Crowley method.
Time frame: Up to approximately 24 months
Population: Participants in the ITT population who had a confirmed objective response (CR or PR) as determined by the investigator per RECIST v1.1 were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel Monotherapy | Duration of Response (DOR) as Determined by Investigator | 4.30 months |
| Atezolizumab + Cabozantinib | Duration of Response (DOR) as Determined by Investigator | 5.55 months |
Secondary
Maximum Plasma Concentration (Cmax) of Cabozantinib
Time frame: Predose on Day 1 of Cycles 1, 2, 3, 4, and 5 (Cycle= 21 days)
Population: Cmax was not collected for this outcome measure because PK of cabozantinib was well characterized through the cabozantinib development for mono- therapy. An established population PK model for cabozantinib is available for the PK data from NCT04471428 (study GO41892). The PK data collected in the current study is sufficient for the population PK model to characterize the exposure of cabozantinib in this study.
Secondary
Maximum Serum Concentration (Cmax) of Atezolizumab
Time frame: 30 minutes (min) postdose on Day 1 of Cycle 1 (Cycle= 21 days)
Population: PK-evaluable population included all participants who had received any dose of atezolizumab and who had evaluable PK samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Docetaxel Monotherapy | Maximum Serum Concentration (Cmax) of Atezolizumab | 450 μg/mL | Geometric Coefficient of Variation 34 |
Secondary
Minimum Plasma Concentration (Cmin) of Cabozantinib
Time frame: Predose on Day 1 of Cycles 1, 2, 3, 4, and 5 (Cycle= 21 days)
Population: PK-evaluable population included all participants who had received any dose of cabozantinib and who had evaluable PK samples. Number analyzed is the number of participants with data available for analysis at the specified timepoint. Different participants may have contributed data for each timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Docetaxel Monotherapy | Minimum Plasma Concentration (Cmin) of Cabozantinib | Cycle 1 Day 1 | NA μg/mL | — |
| Docetaxel Monotherapy | Minimum Plasma Concentration (Cmin) of Cabozantinib | Cycle 2 Day 1 | 0.746 μg/mL | Geometric Coefficient of Variation 111.7 |
| Docetaxel Monotherapy | Minimum Plasma Concentration (Cmin) of Cabozantinib | Cycle 3 Day 1 | 0.418 μg/mL | Geometric Coefficient of Variation 640.7 |
| Docetaxel Monotherapy | Minimum Plasma Concentration (Cmin) of Cabozantinib | Cycle 4 Day 1 | 0.469 μg/mL | Geometric Coefficient of Variation 234.4 |
| Docetaxel Monotherapy | Minimum Plasma Concentration (Cmin) of Cabozantinib | Cycle 5 Day 1 | 0.303 μg/mL | Geometric Coefficient of Variation 402.3 |
Secondary
Minimum Serum Concentration (Cmin) of Atezolizumab
Time frame: Predose on Day 1 of Cycles 1, 2, 3, 4, 8, 12 and 16 (Cycle= 21 days)
Population: Pharmacokinetic (PK)-evaluable population for atezolizumab included all participants who had received any dose of atezolizumab and who had evaluable PK samples. Number analyzed is the number of participants with data available for analysis at the specified timepoint. Different participants may have contributed data for each timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Docetaxel Monotherapy | Minimum Serum Concentration (Cmin) of Atezolizumab | Cycle 1 Day 1 | NA microgram/milliliter (μg/ml) | — |
| Docetaxel Monotherapy | Minimum Serum Concentration (Cmin) of Atezolizumab | Cycle 2 Day 1 | 96.8 microgram/milliliter (μg/ml) | Geometric Coefficient of Variation 48.1 |
| Docetaxel Monotherapy | Minimum Serum Concentration (Cmin) of Atezolizumab | Cycle 16 Day 1 | 209 microgram/milliliter (μg/ml) | Geometric Coefficient of Variation 56.1 |
| Docetaxel Monotherapy | Minimum Serum Concentration (Cmin) of Atezolizumab | Cycle 3 Day 1 | 124 microgram/milliliter (μg/ml) | Geometric Coefficient of Variation 104.4 |
| Docetaxel Monotherapy | Minimum Serum Concentration (Cmin) of Atezolizumab | Cycle 4 Day 1 | 167 microgram/milliliter (μg/ml) | Geometric Coefficient of Variation 47.7 |
| Docetaxel Monotherapy | Minimum Serum Concentration (Cmin) of Atezolizumab | Cycle 8 Day 1 | 194 microgram/milliliter (μg/ml) | Geometric Coefficient of Variation 62.4 |
| Docetaxel Monotherapy | Minimum Serum Concentration (Cmin) of Atezolizumab | Cycle 12 Day 1 | 233 microgram/milliliter (μg/ml) | Geometric Coefficient of Variation 44.7 |
Secondary
Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab
Participants were considered to be ADA positive if they were ADA negative or had missing data at baseline but developed an ADA response following study drug 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 unit greater than the titer of the baseline sample (treatment-enhanced ADA response). The total number of participants who developed ADAs to atezolizumab was determined by summing the ADA-positive participants across all timepoints.
Time frame: Pre-dose on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 and post-treatment follow-up (≤ 30 days after final dose) (Cycle= 21 days)
Population: Safety-evaluable population included all randomized participants who had received any amount of study drug, with participants grouped according to the actual treatment received. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Docetaxel Monotherapy | Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | ADA Incidence after treatment | 37 Participants |
| Docetaxel Monotherapy | Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | ADA Prevalence at Baseline | 2 Participants |
Secondary
OS Rates
OS rates were defined as the percentage of participants who were alive at 1 and 2 years. Participants alive at the time of the analysis were censored at the date when they were last known to be alive as documented by the investigator. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley. Percentages have been rounded off.
Time frame: 1 and 2 years
Population: The ITT population is defined as all randomized participants, whether or not the participant received the assigned treatment. Participants alive at the time of the analysis were censored at the date when they were last known to be alive as documented by the investigator. At the time of the analysis, there were no participants with 24 months or more of survival follow-up, therefore, survival rate at the 2-year timepoint was not estimable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Docetaxel Monotherapy | OS Rates | 1 year | 44.12 percentage of participants |
| Docetaxel Monotherapy | OS Rates | 2 years | NA percentage of participants |
| Atezolizumab + Cabozantinib | OS Rates | 1 year | 43.27 percentage of participants |
| Atezolizumab + Cabozantinib | OS Rates | 2 years | NA percentage of participants |
Comparison: At 1 yearp-value: 0.876795% CI: [-11.63, 9.92]z-test
Secondary
Percentage of Participants With Adverse Events (AEs)
An AE was defined as any untoward medical occurrence in a clinical investigation patient administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any of the following: unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product; any new disease or exacerbation of an existing disease; recurrence of an intermittent medical condition not present at baseline; any deterioration in a laboratory value or other clinical test; AEs related to a protocol-mandated intervention. AEs were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE, v5.0). Percentages have been rounded off.
Time frame: Up to approximately 41.4 months
Population: Safety-evaluable population included all randomized participants who had received any amount of study drug, with participants grouped according to the actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Docetaxel Monotherapy | Percentage of Participants With Adverse Events (AEs) | 94.0 percentage of participants |
| Atezolizumab + Cabozantinib | Percentage of Participants With Adverse Events (AEs) | 98.4 percentage of participants |
Secondary
PFS Rates Assessed by Investigator
PFS rates were defined as the percentage of participants alive and without PD as assessed by the investigator according to RECIST v1.1 at 6 months and 1 year after randomization. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints, including baseline. In addition, the sum of diameters also demonstrated an absolute increase of ≥ 5 mm. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley. Percentages have been rounded off.
Time frame: 6 months and 1 year
Population: The ITT population included all randomized participants, whether or not the participant received the assigned treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Docetaxel Monotherapy | PFS Rates Assessed by Investigator | At 6 months | 23.66 percentage of participants |
| Docetaxel Monotherapy | PFS Rates Assessed by Investigator | At 1 year | 8.38 percentage of participants |
| Atezolizumab + Cabozantinib | PFS Rates Assessed by Investigator | At 6 months | 39.51 percentage of participants |
| Atezolizumab + Cabozantinib | PFS Rates Assessed by Investigator | At 1 year | 14.70 percentage of participants |
Comparison: At 6 monthsp-value: 0.001495% CI: [6.12, 25.59]z-test
Comparison: At 1 yearp-value: 0.071995% CI: [-0.56, 13.21]z-test
Secondary
Progression-Free Survival (PFS) as Determined by Investigator
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), or death from any cause (whichever occurred first). PD was defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum of the longest diameters of the target lesions recorded since the treatment started, including screening, or the appearance of one or more new lesions. In addition, the sum of diameters also demonstrated an absolute increase of ≥ 5 millimeters (mm). Participants who were alive and did not experience PD at the time of analysis, were censored on the date of last tumor assessment. Participants with no post-baseline tumor assessment were censored at the date of randomization. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley.
Time frame: Up to approximately 24 months
Population: The ITT population included all randomized participants, whether or not the participant received the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel Monotherapy | Progression-Free Survival (PFS) as Determined by Investigator | 4.0 months |
| Atezolizumab + Cabozantinib | Progression-Free Survival (PFS) as Determined by Investigator | 4.6 months |
Comparison: Stratified Analysis; Stratification factors include histology, and prior NSCLC treatment regimensp-value: 0.007995% CI: [0.585, 0.923]Log Rank
Comparison: Unstratified analysisp-value: 0.006195% CI: [0.583, 0.915]Log Rank
Secondary
Time to Confirmed Deterioration (TTCD) in Patient-reported Physical Functioning (PF)
TTCD analyses was performed for patient-reported PF (items 1 to 5) of European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30). The PF was measured on 4-point scale (1='Not at all' to 4='Very much'). TTCD for PF was defined as time from date of randomization to first confirmed clinically meaningful decrease from baseline in PF score held for at least 2 consecutive assessments or initial clinically meaningful decrease from baseline followed by death from any cause within 21 days or until next tumor assessment, whichever occurs first. A score change of ≥ of 10-point on EORTC QLQ-C30 PF scale was determined as being clinically meaningful. Scores were averaged, transformed to 0-100 scale; where higher score represented high/healthy level of functioning. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley.
Time frame: Up to approximately 24 months
Population: The ITT population included all randomized participants, whether or not the participant received the assigned treatment. Participants without a confirmed deterioration at the time of analysis were censored at the last time they were known to have not deteriorated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel Monotherapy | Time to Confirmed Deterioration (TTCD) in Patient-reported Physical Functioning (PF) | 5.6 months |
| Atezolizumab + Cabozantinib | Time to Confirmed Deterioration (TTCD) in Patient-reported Physical Functioning (PF) | 7.7 months |
Comparison: Stratified Analysis: Stratification factors include histology, and prior NSCLC treatment regimensp-value: 0.2795% CI: [0.59, 1.16]Log Rank
Comparison: Unstratified Analysisp-value: 0.303195% CI: [0.6, 1.17]Log Rank
Secondary
TTCD in Patient-reported Global Health Status (GHS)
TTCD analyses was performed for GHS and quality of life (QoL) (items 29 and 30) of EORTC QLQ-C30. GHS/ QoL items were scored on a 7-point scale that ranges from very poor to excellent. TTCD for GHS/QoL was defined as the time from the date of randomization to the first confirmed clinically meaningful decrease from baseline in GHS/QoL score held for at least two consecutive assessments or an initial clinically meaningful decrease from baseline followed by death from any cause within 21 days or until the next tumor assessment, whichever occurs first. A score change of ≥ 10-point on the EORTC QLQ-C30 GHS/QoL scale was determined as being clinically meaningful. Scores were averaged, transformed to 0-100 scale; where higher score for GHS/QoL= better health-related QoL. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley.
Time frame: Up to approximately 24 months
Population: Participants without a confirmed deterioration at the time of analysis were censored at the last time they were known to have not deteriorated. The ITT population included all randomized participants, whether or not the participant received the assigned treatment. Only responders were analysed in this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel Monotherapy | TTCD in Patient-reported Global Health Status (GHS) | 14.1 months |
| Atezolizumab + Cabozantinib | TTCD in Patient-reported Global Health Status (GHS) | 8.1 months |
Comparison: Stratification factors include histology, and prior NSCLC treatment regimensp-value: 0.240895% CI: [0.86, 1.79]Log Rank
Comparison: Unstratified Analysisp-value: 0.199295% CI: [0.88, 1.81]Log Rank