Colorectal Cancer
Conditions
Brief summary
A phase Ib/II, open-label, multicenter, randomized study designed to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of immunotherapy-based treatment combinations in patients with metastatic colorectal cancer (mCRC) that became refractory to first- and second-line standard therapies. Eligible patients will be assigned to one of several treatment arms.
Interventions
DRUGRegorafenib
Regorafenib will be administered orally on Days 1-21 of each 28-day cycle.
DRUGAtezolizumab
Atezolizumab will be administered by intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of 21-day cycles, with the exception of the Atezolizumab + Selicrelumab + Bevacizumab, Atezolizumab + Idasanutlin, Atezolizumab + Regorafenib and Atezolizumab + Regorafenib + AB928 arms where the Atezolizumab will be administered by IV infusion every 2 weeks (Q2W) on Days 1 and 15 of each 28-day cycle.
DRUGImprime PGG
Imprime PGG will be administered by IV infusion weekly on Days 1, 8, and 15 of each 21-day cycle.
DRUGBevacizumab
Bevacizumab will be administered by IV infusion on Day 1 of each 21-day cycle for the Atezolizumab + Imprime PGG + Bevacizumab arm, and on Day 1 and Day 15 of each 28-day cycle for the Atezolizumab + Selicrelumab + Bevacizumab arm.
DRUGIsatuximab
Isatuximab will be administered on Day 1, 8 and 15 of cycle 1 and on day 1 of all subsequent cycles. Cycles will be 21 days long.
DRUGSelicrelumab
Selicrelumab will be administered by subcutaneous (SC) injection on Day 1 of cycles 1-4 and every third cycle thereafter. Cycles will be 28 days long.
DRUGIdasanutlin
Idasanutlin will be administered orally on Days 1-5 of each 28-day cycle.
DRUGAB928
AB928 will be administered orally once daily on Days 1-28 of each 28-day cycle.
GENETICLOAd703
LOAd703 will be administered by intratumoral injection on Day 1 of each 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
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Life expectancy ≥ 3 months, as determined by the investigator * Histologically confirmed adenocarcinoma originating from the colon or rectum * Metastatic disease not amenable to local treatment * Disease progression during or following not more than two separate lines of treatment for metastatic colorectal cancer (mCRC) that consisted of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy in combination with a biologic agent * Measurable disease (at least one target lesion) according to RECIST v1.1 * Adequate hematologic and end-organ function obtained within 14 days prior to initiation of study treatment
Exclusion criteria
* High microsatellite instability (MSI-H) tumor * Presence of BRAFV600E mutation * Prior treatment with any of the protocol-specified study treatments * Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies * Biologic treatment within 2 weeks prior to initiation of study treatment, or other systemic treatment for CRC within 2 weeks or 5 half-lives of the drug (whichever is shorter) prior to initiation of study treatment * Treatment with investigational therapy within 28 days prior to initiation of study treatment * Eligibility only for the control arm * Prior allogeneic stem cell or solid organ transplantation * Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the initiation of study treatment * Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressant medication during study treatment * Treatment with 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 last dose of atezolizumab * Current treatment with anti-viral therapy for HBV * Uncontrolled pleural effusion, pericardial effusion, ascites requiring recurrent drainage procedures (once monthly or more frequently), or tumor related-pain, * Uncontrolled or symptomatic hypercalcemia (ionized calcium \>1.5 mmol/L, calcium \>12 mg/dL, or corrected serum calcium \>ULN) * Symptomatic, untreated, or actively progressing CNS metastases * History of leptomeningeal disease * Active or history of autoimmune disease or immune deficiency * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan * History of malignancy other than CRC within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death * Active tuberculosis * Severe infection within 4 weeks prior to initiation of study treatment * Significant cardiovascular disease * Grade ≥3 hemorrhage or bleeding event within 28 days prior to initiation of study treatment * 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 * History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins * Inability to swallow medications * Malabsorption condition that would alter the absorption of orally administered medications * Evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding * Urine dipstick ≥ 2+ protein or ≥ 3.5 g of protein in a 24-hour urine collection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | From randomization until disease progression or loss of clinical benefit (up to 4 years) | The best confirmed overall response rate (ORR) is defined as the percentage of participants with a complete response or partial response on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to RECIST v1.1. Participants could be classified as Stable Disease if the assessment was at least 6 weeks from randomization. Participants were classified as Missing if no post-baseline response assessments were available. Participants were classified as Not Evaluable if all post-baseline response assessments were unevaluable. The differences in ORR between the experimental arms and the corresponding control arm were calculated, along with 95% confidence intervals (CIs), using normal approximation of the binomial distribution. The 95% CIs for ORRs were constructed using the Clopper-Pearson method. The 95% CIs for the difference in rates were constructed using the Wald method with continuity correction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization up to death from any cause (up to 4 years) | Overall survival (OS) is 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 method was used to estimate the median for OS with 95% confidence intervals (CIs) constructed through use of the Brookmeyer and Crowley method. |
| Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 3, 6, 12, and 18 months | Overall survival (OS) is 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. OS is shown as the percentage of participants who were event-free at the landmark timepoints of 3, 6, 12, and 18 months. |
| Progression-Free Survival (PFS) as Determined by Investigator According to RECIST v1.1 | From randomization up to the first occurrence of disease or death from any cause (up to 4 years) | Progression-free survival (PFS) after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), was determined by the investigator according to RECIST v1.1. For participants who did not have documented disease progression or death, PFS was censored at the day of the last tumor assessment. The Kaplan-Meier method was used to estimate the median for PFS with 95% confidence intervals (CIs) constructed through use of the Brookmeyer and Crowley method. |
| Disease Control Rate (DCR), as Determined by the Investigator Per RECIST v1.1 | From randomization until disease progression or loss of clinical benefit (up to 4 years) | Disease control rate is defined as the percentage of participants with stable disease for ≥12 weeks or a complete or partial response, as determined by the investigator according to RECIST v1.1. |
| Percentage of Participants With at Least One Adverse Event (AE) | Adverse event data were collected from baseline up to 6 months after the last dose of study treatment (up to 640 days); deaths (all-cause) were reported from baseline through survival follow-up (up to 4 years) | The incidence, nature, and severity of adverse events (AEs) are reported, with severity determined according to NCI CTCAE v4.0. All AEs were reported until 30 days after the last study dose or until start of new systemic anti-cancer therapy. Serious AEs and AEs of special interest were reported until 135 days (or 180 days for the Atezolizumab + LOAd703 arm only) after the last dose of study treatment. |
| Duration of Response (DOR) as Determined by the Investigator According to RECIST v1.1 | From the date of first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to 4 years) | Duration of response is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause. |
Countries
Australia, France, South Korea, Switzerland, United States
Participant flow
Recruitment details
The study was conducted at 15 centers in 5 countries: United States, France, Republic of Korea, Australia, and Switzerland.
Participants by arm
| Arm | Count |
|---|---|
| Regorafenib (Control) Participants will receive treatment until unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. | 24 |
| Atezolizumab + Imprime PGG + Bevacizumab Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. | 15 |
| Atezolizumab + Isatuximab Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. | 15 |
| Atezolizumab + Selicrelumab + Bevacizumab Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. | 6 |
| Atezolizumab + Idasanutlin Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. | 4 |
| Atezolizumab + Regorafenib Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. | 15 |
| Atezolizumab + Regorafenib + AB928 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. | 15 |
| Atezolizumab + LOAd703 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. | 2 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 18 | 15 | 15 | 4 | 4 | 11 | 12 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Study Terminated By Sponsor | 1 | 0 | 0 | 0 | 0 | 2 | 3 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 0 | 0 | 2 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Regorafenib (Control) | Atezolizumab + Imprime PGG + Bevacizumab | Atezolizumab + Isatuximab | Atezolizumab + Selicrelumab + Bevacizumab | Atezolizumab + Idasanutlin | Atezolizumab + Regorafenib | Atezolizumab + Regorafenib + AB928 | Atezolizumab + LOAd703 | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous Age (year) | 59.5 Years STANDARD_DEVIATION 10.3 | 57.8 Years STANDARD_DEVIATION 5.9 | 52.3 Years STANDARD_DEVIATION 12 | 66.8 Years STANDARD_DEVIATION 10 | 56.3 Years STANDARD_DEVIATION 6.8 | 56.4 Years STANDARD_DEVIATION 8.2 | 55.1 Years STANDARD_DEVIATION 9.2 | 58.0 Years STANDARD_DEVIATION 11.3 | 57.2 Years STANDARD_DEVIATION 9.7 |
| ECOG score 0 | 11 Participants | 8 Participants | 5 Participants | 5 Participants | 1 Participants | 7 Participants | 7 Participants | 1 Participants | 45 Participants |
| ECOG score 1 | 13 Participants | 7 Participants | 10 Participants | 1 Participants | 3 Participants | 8 Participants | 8 Participants | 1 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 10 Participants | 11 Participants | 4 Participants | 4 Participants | 11 Participants | 14 Participants | 1 Participants | 76 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 8 Participants |
| Number of Metastatic Sites at Enrollment 1 | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 6 Participants |
| Number of Metastatic Sites at Enrollment 2 | 4 Participants | 5 Participants | 3 Participants | 3 Participants | 3 Participants | 7 Participants | 5 Participants | 0 Participants | 30 Participants |
| Number of Metastatic Sites at Enrollment 3 | 9 Participants | 5 Participants | 8 Participants | 0 Participants | 0 Participants | 2 Participants | 6 Participants | 2 Participants | 32 Participants |
| Number of Metastatic Sites at Enrollment >=4 | 8 Participants | 4 Participants | 4 Participants | 3 Participants | 1 Participants | 5 Participants | 3 Participants | 0 Participants | 28 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 6 Participants | 4 Participants | 0 Participants | 1 Participants | 5 Participants | 8 Participants | 0 Participants | 31 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) White | 15 Participants | 7 Participants | 10 Participants | 5 Participants | 3 Participants | 7 Participants | 6 Participants | 2 Participants | 55 Participants |
| Sex: Female, Male Female | 12 Participants | 7 Participants | 6 Participants | 1 Participants | 3 Participants | 11 Participants | 4 Participants | 1 Participants | 45 Participants |
| Sex: Female, Male Male | 12 Participants | 8 Participants | 9 Participants | 5 Participants | 1 Participants | 4 Participants | 11 Participants | 1 Participants | 51 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 |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 18 / 24 | 15 / 15 | 15 / 15 | 4 / 6 | 4 / 4 | 11 / 15 | 12 / 15 | 1 / 2 |
| other Total, other adverse events | 19 / 19 | 15 / 15 | 15 / 15 | 6 / 6 | 4 / 4 | 15 / 15 | 15 / 15 | 2 / 2 |
| serious Total, serious adverse events | 5 / 19 | 1 / 15 | 5 / 15 | 3 / 6 | 1 / 4 | 7 / 15 | 7 / 15 | 1 / 2 |
Outcome results
Primary
Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
The best confirmed overall response rate (ORR) is defined as the percentage of participants with a complete response or partial response on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to RECIST v1.1. Participants could be classified as Stable Disease if the assessment was at least 6 weeks from randomization. Participants were classified as Missing if no post-baseline response assessments were available. Participants were classified as Not Evaluable if all post-baseline response assessments were unevaluable. The differences in ORR between the experimental arms and the corresponding control arm were calculated, along with 95% confidence intervals (CIs), using normal approximation of the binomial distribution. The 95% CIs for ORRs were constructed using the Clopper-Pearson method. The 95% CIs for the difference in rates were constructed using the Wald method with continuity correction.
Time frame: From randomization until disease progression or loss of clinical benefit (up to 4 years)
Population: The efficacy evaluable population included all patients who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib (Control) | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Complete Response (CR) | 0 Percentage of Participants |
| Regorafenib (Control) | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Responders (CR + PR) | 0 Percentage of Participants |
| Regorafenib (Control) | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Missing | 10.5 Percentage of Participants |
| Regorafenib (Control) | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Progressive Disease (PD) | 26.3 Percentage of Participants |
| Regorafenib (Control) | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Partial Response (PR) | 0 Percentage of Participants |
| Regorafenib (Control) | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Stable Disease (SD) | 63.2 Percentage of Participants |
| Regorafenib (Control) | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Not Evaluable | 0 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Not Evaluable | 0 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Stable Disease (SD) | 33.3 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Responders (CR + PR) | 0 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Complete Response (CR) | 0 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Partial Response (PR) | 0 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Missing | 0 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Progressive Disease (PD) | 66.7 Percentage of Participants |
| Atezolizumab + Isatuximab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Missing | 0 Percentage of Participants |
| Atezolizumab + Isatuximab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Responders (CR + PR) | 0 Percentage of Participants |
| Atezolizumab + Isatuximab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Stable Disease (SD) | 20.0 Percentage of Participants |
| Atezolizumab + Isatuximab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Complete Response (CR) | 0 Percentage of Participants |
| Atezolizumab + Isatuximab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Partial Response (PR) | 0 Percentage of Participants |
| Atezolizumab + Isatuximab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Not Evaluable | 13.3 Percentage of Participants |
| Atezolizumab + Isatuximab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Progressive Disease (PD) | 66.7 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Partial Response (PR) | 0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Missing | 16.7 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Not Evaluable | 0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Stable Disease (SD) | 50 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Complete Response (CR) | 0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Responders (CR + PR) | 0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Progressive Disease (PD) | 33.3 Percentage of Participants |
| Atezolizumab + Idasanutlin | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Missing | 0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Stable Disease (SD) | 0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Complete Response (CR) | 0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Not Evaluable | 0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Progressive Disease (PD) | 100 Percentage of Participants |
| Atezolizumab + Idasanutlin | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Responders (CR + PR) | 0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Partial Response (PR) | 0 Percentage of Participants |
| Atezolizumab + Regorafenib | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Responders (CR + PR) | 6.7 Percentage of Participants |
| Atezolizumab + Regorafenib | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Complete Response (CR) | 0 Percentage of Participants |
| Atezolizumab + Regorafenib | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Stable Disease (SD) | 33.3 Percentage of Participants |
| Atezolizumab + Regorafenib | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Missing | 13.3 Percentage of Participants |
| Atezolizumab + Regorafenib | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Partial Response (PR) | 6.7 Percentage of Participants |
| Atezolizumab + Regorafenib | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Not Evaluable | 0 Percentage of Participants |
| Atezolizumab + Regorafenib | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Progressive Disease (PD) | 46.7 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Complete Response (CR) | 0 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Stable Disease (SD) | 53.3 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Responders (CR + PR) | 6.7 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Partial Response (PR) | 6.7 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Progressive Disease (PD) | 26.7 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Not Evaluable | 13.3 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Missing | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Progressive Disease (PD) | 100 Percentage of Participants |
| Atezolizumab + LOAd703 | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Stable Disease (SD) | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Complete Response (CR) | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Responders (CR + PR) | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Partial Response (PR) | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Missing | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Not Evaluable | 0 Percentage of Participants |
95% CI: [-11.92, 25.25]
95% CI: [-11.92, 25.25]
Secondary
Disease Control Rate (DCR), as Determined by the Investigator Per RECIST v1.1
Disease control rate is defined as the percentage of participants with stable disease for ≥12 weeks or a complete or partial response, as determined by the investigator according to RECIST v1.1.
Time frame: From randomization until disease progression or loss of clinical benefit (up to 4 years)
Population: The efficacy evaluable population included all patients who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regorafenib (Control) | Disease Control Rate (DCR), as Determined by the Investigator Per RECIST v1.1 | 15.8 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Disease Control Rate (DCR), as Determined by the Investigator Per RECIST v1.1 | 13.3 Percentage of Participants |
| Atezolizumab + Isatuximab | Disease Control Rate (DCR), as Determined by the Investigator Per RECIST v1.1 | 6.7 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Disease Control Rate (DCR), as Determined by the Investigator Per RECIST v1.1 | 33.3 Percentage of Participants |
| Atezolizumab + Idasanutlin | Disease Control Rate (DCR), as Determined by the Investigator Per RECIST v1.1 | 0 Percentage of Participants |
| Atezolizumab + Regorafenib | Disease Control Rate (DCR), as Determined by the Investigator Per RECIST v1.1 | 13.3 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Disease Control Rate (DCR), as Determined by the Investigator Per RECIST v1.1 | 40.0 Percentage of Participants |
| Atezolizumab + LOAd703 | Disease Control Rate (DCR), as Determined by the Investigator Per RECIST v1.1 | 0 Percentage of Participants |
Secondary
Duration of Response (DOR) as Determined by the Investigator According to RECIST v1.1
Duration of response is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause.
Time frame: From the date of first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to 4 years)
Population: The duration of response analysis included all participants from the efficacy evaluable population who had a confirmed overall response; only 1 participant in each of the atezolizumab + regorafenib arm and the atezolizumab + regorafenib + AB928 arm had a confirmed response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Regorafenib | Duration of Response (DOR) as Determined by the Investigator According to RECIST v1.1 | 3.12 Months |
| Atezolizumab + Regorafenib + AB928 | Duration of Response (DOR) as Determined by the Investigator According to RECIST v1.1 | 5.75 Months |
Secondary
Overall Survival (OS)
Overall survival (OS) is 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 method was used to estimate the median for OS with 95% confidence intervals (CIs) constructed through use of the Brookmeyer and Crowley method.
Time frame: From randomization up to death from any cause (up to 4 years)
Population: The efficacy evaluable population included all participants who received at least one dose of each study drug for their assigned treatment regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regorafenib (Control) | Overall Survival (OS) | 10.15 Months |
| Atezolizumab + Imprime PGG + Bevacizumab | Overall Survival (OS) | 5.72 Months |
| Atezolizumab + Isatuximab | Overall Survival (OS) | 5.13 Months |
| Atezolizumab + Selicrelumab + Bevacizumab | Overall Survival (OS) | 14.36 Months |
| Atezolizumab + Idasanutlin | Overall Survival (OS) | 5.93 Months |
| Atezolizumab + Regorafenib | Overall Survival (OS) | 11.01 Months |
| Atezolizumab + Regorafenib + AB928 | Overall Survival (OS) | 8.67 Months |
| Atezolizumab + LOAd703 | Overall Survival (OS) | 4.07 Months |
Comparison: Atezolizumab + Imprime PGG + Bevacizumab vs. Regorafenib (Control) Hazard Ratio for OS95% CI: [0.71, 2.93]
Comparison: Atezolizumab + Isatuximab vs. Regorafenib (Control) Hazard Ratio for OS95% CI: [0.68, 2.81]
Comparison: Atezolizumab + Selicrelumab + Bevacizumab vs. Regorafenib (Control) Hazard Ratio for OS95% CI: [0.3, 2.72]
Comparison: Atezolizumab + Idasanutlin vs. Regorafenib (Control) Hazard Ratio for OS95% CI: [0.42, 3.84]
Comparison: Atezolizumab + Regorafenib vs. Regorafenib (Control) Hazard Ratio for OS95% CI: [0.39, 1.88]
Comparison: Atezolizumab + Regorafenib + AB928 vs. Regorafenib (Control) Hazard Ratio for OS95% CI: [0.43, 1.96]
Comparison: Atezolizumab + LOAd703 vs. Regorafenib (Control) Hazard Ratio for OS95% CI: [0.33, 24.85]
Secondary
Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS)
Overall survival (OS) is 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. OS is shown as the percentage of participants who were event-free at the landmark timepoints of 3, 6, 12, and 18 months.
Time frame: 3, 6, 12, and 18 months
Population: The efficacy evaluable population included all participants who received at least one dose of each study drug for their assigned treatment regimen. The number analyzed at each landmark timepoint indicates the number of participants who were remaining at risk for an event. The event-free rate was not estimable (NE) for landmark timepoints at which 0 participants were remaining at risk for an an event.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib (Control) | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 6 Months | 63.16 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 12 Months | 34.45 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 18 Months | 17.22 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 3 Months | 84.21 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 12 Months | 20.00 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 18 Months | 6.67 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 3 Months | 100.00 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 6 Months | 46.67 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 18 Months | 20.00 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 12 Months | 26.67 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 3 Months | 73.33 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 6 Months | 40.00 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 3 Months | 100.00 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 6 Months | 80.00 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 18 Months | 26.67 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 12 Months | 53.33 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 3 Months | 75.00 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 6 Months | 50.00 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 12 Months | 25.00 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 18 Months | 25.00 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 12 Months | 39.89 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 6 Months | 71.79 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 3 Months | 78.97 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 18 Months | 23.93 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 3 Months | 86.67 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 6 Months | 73.33 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 12 Months | 33.33 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 18 Months | 26.67 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | 3 Months | 100.00 Percentage of Participants |
Comparison: Difference in OS event-free rate at 3 months for the Atezolizumab + Imprime PGG + Bevacizumab vs. Regorafenib (Control) arms95% CI: [-0.61, 32.19]
Comparison: Difference in OS event-free rate at 6 months for the Atezolizumab + Imprime PGG + Bevacizumab vs. Regorafenib (Control) arms95% CI: [-49.78, 16.79]
Comparison: Difference in OS event-free rate at 12 months for the Atezolizumab + Imprime PGG + Bevacizumab vs. Regorafenib (Control) arms95% CI: [-44.37, 15.47]
Comparison: Difference in OS event-free rate at 18 months for the Atezolizumab + Imprime PGG + Bevacizumab vs. Regorafenib (Control) arms95% CI: [-32.25, 11.14]
Comparison: Difference in OS event-free rate at 3 months for the Atezolizumab + Isatuximab vs. Regorafenib (Control) arms95% CI: [-38.62, 16.87]
Comparison: Difference in OS event-free rate at 6 months for the Atezolizumab + Isatuximab vs. Regorafenib (Control) arms95% CI: [-56.1, 9.78]
Comparison: Difference in OS event-free rate at 12 months for the Atezolizumab + Isatuximab vs. Regorafenib (Control) arms95% CI: [-39.19, 23.62]
Comparison: Difference in OS event-free rate at 18 months for the Atezolizumab + Isatuximab vs. Regorafenib (Control) arms95% CI: [-24.08, 29.63]
Comparison: Difference in OS event-free rate at 3 months for the Atezolizumab + Selicrelumab + Bevacizumab vs. Regorafenib (Control) arms95% CI: [-0.61, 32.19]
Comparison: Difference in OS event-free rate at 6 months for the Atezolizumab + Selicrelumab + Bevacizumab vs. Regorafenib (Control) arms95% CI: [-24.39, 58.07]
Comparison: Difference in OS event-free rate at 12 months for the Atezolizumab + Selicrelumab + Bevacizumab vs. Regorafenib (Control) arms95% CI: [-34.53, 72.3]
Comparison: Difference in OS event-free rate at 18 months for the Atezolizumab + Selicrelumab + Bevacizumab vs. Regorafenib (Control) arms95% CI: [-38.19, 57.08]
Comparison: Difference in OS event-free rate at 3 months for the Atezolizumab + Idasanutlin vs. Regorafenib (Control) arms95% CI: [-54.7, 36.28]
Comparison: Difference in OS event-free rate at 6 months for the Atezolizumab + Idasanutlin vs. Regorafenib (Control) arms95% CI: [-66.74, 40.43]
Comparison: Difference in OS event-free rate at 12 months for the Atezolizumab + Idasanutlin vs. Regorafenib (Control) arms95% CI: [-57.26, 38.36]
Comparison: Difference in OS event-free rate at 18 months for the Atezolizumab + Idasanutlin vs. Regorafenib (Control) arms95% CI: [-38.18, 53.73]
Comparison: Difference in OS event-free rate at 3 months for the Atezolizumab + Regorafenib vs. Regorafenib (Control) arms95% CI: [-32.03, 21.56]
Comparison: Difference in OS event-free rate at 6 months for the Atezolizumab + Regorafenib vs. Regorafenib (Control) arms95% CI: [-23.33, 40.6]
Comparison: Difference in OS event-free rate at 12 months for the Atezolizumab + Regorafenib vs. Regorafenib (Control) arms95% CI: [-29.19, 40.06]
Comparison: Difference in OS event-free rate at 18 months for the Atezolizumab + Regorafenib vs. Regorafenib (Control) arms95% CI: [-22.64, 36.06]
Comparison: Difference in OS event-free rate at 3 months for the Atezolizumab + Regorafenib + AB928 vs. Regorafenib (Control) arms95% CI: [-21.31, 26.22]
Comparison: Difference in OS event-free rate at 6 months for the Atezolizumab + Regorafenib + AB928 vs. Regorafenib (Control) arms95% CI: [-20.99, 41.34]
Comparison: Difference in OS event-free rate at 12 months for the Atezolizumab + Regorafenib + AB928 vs. Regorafenib (Control) arms95% CI: [-33.59, 31.36]
Comparison: Difference in OS event-free rate at 18 months for the Atezolizumab + Regorafenib + AB928 vs. Regorafenib (Control) arms95% CI: [-19.06, 37.94]
Comparison: Difference in OS event-free rate at 3 months for the Atezolizumab +LOAd703 vs. Regorafenib (Control) arms95% CI: [-0.61, 32.19]
Secondary
Percentage of Participants With at Least One Adverse Event (AE)
The incidence, nature, and severity of adverse events (AEs) are reported, with severity determined according to NCI CTCAE v4.0. All AEs were reported until 30 days after the last study dose or until start of new systemic anti-cancer therapy. Serious AEs and AEs of special interest were reported until 135 days (or 180 days for the Atezolizumab + LOAd703 arm only) after the last dose of study treatment.
Time frame: Adverse event data were collected from baseline up to 6 months after the last dose of study treatment (up to 640 days); deaths (all-cause) were reported from baseline through survival follow-up (up to 4 years)
Population: The safety-evaluable population included all patients who received any amount of dose of any component of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | AE with a Fatal Outcome | 10.5 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | Withdrawn from Stage due to an AE | 15.8 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | Grade 3-5 AE | 68.4 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | Death | 89.5 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 5 | 10.5 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Dose Modification/Interruption | 47.4 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Withdrawal from any Treatment | 10.5 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | Related AE | 94.7 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 4 | 5.3 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Dose Modification/Interruption | 63.2 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Withdrawal from any Treatment | 26.3 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | Related SAE | 5.3 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Dose Modification/Interruption | 5.3 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Withdrawal from any Treatment | 21.1 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | Serious AE (SAE) | 26.3 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 3 | 52.6 Percentage of Participants |
| Regorafenib (Control) | Percentage of Participants With at Least One Adverse Event (AE) | Adverse Event (AE) | 100 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | AE with a Fatal Outcome | 0 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Dose Modification/Interruption | 0 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Related SAE | 6.7 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Withdrawal from any Treatment | 6.7 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Adverse Event (AE) | 100 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Death | 100 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Withdrawn from Stage due to an AE | 6.7 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Serious AE (SAE) | 6.7 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Withdrawal from any Treatment | 6.7 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Withdrawal from any Treatment | 6.7 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Dose Modification/Interruption | 40.0 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Related AE | 86.7 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Dose Modification/Interruption | 33.3 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Grade 3-5 AE | 20.0 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 5 | 0 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 4 | 0 Percentage of Participants |
| Atezolizumab + Imprime PGG + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 3 | 20.0 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Withdrawal from any Treatment | 0 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | AE with a Fatal Outcome | 0 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | Related SAE | 0 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 5 | 0 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | Serious AE (SAE) | 33.3 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | Withdrawn from Stage due to an AE | 0 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 4 | 6.7 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | Death | 100 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | Adverse Event (AE) | 100 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | Related AE | 86.7 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Dose Modification/Interruption | 13.3 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 3 | 40.0 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | Grade 3-5 AE | 46.7 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Withdrawal from any Treatment | 0 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Withdrawal from any Treatment | 0 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Dose Modification/Interruption | 6.7 Percentage of Participants |
| Atezolizumab + Isatuximab | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Dose Modification/Interruption | 0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 5 | 0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Dose Modification/Interruption | 50.0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Related AE | 100 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Withdrawn from Stage due to an AE | 0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Death | 66.7 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Withdrawal from any Treatment | 0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | AE with a Fatal Outcome | 0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 4 | 0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Serious AE (SAE) | 50.0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Adverse Event (AE) | 100 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Withdrawal from any Treatment | 0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Grade 3-5 AE | 50.0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 3 | 50.0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Withdrawal from any Treatment | 0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Dose Modification/Interruption | 33.3 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | Related SAE | 50.0 Percentage of Participants |
| Atezolizumab + Selicrelumab + Bevacizumab | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Dose Modification/Interruption | 50.0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 3 | 50.0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Dose Modification/Interruption | 75.0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | Grade 3-5 AE | 75.0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Dose Modification/Interruption | 75.0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Withdrawal from any Treatment | 0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | Withdrawn from Stage due to an AE | 0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Withdrawal from any Treatment | 0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Dose Modification/Interruption | 0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | Adverse Event (AE) | 100 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | Death | 100 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | Related SAE | 25.0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | Serious AE (SAE) | 25.0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | Related AE | 100 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 5 | 0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | AE with a Fatal Outcome | 0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Withdrawal from any Treatment | 0 Percentage of Participants |
| Atezolizumab + Idasanutlin | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 4 | 25.0 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | Related AE | 93.3 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Withdrawal from any Treatment | 6.7 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | Death | 73.3 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | Withdrawn from Stage due to an AE | 6.7 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | AE with a Fatal Outcome | 6.7 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Dose Modification/Interruption | 86.7 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 4 | 6.7 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | Serious AE (SAE) | 46.7 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Withdrawal from any Treatment | 20.0 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | Related SAE | 26.7 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Dose Modification/Interruption | 26.7 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Withdrawal from any Treatment | 6.7 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Dose Modification/Interruption | 73.3 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | Grade 3-5 AE | 66.7 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 3 | 53.3 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 5 | 6.7 Percentage of Participants |
| Atezolizumab + Regorafenib | Percentage of Participants With at Least One Adverse Event (AE) | Adverse Event (AE) | 100 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 3 | 46.7 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Withdrawal from any Treatment | 6.7 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | Related SAE | 33.3 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Dose Modification/Interruption | 93.3 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Dose Modification/Interruption | 46.7 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Withdrawal from any Treatment | 0 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | Death | 80.0 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | Grade 3-5 AE | 60.0 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 4 | 13.3 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 5 | 0 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | Serious AE (SAE) | 46.7 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | Adverse Event (AE) | 100 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | AE with a Fatal Outcome | 0 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | Withdrawn from Stage due to an AE | 6.7 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | Related AE | 100 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Dose Modification/Interruption | 93.3 Percentage of Participants |
| Atezolizumab + Regorafenib + AB928 | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Withdrawal from any Treatment | 6.7 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | Withdrawn from Stage due to an AE | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Withdrawal from any Treatment | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Withdrawal from any Treatment | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | Adverse Event (AE) | 100 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 4 | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | Related SAE | 50.0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | Serious AE (SAE) | 50.0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | Death | 50.0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | Related AE | 50.0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | Related AE Leading to Dose Modification/Interruption | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Dose Modification/Interruption | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 5 | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | SAE Leading to Withdrawal from any Treatment | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | Worst Grade AE: 3 | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | AE with a Fatal Outcome | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | AE Leading to Dose Modification/Interruption | 0 Percentage of Participants |
| Atezolizumab + LOAd703 | Percentage of Participants With at Least One Adverse Event (AE) | Grade 3-5 AE | 0 Percentage of Participants |
Secondary
Progression-Free Survival (PFS) as Determined by Investigator According to RECIST v1.1
Progression-free survival (PFS) after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), was determined by the investigator according to RECIST v1.1. For participants who did not have documented disease progression or death, PFS was censored at the day of the last tumor assessment. The Kaplan-Meier method was used to estimate the median for PFS with 95% confidence intervals (CIs) constructed through use of the Brookmeyer and Crowley method.
Time frame: From randomization up to the first occurrence of disease or death from any cause (up to 4 years)
Population: The efficacy evaluable population included all patients who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regorafenib (Control) | Progression-Free Survival (PFS) as Determined by Investigator According to RECIST v1.1 | 2.83 Months |
| Atezolizumab + Imprime PGG + Bevacizumab | Progression-Free Survival (PFS) as Determined by Investigator According to RECIST v1.1 | 1.51 Months |
| Atezolizumab + Isatuximab | Progression-Free Survival (PFS) as Determined by Investigator According to RECIST v1.1 | 1.41 Months |
| Atezolizumab + Selicrelumab + Bevacizumab | Progression-Free Survival (PFS) as Determined by Investigator According to RECIST v1.1 | 4.21 Months |
| Atezolizumab + Idasanutlin | Progression-Free Survival (PFS) as Determined by Investigator According to RECIST v1.1 | 1.26 Months |
| Atezolizumab + Regorafenib | Progression-Free Survival (PFS) as Determined by Investigator According to RECIST v1.1 | 1.81 Months |
| Atezolizumab + Regorafenib + AB928 | Progression-Free Survival (PFS) as Determined by Investigator According to RECIST v1.1 | 4.60 Months |
| Atezolizumab + LOAd703 | Progression-Free Survival (PFS) as Determined by Investigator According to RECIST v1.1 | 1.58 Months |
95% CI: [0.67, 2.73]
95% CI: [1.08, 4.88]
95% CI: [0.29, 2.18]
95% CI: [0.64, 6.24]
95% CI: [0.83, 3.63]
95% CI: [0.39, 1.63]
95% CI: [0.94, 33.82]