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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
366
Cabozantinib will be administered orally, once daily at a dose of 40 mg on Days 1-21 of each cycle.
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.
Docetaxel will be administered by IV infusion at a starting dose of 75mg/m2 on Day 1 of each 21-day cycle.
Stanford University
Palo Alto, California, United States
Kaiser Permanente - San Diego
San Diego, California, United States
Sansum Clinic
Santa Barbara, California, United States
Rocky Mountain Cancer Centers
Denver, Colorado, United States
Regional Cancer Care Associates
Bethesda, Maryland, United States
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
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
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
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
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
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
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
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
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
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)
Maximum Serum Concentration (Cmax) of Atezolizumab
Time frame: 30 minutes (min) postdose on Day 1 of Cycle 1 (Cycle= 21 days)
Minimum Plasma Concentration (Cmin) of Cabozantinib
Time frame: Predose on Day 1 of Cycles 1, 2, 3, 4, and 5 (Cycle= 21 days)
Maximum Plasma Concentration (Cmax) of Cabozantinib
Time frame: 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
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)
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