A Phase 3 interventional study of Cobimetinib and Atezolizumab in Advanced BRAFV600 Wild-type Melanoma, sponsored by Hoffmann-La Roche. Terminated at 121 sites in 15 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-09-21.
Sponsored by Hoffmann-La Roche · Phase 3, Interventional, and Treatment
This is a Phase III, multicenter, open-label, randomized study designed to evaluate the efficacy, safety, and pharmacokinetics of cobimetinib plus atezolizumab compared with pembrolizumab in treatment-naive participants with advanced BRAFV600 wild-type melanoma.
Disease-Specific Inclusion Criteria
Exclusion Criteria:
General Exclusion Criteria
Participants will receive 60 mg of cobimetinib orally from Days 1 to 21 along with 840 mg of atezolizumab by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurs first. There will be no cobimetinib administration for 7 days (Days 22-28) in each cycle.
Drug: Cobimetinib · Drug: Atezolizumab
Participants will receive 200 mg of pembrolizumab administered by IV infusion every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurs first.
Drug: Pembrolizumab
Cobimetinib 60 mg tablets orally once daily on a 21 days on, 7 days off schedule.
Atezolizumab 840 mg as IV infusion once in every 2 weeks.
Pembrolizumab 200 mg as IV infusion once in every 3 weeks.
Progression Free Survival (PFS) as Determined by the Independent Review Committee (IRC)
PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions.
Time frame: Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months
PFS as Determined by the Investigator
PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions.
Time frame: Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months
Objective Response as Determined by the Investigator
Objective response rate is defined as the percentage of participants with a complete response (CR) or a partial response (PR) on two consecutive occasions \>/=4 weeks apart, as determined by the investigator through the use of RECIST v1.1. For target lesion, CR: the disappearance of all target lesions, any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. For non-target lesion, CR: the disappearance of all non-target lesions and (if applicable) normalization of tumor marker level, all lymph nodes must be non-pathological in size (\<10 mm short axis).
Time frame: Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months
Objective Response as Determined by IRC
Objective response, defined as a complete response or partial response on two consecutive occasions ≥4 weeks apart, as determined by IRC according to RECIST v1.1
Time frame: Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months
Disease Control Rate (DCR)
DCR is defined as the proportion of participants with a complete response, a partial response, or stable disease at 16 weeks. For target lesion, CR: the disappearance of all target lesions, any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. For non-target lesion, CR: the disappearance of all non-target lesions and (if applicable) normalization of tumor marker level, all lymph nodes must be non-pathological in size (\<10 mm short axis). Stable disease (SD): neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD.
Time frame: Week 16
Overall Survival (OS)
OS is defined as the time from randomization to death from any cause.
Time frame: From randomization up to approximately 3 years
Duration of Objective Response Determined by the IRC
Duration of objective response, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first.
Time frame: Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months
Duration of Objective Response Determined by the Investigator
Duration of objective response is defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator through use of RECIST v1.1, or death from any cause, whichever occurs first.
Time frame: Up to 3 years
Two-year Landmark Survival
Two-year landmark survival is defined as the rate of survival at 2 years. Two-year landmark survival is defined as the rate of survival at 2 years and was calculated using Kaplan-Meier analysis, which is commonly used to estimate the probability of an event at time 't.'
Time frame: At 2 years
Change From Baseline in Health-related Quality of Life (HRQoL) Scores
HRQoL scores are assessed through global health status (GHS)/ quality of life (QoL) subscale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30). These are based on questions 29 and 30 of the EORTC QLQ-C30. These questions on global health status/QoL scale are coded on 7-point scale (1=very poor to 7=excellent). Raw scores will be linearly transformed to obtain the score ranging from 0 to 100, where higher score represents a higher ("better") level of functioning.
Time frame: Up to approximately 16 months. Follow up is reported at weeks after participant treatment discontinuation, which could occur at any time during the study. Total time frame does not exceed 16 months.
Number of Participants With Adverse Events (AEs)
An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: Up to approximately 16 months
Number of Participants With Abnormal Vital Signs
Vital signs will include temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure.
Time frame: From baseline up to approximately 3 years
Number of Participants With Laboratory Abnormalities
Participants with laboratory abnormalities (values outside of a defined range) will be reported.
Time frame: Up to approximately 16 months
Plasma Concentration of Cobimetinib
Time frame: Days 1 and 15 of Cycle 1
Serum Concentration of Atezolizumab
Time frame: Day 1 of Cycles 1, 2, and 3
Percentage of Participants With Anti-drug Antibodies (ADAs)
Participants with ADAs during the study relative to the prevalence of ADAs at baseline will be reported.
Time frame: Day 1 of Cycle 1, 2, 3 and 30 days after treatment discontinuation
| Milestone | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| Started | 224 | 222 |
| Completed | 0 | 0 |
| Not completed | 224 | 222 |
| Withdrew: Adverse event | 1 | 2 |
| Withdrew: Missing | 0 | 2 |
| Withdrew: Other | 3 | 2 |
| Withdrew: Symptomatic deterioration | 0 | 1 |
| Withdrew: Progressive disease | 6 | 5 |
| Withdrew: Physician decision | 1 | 3 |
| Withdrew: Study terminated by sponsor | 112 | 102 |
| Withdrew: Withdrawal by subject | 26 | 25 |
| Withdrew: Protocol deviation | 3 | 0 |
| Withdrew: Lost to follow-up | 6 | 11 |
| Withdrew: Death | 66 | 69 |
PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions.
| Months | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| Progression Free Survival (PFS) as Determined by the Independent Review Committee (IRC) | 5.7 (3.7 to 9.6) | 5.5 (3.8 to 7.2) |
PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions.
| Months | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| PFS as Determined by the Investigator | 7.2 (3.8 to 10.1) | 5.6 (3.9 to 6.6) |
Objective response rate is defined as the percentage of participants with a complete response (CR) or a partial response (PR) on two consecutive occasions \>/=4 weeks apart, as determined by the investigator through the use of RECIST v1.1. For target lesion, CR: the disappearance of all target lesions, any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. For non-target lesion, CR: the disappearance of all non-target lesions and (if applicable) normalization of tumor marker level, all lymph nodes must be non-pathological in size (\<10 mm short axis).
| Percentage of Participants | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| Objective Response as Determined by the Investigator | 36.7 (30.29 to 43.38) | 27.9 (22.13 to 34.32) |
Objective response, defined as a complete response or partial response on two consecutive occasions ≥4 weeks apart, as determined by IRC according to RECIST v1.1
| Percentage of Participants | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| Objective Response as Determined by IRC | 31.6 (25.27 to 38.38) | 26.0 (20.11 to 32.57) |
DCR is defined as the proportion of participants with a complete response, a partial response, or stable disease at 16 weeks. For target lesion, CR: the disappearance of all target lesions, any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. For non-target lesion, CR: the disappearance of all non-target lesions and (if applicable) normalization of tumor marker level, all lymph nodes must be non-pathological in size (\<10 mm short axis). Stable disease (SD): neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD.
| Percentage of Participants | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| Investigator-assessed | 49.8 (43.00 to 56.56) | 46.8 (40.14 to 53.64) |
| IRC-assessed | 44.2 (37.28 to 51.24) | 45.6 (38.62 to 52.69) |
OS is defined as the time from randomization to death from any cause.
| Months | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| Overall Survival (OS) | 29.3 (21.5 to NA) | NA (24.1 to NA) |
Duration of objective response, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first.
| Months | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| Duration of Objective Response Determined by the IRC | NA (NA to NA) | NA (9.2 to NA) |
Duration of objective response is defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator through use of RECIST v1.1, or death from any cause, whichever occurs first.
| Months | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| Duration of Objective Response Determined by the Investigator | NA (NA to NA) | NA (9.2 to NA) |
Two-year landmark survival is defined as the rate of survival at 2 years. Two-year landmark survival is defined as the rate of survival at 2 years and was calculated using Kaplan-Meier analysis, which is commonly used to estimate the probability of an event at time 't.'
| Percentage | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| Two-year Landmark Survival | 57.88 (48.25 to 67.52) | 60.19 (51.58 to 68.79) |
HRQoL scores are assessed through global health status (GHS)/ quality of life (QoL) subscale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30). These are based on questions 29 and 30 of the EORTC QLQ-C30. These questions on global health status/QoL scale are coded on 7-point scale (1=very poor to 7=excellent). Raw scores will be linearly transformed to obtain the score ranging from 0 to 100, where higher score represents a higher ("better") level of functioning.
| Units on a Scale | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| Baseline value | 73.27 ± 20.41 | 73.85 ± 19.73 |
| Week 4 | -2.99 ± 17.05 | -9.14 ± 20.83 |
| Week 8 | -3.15 ± 18.67 | -5.21 ± 18.18 |
| Week 12 | -1.77 ± 19.93 | -7.65 ± 21.20 |
| Week 16 | 1.16 ± 15.02 | -6.44 ± 20.58 |
| Week 20 | 1.69 ± 17.50 | -6.31 ± 19.17 |
| Week 24 | -1.84 ± 19.82 | -2.49 ± 15.98 |
| Week 28 | 2.46 ± 19.07 | -3.86 ± 19.10 |
| Week 32 | -0.88 ± 22.41 | -4.66 ± 20.94 |
| Week 36 | 4.17 ± 20.56 | -6.00 ± 18.24 |
| Week 40 | 7.22 ± 19.38 | -4.63 ± 21.62 |
| Week 44 | 0.46 ± 19.27 | 1.67 ± 12.91 |
| Week 48 | 7.64 ± 13.04 | 0.00 ± 15.96 |
| Week 52 | 1.67 ± 12.36 | 8.33 ± 15.21 |
| Week 56 | -11.11 ± 17.21 | -2.08 ± 4.17 |
| Week 60 | -8.33 ± 11.79 | -4.17 ± 5.89 |
| Week 64 | 33.33 ± NA | — |
| Treatment Discontinuation | -6.05 ± 22.53 | -14.42 ± 25.68 |
| Follow-up 4 | -7.64 ± 14.85 | -2.27 ± 18.67 |
| Follow-up 8 | -14.25 ± 21.96 | -14.10 ± 24.15 |
| Follow-up 12 | -21.38 ± 24.34 | -24.31 ± 28.08 |
| Follow-up 16 | -13.73 ± 19.53 | -23.61 ± 23.26 |
| Follow-up 20 | -20.83 ± 26.53 | -8.33 ± 12.91 |
| Follow-up 24 | -17.71 ± 29.36 | -10.00 ± 14.91 |
| Follow-up 28 | -27.78 ± 22.15 | -16.67 ± 23.57 |
An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
| Number of Participants | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | 195 | 218 |
Vital signs will include temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure.
| Participants | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| Sitting diastolic blood pressure - low | 41 | 42 |
| Sitting diastolic blood pressure - high | 77 | 85 |
| Sitting systolic blood pressure - low | 4 | 7 |
| Sitting systolic blood pressure - high | 53 | 47 |
| Pulse rate - low | 58 | 67 |
| Pulse rate - high | 13 | 27 |
| Respiratory rate - low | 8 | 11 |
| Respiratory rate - high | 55 | 52 |
| Temperature - low | 91 | 93 |
| Temperature - high | 20 | 47 |
Participants with laboratory abnormalities (values outside of a defined range) will be reported.
| Number of Participants | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| SGPT/ALT | 1 | 1 |
| Amylase | 4 | 5 |
| SGOT/AST | 0 | 2 |
| Calcium | 0 | 1 |
| Creatine Kinase | 1 | 17 |
| Creatinine | 1 | 4 |
| Glucose | 8 | 13 |
| Triacylglycerol Lipase | 8 | 10 |
| Magnesium | 3 | 2 |
| Phosphorus | 6 | 10 |
| Potassium | 1 | 6 |
| Sodium | 2 | 4 |
| Uric Acid | 36 | 30 |
| Hemoglobin | 2 | 2 |
| Lymphocytes Abs | 6 | 15 |
| Neutrophils, Total, Abs | 0 | 1 |
| Total Leukocyte Count | 3 | 0 |
| nanograms/mL | Cobimetinib and Atezolizumab |
|---|---|
| Cycle 1 Day 1 | 49.2 ± 614.7 |
| Cycle 1 Day 15 pre-dose | 126 ± 284.1 |
| Cycle 1 Day 15 post-dose | 231 ± 213.3 |
| micrograms/mL | Cobimetinib and Atezolizumab |
|---|---|
| Cycle 1 Day 1 | 256 ± 35.3 |
| Cycle 2 Day 1 | 72.2 ± 177.1 |
| Cycle 3 Day 1 | 126 ± 104.3 |
Participants with ADAs during the study relative to the prevalence of ADAs at baseline will be reported.
| Percentage of participants | Cobimetinib and Atezolizumab |
|---|---|
| Percentage of Participants With Anti-drug Antibodies (ADAs) | 23.2 |
Collected over For up to 135 days after the last dose of study drug, or until a new systemic anti-cancer therapy was initiated, whichever occurred first (a maximum of approximately 3 years).. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Pembrolizumab | 68/224 (30.4%) | 56/216 (25.9%) | 173/216 (80.1%) |
| Cobimetinib and Atezolizumab | 70/222 (31.5%) | 105/220 (47.7%) | 209/220 (95%) |
| Event | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| PyrexiaGeneral disorders | 2/216 | 12/220 |
| DiarrhoeaGastrointestinal disorders | 2/216 | 9/220 |
| SepsisInfections and infestations | 0/216 | 6/220 |
| Pulmonary embolismRespiratory, thoracic and mediastinal disorders | 5/216 | 3/220 |
| VomitingGastrointestinal disorders | 0/216 | 5/220 |
| AstheniaGeneral disorders | 3/216 | 4/220 |
| RashSkin and subcutaneous tissue disorders | 1/216 | 4/220 |
| RhabdomyolysisMusculoskeletal and connective tissue disorders | 0/216 | 4/220 |
| Abdominal pain upperGastrointestinal disorders | 3/216 | 1/220 |
| PancreatitisGastrointestinal disorders | 3/216 | 1/220 |
| Event | Pembrolizumab | Cobimetinib and Atezolizumab |
|---|---|---|
| DiarrhoeaGastrointestinal disorders | 42/216 | 120/220 |
| RashSkin and subcutaneous tissue disorders | 27/216 | 90/220 |
| Blood creatine phosphokinase increasedInvestigations | 13/216 | 81/220 |
| PyrexiaGeneral disorders | 17/216 | 65/220 |
| AstheniaGeneral disorders | 42/216 | 59/220 |
| NauseaGastrointestinal disorders | 28/216 | 54/220 |
| Oedema peripheralGeneral disorders | 17/216 | 50/220 |
| Dermatitis acneiformSkin and subcutaneous tissue disorders | 3/216 | 50/220 |
| PruritisSkin and subcutaneous tissue disorders | 35/216 | 44/220 |
| FatigueGeneral disorders | 42/216 | 43/220 |
| Age, Continuous(Years) | Pembrolizumab | Cobimetinib and Atezolizumab | Total |
|---|---|---|---|
| Mean | 63.5 ± 12.9 | 63.6 ± 13.1 | 63.6 ± 13.0 |
| Sex: Female, Male(Participants) | Pembrolizumab | Cobimetinib and Atezolizumab | Total |
|---|---|---|---|
| Female | 83 | 93 | 176 |
| Male | 141 | 129 | 270 |
| Ethnicity (NIH/OMB)(Participants) | Pembrolizumab | Cobimetinib and Atezolizumab | Total |
|---|---|---|---|
| Hispanic or Latino | 7 | 15 | 22 |
| Not Hispanic or Latino | 190 | 180 | 370 |
| Unknown or Not Reported | 27 | 27 | 54 |
| Race (NIH/OMB)(Participants) | Pembrolizumab | Cobimetinib and Atezolizumab | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 6 | 6 | 12 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 1 | 6 | 7 |
| White | 198 | 188 | 386 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 19 | 22 | 41 |
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