Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
The purpose of the study is to compare the overall response rate (ORR) in non-small cell lung cancer (NSCLC) participants treated with daratumumab in combination with atezolizumab versus atezolizumab alone.
Detailed description
This randomized (study medication assigned to participants by chance), multicenter study will provide study treatment (atezolizumab alone or atezolizumab+daratumumab) to participants with previously treated advanced or metastatic NSCLC to assess the anti-tumor activity and safety. Participants who receive atezolizumab treatment with confirmed disease progression based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be eligible to crossover to treatment (atezolizumab + daratumumab) if they meet crossover eligibility criteria. It is expected that 100 participants will enroll in the study including 6 participants in the safety run in phase. Data Monitoring Committee (DMC) will review ongoing data, and may formulate recommendations on study conduct, including expansion of enrollment of some PD-L1 subgroups, resulting in greater than 96 participants. The participants in the safety run in phase will be administered the combination of daratumumab and atezolizumab to determine the safety and tolerability that will be evaluated by the Safety Evaluation Team (SET) for dose limiting toxicity before the random assignment of participants in a 1:1 ratio in 2 treatment arms. The study consists of 3 phases: Screening Phase (up to 28 days), Treatment Phase and Post-Treatment Follow-up Phase which will continue until death, lost to follow-up, withdrawal of consent, or the End of the Study \[the study end is approximately 6 to 12 months after that last participant is enrolled\]. Participants will undergo tumor assessments (RECIST 1.1), immunogenicity, pharmacokinetics, biomarkers and safety evaluations (adverse events, laboratory tests, electrocardiogram \[ECGs\], vital sign measurements, physical examinations, Eastern Cooperative Oncology Group \[ECOG\] performance status score) over the time.
Interventions
DRUGAtezolizumab
Participants will receive atezolizumab 1200 mg intravenously.
DRUGDaratumumab
Participants will receive daratumumab 16 mg/kg intravenously.
Sponsors
Genentech, Inc.
Janssen Research & Development, LLC
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
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Have histologically or cytologically confirmed advanced or metastatic non-small cell lung cancer (NSCLC) (Stage IIIb or greater) * Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 * Tumor cell programmed death-ligand 1 (PD-L1) score of tumor cells (TC)1-3 and immune cell PD-L1 score of tumor-infiltrating immune cells (IC)0-3 as determined by an immunohistochemistry (IHC) assay performed by the central laboratory on tissue obtained after the last line of therapy * A woman of childbearing potential must have a negative highly sensitive serum (beta-human chorionic gonadotropin \[beta- hCG\]) at Screening within 14 days prior to study drug administration Inclusion Criteria for Crossover: * Participants must have been randomized to Arm A of the study and had radiographic disease progression according to RECIST 1.1 * Participants must have a mandatory biopsy at the time of disease progression according to RECIST 1.1 prior to crossing over. If not clinically feasible, discussion with Sponsor is required * The first dose of atezolizumab in the crossover arm should be within 42 days of last dose but no less than 21 days from the last dose prior to crossing over
Exclusion criteria
* Received any of the following prescribed medications or therapies in the past: 1. Anti-cluster of differentiation(CD)38 therapy, including daratumumab 2. CD137 agonists, immune checkpoint inhibitors including but not limited to CTLA-4, anti-PD-1, and anti-PD-L1 therapies * Known to be seropositive for human immunodeficiency virus (HIV) * Prior allogeneic bone marrow transplantation or solid organ transplant * History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins * Active hepatitis B, defined by a positive test for hepatitis B surface antigen \[HBsAg\] or prior history of hepatitis B, defined by presence of antibodies to hepatitis B core antigen \[anti-HBc\], regardless of hepatitis B surface antibody \[anti-HBs\] status; active hepatitis C or prior history of hepatitis C (anti-HCV positive), except in the setting of a sustained virologic response (SVR), defined as aviremia 12 weeks after completion of antiviral therapy. If hepatitis C virus (HCV) antibodies are detected, an HCV RNA test for viral load by polymerase chain reaction (PCR) should be performed at least 12 weeks after completion of antiviral therapy to rule out active infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Response Rate (ORR) | Up to 1.5 years | ORR was defined as the percentage of participants with partial response (PR) or complete response (CR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Criteria for CR: Disappearance of all target lesions; all lymph nodes must be of non-pathological in size (less than \[\<\]10 millimeter \[mm\] short axis; normalization of tumor marker level. Criteria for PR: greater than or equal to (\>=)30 percent (%) decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. Overall Response (OR) = CR + PR. The outcome measure (OM) was planned to be reported for participants based on their initial assignment to Randomized Phase: Atezolizumab'. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DoR) | Up to 1.5 years | Duration of response was defined as duration from date of initial documentation of disease response to date of first objectively documented evidence of recurrence or progressive disease (PD) or death, whichever occurred first. PD: Sum of diameters increased by \>=20% and \>=5 millimeter (mm) from nadir (including baseline if it was smallest sum). Participants with measurable disease: for unequivocal progression based on non-target disease, overall level of substantial worsening that merits discontinuation of therapy (if target disease was stable disease \[SD\]/PR). Participants without measurable disease: for unequivocal progression of non-target disease, increase in overall tumor burden comparable to increase required for PD of measurable disease. Appearance of 1/ more new lesions or unequivocal progression of non-target lesion was also considered as PD. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'. |
| Clinical Benefit Rate | Up to 1.5 years | Clinical benefit rate was defined as percentage of participants who achieved disease control (CR, PR, or SD). RECIST 1.1 Criteria for CR: Disappearance of all target lesions; all lymph nodes of non-pathological in size (\<10 mm short axis); normalization of tumor marker level. Criteria for PR: \>=30 % decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. Criteria for SD: \<30% decrease in sum of diameters of all target lesions compared with baseline and \<20% increase compared with nadir, in absence of new lesions or unequivocal progression of nontarget lesions. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'. |
| Progression-Free Survival (PFS) | Up to 1.5 years | PFS was defined as the duration from the date of randomization until the first documented disease progression (PD) or death, whichever occurred first. PD: Sum of diameters increased by \>=20% and \>=5 millimeter (mm) from nadir (including baseline if it was smallest sum). Participants with measurable disease: for unequivocal progression based on non-target disease, overall level of substantial worsening that merits discontinuation of therapy (if target disease was stable disease \[SD\]/PR). Participants without measurable disease: for unequivocal progression of non-target disease, increase in overall tumor burden comparable to increase required for PD of measurable disease. Appearance of 1/ more new lesions or unequivocal progression of non-target lesion was also considered as PD. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'. |
| Overall Survival (OS) | Up to 1.5 years | Overall Survival was defined as the duration from the date of randomization to the date of participant's death due to any cause. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'. |
| Number of Participants With Adverse Events | Up to 1.5 years | An adverse event (AE) is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Crossover participants were counted twice (in 'Randomized Phase: Atezo arm' and in 'Randomized Phase: Atezo Crossed Over to Dara + Atezo') for safety analysis. For cross-over participants, AEs after initiation of cross-over treatment were summarized separately in the crossover arm, however, AEs occurred before crossover treatment were included in 'Randomized Phase: Atezolizumab arm'. |
| Atezolizumab Serum Concentration | C1D1:predose and postdose; C1D2:predose and postdose; C2D1, C3D1:predose; C3D15:predose and postdose; C4D1:predose and postdose; C8D1:predose and postdose; C12D1:predose; end of treatment (37 days after last dose); and post last dose (up to 1.5 years) | Atezolizumab serum concentrations were reported. Each cycle was of 21-days. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'. |
| Number of Participants With Anti-Daratumumab Antibodies | Up to 1.5 years | Number of participants with antibodies to daratumumab (tested using a validated immunoassay method) were reported. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'. |
| Number of Participants With Anti-Atezolizumab Antibodies | Up to 1.5 years | Number of participants with antibodies to atezolizumab (tested using a validated immunoassay method) were reported. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'. |
| Daratumumab Serum Concentration | Cycle 1 Day 1 (C1D1):predose and postdose; C2D1 and C3D1:predose; C3D15: predose and postdose; C4D1: predose and postdose; C8D1: predose and postdose; C12D1: predose; end of treatment (37 days after last dose); and post last dose (up to 1.5 years) | Daratumumab serum concentrations were reported. Each cycle was of 21-days. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'. |
Countries
France, Hungary, Poland, Spain, United States
Participant flow
Pre-assignment details
A total of 100 participants were enrolled in the study (7 in phase 1b \[safety run-in phase\], and 93 in Phase 2 \[randomized phase\]). Among them, 99 participants (7 in phase 1b \[safety run-in phase\], and 92 in phase 2 \[randomized phase\]) were randomized as 1 participant was randomized after the clinical cutoff date (17-May-2018).
Participants by arm
| Arm | Count |
|---|---|
| Safety Run-in Phase: Daratumumab + Atezolizumab Participants received daratumumab (Dara) 16 milligram per kilogram (mg/kg) intravenously (IV) weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab (Atezo) IV at a dose of 1200 milligram (mg) on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria. | 7 |
| Randomized Phase: Atezolizumab Participants received atezolizumab IV at a dose of 1200 milligram (mg) on Day 1 of every 21-day cycle until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria. | 46 |
| Randomized Phase: Daratumumab + Atezolizumab Participants received daratumumab 16 mg/kg IV weekly on Days 1, 8, and 15 for first 3 cycles and then on Day 1 of each 21-day cycle thereafter along with atezolizumab IV at a dose of 1200 mg on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter until disease progression, unacceptable toxicity or other protocol-defined treatment discontinuation criteria. | 46 |
| Total | 99 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 5 | 12 | 20 |
| Overall Study | Ongoing | 2 | 32 | 24 |
| Overall Study | Other | 0 | 2 | 2 |
Baseline characteristics
| Characteristic | Total | Safety Run-in Phase: Daratumumab + Atezolizumab | Randomized Phase: Daratumumab + Atezolizumab | Randomized Phase: Atezolizumab |
|---|---|---|---|---|
| Age, Continuous | 62.3 years STANDARD_DEVIATION 10.29 | 61 years STANDARD_DEVIATION 9.73 | 63.2 years STANDARD_DEVIATION 10.76 | 61.7 years STANDARD_DEVIATION 10.05 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG Score 0 | 34 Participants | 3 Participants | 12 Participants | 19 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG Score 1 | 64 Participants | 4 Participants | 33 Participants | 27 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG Score 2 | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 83 Participants | 7 Participants | 40 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants | 0 Participants | 6 Participants | 9 Participants |
| Race/Ethnicity, Customized Other | 17 Participants | 0 Participants | 6 Participants | 11 Participants |
| Race/Ethnicity, Customized White Non-Hispanic | 82 Participants | 7 Participants | 40 Participants | 35 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 16 Participants | 0 Participants | 5 Participants | 11 Participants |
| Race (NIH/OMB) White | 83 Participants | 7 Participants | 41 Participants | 35 Participants |
| Region of Enrollment FRANCE | 16 Participants | 0 Participants | 6 Participants | 10 Participants |
| Region of Enrollment HUNGARY | 15 Participants | 0 Participants | 7 Participants | 8 Participants |
| Region of Enrollment SPAIN | 49 Participants | 3 Participants | 27 Participants | 19 Participants |
| Region of Enrollment UNITED STATES | 19 Participants | 4 Participants | 6 Participants | 9 Participants |
| Sex: Female, Male Female | 29 Participants | 3 Participants | 8 Participants | 18 Participants |
| Sex: Female, Male Male | 70 Participants | 4 Participants | 38 Participants | 28 Participants |
| Time from initial diagnosis | 17.6 months STANDARD_DEVIATION 17.37 | 10.3 months STANDARD_DEVIATION 9.29 | 17.6 months STANDARD_DEVIATION 14.17 | 18.8 months STANDARD_DEVIATION 20.89 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 7 | 9 / 44 | 20 / 44 | 3 / 8 |
| other Total, other adverse events | 7 / 7 | 41 / 44 | 41 / 44 | 8 / 8 |
| serious Total, serious adverse events | 4 / 7 | 15 / 44 | 21 / 44 | 3 / 8 |
Outcome results
Primary
Percentage of Participants With Overall Response Rate (ORR)
ORR was defined as the percentage of participants with partial response (PR) or complete response (CR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Criteria for CR: Disappearance of all target lesions; all lymph nodes must be of non-pathological in size (less than \[\<\]10 millimeter \[mm\] short axis; normalization of tumor marker level. Criteria for PR: greater than or equal to (\>=)30 percent (%) decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. Overall Response (OR) = CR + PR. The outcome measure (OM) was planned to be reported for participants based on their initial assignment to Randomized Phase: Atezolizumab'.
Time frame: Up to 1.5 years
Population: Intent-to-treat (ITT) analysis set included all participants who had entered the Randomized phase of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Phase: Atezolizumab | Percentage of Participants With Overall Response Rate (ORR) | 13.0 Percentage of participants |
| Randomized Phase: Daratumumab + Atezolizumab | Percentage of Participants With Overall Response Rate (ORR) | 4.3 Percentage of participants |
95% CI: [0.03, 1.92]
Secondary
Atezolizumab Serum Concentration
Atezolizumab serum concentrations were reported. Each cycle was of 21-days. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'.
Time frame: C1D1:predose and postdose; C1D2:predose and postdose; C2D1, C3D1:predose; C3D15:predose and postdose; C4D1:predose and postdose; C8D1:predose and postdose; C12D1:predose; end of treatment (37 days after last dose); and post last dose (up to 1.5 years)
Population: PK-evaluable analysis set: all participants who received at least 1 dose of daratumumab/atezolizumab and had at least 1 postinfusion sample collected. Here N (number of participants analyzed): participants evaluable for this outcome measure, and n (number of participants analyzed): participants evaluable for this outcome measure at given timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Randomized Phase: Atezolizumab | Atezolizumab Serum Concentration | Cycle 2 Day 1 Predose | 91.16 Microgram per milliliter (mcg/mL) | Standard Deviation 15.305 |
| Randomized Phase: Atezolizumab | Atezolizumab Serum Concentration | Post Last Dose | 33.10 Microgram per milliliter (mcg/mL) | — |
| Randomized Phase: Atezolizumab | Atezolizumab Serum Concentration | Cycle 3 Day 1 Predose | 176.50 Microgram per milliliter (mcg/mL) | Standard Deviation 33.234 |
| Randomized Phase: Atezolizumab | Atezolizumab Serum Concentration | End of Treatment | 136.43 Microgram per milliliter (mcg/mL) | Standard Deviation 73.002 |
| Randomized Phase: Atezolizumab | Atezolizumab Serum Concentration | Cycle 1 Day 2 Predose | 0.00 Microgram per milliliter (mcg/mL) | Standard Deviation 0 |
| Randomized Phase: Atezolizumab | Atezolizumab Serum Concentration | Cycle 4 Day 1 Postdose | 612.25 Microgram per milliliter (mcg/mL) | Standard Deviation 81.578 |
| Randomized Phase: Atezolizumab | Atezolizumab Serum Concentration | Cycle 1 Day 2 Postdose | 362.14 Microgram per milliliter (mcg/mL) | Standard Deviation 43.434 |
| Randomized Phase: Atezolizumab | Atezolizumab Serum Concentration | Cycle 4 Day 1 Predose | 166.50 Microgram per milliliter (mcg/mL) | Standard Deviation 37.477 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 1 Day 1 Predose | 0.00 Microgram per milliliter (mcg/mL) | Standard Deviation 0 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 1 Day 1 Postdose | 396.51 Microgram per milliliter (mcg/mL) | Standard Deviation 103.196 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 2 Day 1 Predose | 78.85 Microgram per milliliter (mcg/mL) | Standard Deviation 30.575 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 3 Day 1 Predose | 117.61 Microgram per milliliter (mcg/mL) | Standard Deviation 33.227 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 4 Day 1 Predose | 145.64 Microgram per milliliter (mcg/mL) | Standard Deviation 37.323 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 4 Day 1 Postdose | 539.24 Microgram per milliliter (mcg/mL) | Standard Deviation 116.291 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 8 Day 1 Predose | 158.23 Microgram per milliliter (mcg/mL) | Standard Deviation 77.778 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 8 Day 1 Postdose | 527.50 Microgram per milliliter (mcg/mL) | Standard Deviation 213.492 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 12 Day 1 Predose | 183.00 Microgram per milliliter (mcg/mL) | — |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | End of Treatment | 129.55 Microgram per milliliter (mcg/mL) | Standard Deviation 79.72 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Post Last Dose | 13.17 Microgram per milliliter (mcg/mL) | Standard Deviation 8.386 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 4 Day 1 Postdose | 482.33 Microgram per milliliter (mcg/mL) | Standard Deviation 139.879 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Post Last Dose | 115.10 Microgram per milliliter (mcg/mL) | Standard Deviation 146.937 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | End of Treatment | 141.62 Microgram per milliliter (mcg/mL) | Standard Deviation 71.756 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 8 Day 1 Postdose | 515.25 Microgram per milliliter (mcg/mL) | Standard Deviation 214.177 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 2 Day 1 Predose | 81.90 Microgram per milliliter (mcg/mL) | Standard Deviation 20.021 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 1 Day 1 Predose | 0.00 Microgram per milliliter (mcg/mL) | Standard Deviation 0 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 3 Day 1 Predose | 123.51 Microgram per milliliter (mcg/mL) | Standard Deviation 31.882 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 1 Day 2 Postdose | 343.82 Microgram per milliliter (mcg/mL) | Standard Deviation 135.476 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 12 Day 1 Predose | 248.00 Microgram per milliliter (mcg/mL) | — |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 4 Day 1 Predose | 157.79 Microgram per milliliter (mcg/mL) | Standard Deviation 37.819 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 1 Day 2 Predose | 0.00 Microgram per milliliter (mcg/mL) | Standard Deviation 0 |
| Randomized Phase: Daratumumab + Atezolizumab | Atezolizumab Serum Concentration | Cycle 1 Day 1 Postdose | 440.00 Microgram per milliliter (mcg/mL) | Standard Deviation 93.145 |
Secondary
Clinical Benefit Rate
Clinical benefit rate was defined as percentage of participants who achieved disease control (CR, PR, or SD). RECIST 1.1 Criteria for CR: Disappearance of all target lesions; all lymph nodes of non-pathological in size (\<10 mm short axis); normalization of tumor marker level. Criteria for PR: \>=30 % decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. Criteria for SD: \<30% decrease in sum of diameters of all target lesions compared with baseline and \<20% increase compared with nadir, in absence of new lesions or unequivocal progression of nontarget lesions. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'.
Time frame: Up to 1.5 years
Population: ITT analysis set included all participants who had entered the Randomized phase of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Phase: Atezolizumab | Clinical Benefit Rate | 43.5 Percentage of Participants |
| Randomized Phase: Daratumumab + Atezolizumab | Clinical Benefit Rate | 52.2 Percentage of Participants |
Secondary
Daratumumab Serum Concentration
Daratumumab serum concentrations were reported. Each cycle was of 21-days. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'.
Time frame: Cycle 1 Day 1 (C1D1):predose and postdose; C2D1 and C3D1:predose; C3D15: predose and postdose; C4D1: predose and postdose; C8D1: predose and postdose; C12D1: predose; end of treatment (37 days after last dose); and post last dose (up to 1.5 years)
Population: Pharmacokinetic (PK)-evaluable analysis set included all participants who had received at least 1 dose of daratumumab or atezolizumab and had at least 1 postinfusion sample collected. Here 'n' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure at a given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Randomized Phase: Atezolizumab | Daratumumab Serum Concentration | Cycle 1 Day 1 Predose | 0.00 Microgram per milliliter (mcg/mL) | Standard Deviation 0 |
| Randomized Phase: Atezolizumab | Daratumumab Serum Concentration | Cycle 1 Day 1 Postdose | 417.13 Microgram per milliliter (mcg/mL) | Standard Deviation 141.626 |
| Randomized Phase: Atezolizumab | Daratumumab Serum Concentration | Cycle 2 Day 1 Predose | 393.95 Microgram per milliliter (mcg/mL) | Standard Deviation 139.48 |
| Randomized Phase: Atezolizumab | Daratumumab Serum Concentration | Cycle 3 Day 1 Predose | 740.17 Microgram per milliliter (mcg/mL) | Standard Deviation 99.515 |
| Randomized Phase: Atezolizumab | Daratumumab Serum Concentration | Cycle 3 Day 15 Predose | 843.22 Microgram per milliliter (mcg/mL) | Standard Deviation 156.792 |
| Randomized Phase: Atezolizumab | Daratumumab Serum Concentration | Cycle 3 Day 15 Postdose | 1088.73 Microgram per milliliter (mcg/mL) | Standard Deviation 282.349 |
| Randomized Phase: Atezolizumab | Daratumumab Serum Concentration | Cycle 4 Day 1 Predose | 899.90 Microgram per milliliter (mcg/mL) | Standard Deviation 123.305 |
| Randomized Phase: Atezolizumab | Daratumumab Serum Concentration | Cycle 4 Day 1 Postdose | 1416.40 Microgram per milliliter (mcg/mL) | Standard Deviation 353.415 |
| Randomized Phase: Atezolizumab | Daratumumab Serum Concentration | Cycle 8 Day 1 Predose | 254.87 Microgram per milliliter (mcg/mL) | — |
| Randomized Phase: Atezolizumab | Daratumumab Serum Concentration | Cycle 8 Day 1 Postdose | 824.64 Microgram per milliliter (mcg/mL) | — |
| Randomized Phase: Atezolizumab | Daratumumab Serum Concentration | End of Treatment | 405.14 Microgram per milliliter (mcg/mL) | Standard Deviation 242.189 |
| Randomized Phase: Atezolizumab | Daratumumab Serum Concentration | Post Last Dose | 41.84 Microgram per milliliter (mcg/mL) | Standard Deviation 23.082 |
| Randomized Phase: Daratumumab + Atezolizumab | Daratumumab Serum Concentration | Cycle 8 Day 1 Postdose | 617.21 Microgram per milliliter (mcg/mL) | Standard Deviation 239.962 |
| Randomized Phase: Daratumumab + Atezolizumab | Daratumumab Serum Concentration | Cycle 4 Day 1 Predose | 574.81 Microgram per milliliter (mcg/mL) | Standard Deviation 181.193 |
| Randomized Phase: Daratumumab + Atezolizumab | Daratumumab Serum Concentration | Cycle 1 Day 1 Predose | 0.00 Microgram per milliliter (mcg/mL) | Standard Deviation 0 |
| Randomized Phase: Daratumumab + Atezolizumab | Daratumumab Serum Concentration | Cycle 12 Day 1 Predose | 260.21 Microgram per milliliter (mcg/mL) | Standard Deviation 17.163 |
| Randomized Phase: Daratumumab + Atezolizumab | Daratumumab Serum Concentration | Cycle 1 Day 1 Postdose | 296.12 Microgram per milliliter (mcg/mL) | Standard Deviation 85.66 |
| Randomized Phase: Daratumumab + Atezolizumab | Daratumumab Serum Concentration | Cycle 4 Day 1 Postdose | 856.30 Microgram per milliliter (mcg/mL) | Standard Deviation 244.698 |
| Randomized Phase: Daratumumab + Atezolizumab | Daratumumab Serum Concentration | Cycle 2 Day 1 Predose | 278.42 Microgram per milliliter (mcg/mL) | Standard Deviation 89.34 |
| Randomized Phase: Daratumumab + Atezolizumab | Daratumumab Serum Concentration | Post Last Dose | 112.63 Microgram per milliliter (mcg/mL) | Standard Deviation 115.727 |
| Randomized Phase: Daratumumab + Atezolizumab | Daratumumab Serum Concentration | Cycle 3 Day 1 Predose | 487.65 Microgram per milliliter (mcg/mL) | Standard Deviation 124.935 |
| Randomized Phase: Daratumumab + Atezolizumab | Daratumumab Serum Concentration | Cycle 8 Day 1 Predose | 288.84 Microgram per milliliter (mcg/mL) | Standard Deviation 177.187 |
| Randomized Phase: Daratumumab + Atezolizumab | Daratumumab Serum Concentration | Cycle 3 Day 15 Predose | 552.79 Microgram per milliliter (mcg/mL) | Standard Deviation 180.549 |
| Randomized Phase: Daratumumab + Atezolizumab | Daratumumab Serum Concentration | End of Treatment | 187.75 Microgram per milliliter (mcg/mL) | Standard Deviation 110.531 |
| Randomized Phase: Daratumumab + Atezolizumab | Daratumumab Serum Concentration | Cycle 3 Day 15 Postdose | 827.72 Microgram per milliliter (mcg/mL) | Standard Deviation 266.085 |
Secondary
Duration of Response (DoR)
Duration of response was defined as duration from date of initial documentation of disease response to date of first objectively documented evidence of recurrence or progressive disease (PD) or death, whichever occurred first. PD: Sum of diameters increased by \>=20% and \>=5 millimeter (mm) from nadir (including baseline if it was smallest sum). Participants with measurable disease: for unequivocal progression based on non-target disease, overall level of substantial worsening that merits discontinuation of therapy (if target disease was stable disease \[SD\]/PR). Participants without measurable disease: for unequivocal progression of non-target disease, increase in overall tumor burden comparable to increase required for PD of measurable disease. Appearance of 1/ more new lesions or unequivocal progression of non-target lesion was also considered as PD. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'.
Time frame: Up to 1.5 years
Population: ITT analysis set included all participants who had entered the Randomized phase of the study. Here, N (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Phase: Atezolizumab | Duration of Response (DoR) | 5.8 Months |
| Randomized Phase: Daratumumab + Atezolizumab | Duration of Response (DoR) | 2.9 Months |
Secondary
Number of Participants With Adverse Events
An adverse event (AE) is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Crossover participants were counted twice (in 'Randomized Phase: Atezo arm' and in 'Randomized Phase: Atezo Crossed Over to Dara + Atezo') for safety analysis. For cross-over participants, AEs after initiation of cross-over treatment were summarized separately in the crossover arm, however, AEs occurred before crossover treatment were included in 'Randomized Phase: Atezolizumab arm'.
Time frame: Up to 1.5 years
Population: Safety analysis set included all participants who had received at least 1 administration of any study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Phase: Atezolizumab | Number of Participants With Adverse Events | 7 Participants |
| Randomized Phase: Daratumumab + Atezolizumab | Number of Participants With Adverse Events | 42 Participants |
| Randomized Phase: Daratumumab + Atezolizumab | Number of Participants With Adverse Events | 44 Participants |
| Randomized Phase: Atezo Crossed Over to Dara + Atezo | Number of Participants With Adverse Events | 8 Participants |
Secondary
Number of Participants With Anti-Atezolizumab Antibodies
Number of participants with antibodies to atezolizumab (tested using a validated immunoassay method) were reported. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'.
Time frame: Up to 1.5 years
Population: The immunogenicity-evaluable analysis set included all participants who received at least 1 dose of atezolizumab or daratumumab and had appropriate samples for detection of antibodies to atezolizumab or daratumumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Phase: Atezolizumab | Number of Participants With Anti-Atezolizumab Antibodies | 0 Participants |
| Randomized Phase: Daratumumab + Atezolizumab | Number of Participants With Anti-Atezolizumab Antibodies | 6 Participants |
| Randomized Phase: Daratumumab + Atezolizumab | Number of Participants With Anti-Atezolizumab Antibodies | 5 Participants |
Secondary
Number of Participants With Anti-Daratumumab Antibodies
Number of participants with antibodies to daratumumab (tested using a validated immunoassay method) were reported. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'.
Time frame: Up to 1.5 years
Population: The immunogenicity-evaluable analysis set included all participants who received at least 1 dose of atezolizumab or daratumumab and had appropriate samples for detection of antibodies to atezolizumab or daratumumab. Here 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Phase: Atezolizumab | Number of Participants With Anti-Daratumumab Antibodies | 0 Participants |
| Randomized Phase: Daratumumab + Atezolizumab | Number of Participants With Anti-Daratumumab Antibodies | 0 Participants |
Secondary
Overall Survival (OS)
Overall Survival was defined as the duration from the date of randomization to the date of participant's death due to any cause. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'.
Time frame: Up to 1.5 years
Population: ITT analysis set included all participants who had entered the Randomized phase of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Phase: Atezolizumab | Overall Survival (OS) | NA Months |
| Randomized Phase: Daratumumab + Atezolizumab | Overall Survival (OS) | 7.13 Months |
Secondary
Progression-Free Survival (PFS)
PFS was defined as the duration from the date of randomization until the first documented disease progression (PD) or death, whichever occurred first. PD: Sum of diameters increased by \>=20% and \>=5 millimeter (mm) from nadir (including baseline if it was smallest sum). Participants with measurable disease: for unequivocal progression based on non-target disease, overall level of substantial worsening that merits discontinuation of therapy (if target disease was stable disease \[SD\]/PR). Participants without measurable disease: for unequivocal progression of non-target disease, increase in overall tumor burden comparable to increase required for PD of measurable disease. Appearance of 1/ more new lesions or unequivocal progression of non-target lesion was also considered as PD. The OM was planned to be reported for participants based on their initial assignment to 'Randomized Phase: Atezolizumab'.
Time frame: Up to 1.5 years
Population: ITT analysis set included all participants who had entered the Randomized phase of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Phase: Atezolizumab | Progression-Free Survival (PFS) | 1.48 Months |
| Randomized Phase: Daratumumab + Atezolizumab | Progression-Free Survival (PFS) | 1.68 Months |