Colorectal Cancer
Conditions
Brief summary
This randomized, multi-center, active-controlled, open-label, parallel-group study will investigate the efficacy and safety of biomarker-driven maintenance treatment for first-line mCRC. Participants with mCRC are eligible for entry and cannot have received any prior chemotherapy in the metastatic setting. The entire study duration is anticipated to be approximately 7.5 years.
Interventions
DRUGCetuximab
500 mg/m\^2 via IV infusion on Day 1 of every 2-week cycle
DRUGFOLFOX induction regimen
Administered per the Investigator's discretion in accordance with locally approved prescribing information.
DRUGFluoropyrimidine (5-FU/LV or capecitabine)
Per Investigator's discretion: 5-FU 1600-2400 mg/m\^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m\^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m\^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information.
DRUGAtezolizumab
800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle, or a fixed dose of 840 mg
DRUGVemurafenib
960 mg vermurafenib BID by mouth
DRUGBevacizumab
5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information
DRUGTrastuzumab
Initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses by IV infusion on Day 1 of every 3-week treatment cycle
DRUGPertuzumab
Initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses by IV infusion on Day 1 of each 3-week treatment cycle
DRUGCobimetinib
60 mg orally once daily for 3 weeks followed by a 1-week treatment break
DRUG5-FU/LV
1600-2400 mg/m\^2 5-FU via 46-hour IV infusion in combination with 400 mg/m\^2 LV via 2-hour infusion on Day 1 of every 2-week cycle until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first. The fluoropyrimidine should be administered in accordance with local prescribing information.
DRUGCapecitabine
1000 mg/m\^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The fluoropyrimidine should be administered in accordance with local prescribing information.
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
* ECOG PS of less than or equal to (\<=) 2 * At least 16 weeks of life expectancy at time of entry into the study * Histologically confirmed colorectal cancer (CRC) with mCRC confirmed radiologically * Measureable, unresectable disease according to RECIST 1.1 * No prior chemotherapy for CRC in the metastatic setting * Archival tumor formalin-fixed paraffin-embedded tissue block from the primary tumor obtained at the time of the initial diagnosis is available * Adequate hematological, liver and renal function * Agreement to use highly effective measures of contraception
Exclusion criteria
for All Participants: * Less than 6 months from completion of any prior neoadjuvant or adjuvant chemotherapy, radiotherapy * Prior or current treatment with bevacizumab or any other anti-angiogenic drug (vascular endothelial growth factor or vascular endothelial growth factor receptor therapies or tyrosine kinase inhibitors) * Current or recent (within 10 days of study enrollment) use of aspirin (more than \[\>\] 325 milligrams per day \[mg/day\]), clopidogrel (\> 75 mg/day), or current or recent (within 10 days prior to the start of study induction treatment) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes (prophylactic uses allowed) * Active infection requiring intravenous antibiotics at the start of study induction treatment * Previous or concurrent malignancy, except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the participant has been disease-free for 5 years prior to study entry * Inadequately controlled hypertension; prior history of hypertensive crisis or hypertensive encephalopathy * Clinically significant (active) cardiovascular disease, for example cerebrovascular accidents \<= 6 months prior to start of study induction treatment, myocardial infarction \<= 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Functional Classification Grade II or greater congestive heart failure, or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment * Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of start of study induction treatment * Active symptomatic or untreated central nervous system (CNS) metastases; CNS disease other than supratentorial or cerebellar metastases (in other words, patients with metastases to midbrain, pons, medulla or spinal cord are excluded); history of or known carcinomatous meningitis * Known hypersensitivity to any component of any of the study induction or maintenance treatment medications * Pregnancy or lactation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | From randomization until disease progression or death from any cause, up to 5 years | PFS is defined as the time from randomization to the first occurrence of disease progression 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events | From baseline until end of study (up to 5 years) | — |
| Overall Response | From randomization until disease progression, up to 5 years | Calculated as the number of participants with a best overall response of CR or PR according to RECIST 1.1. CR: disappearance of all target lesions. 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. OR= CR + PR. |
| Disease Control Rate (DCR) | From randomization until disease progression, up to 5 years | DCR is defined as the percentage of participants with CR, PR, or stable disease (SD) at 16 weeks. Per RECIST v1.1, CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum on study. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline, or the appearance of one or more new lesions. |
| Overall Survival (OS) | From randomization until death from any cause, up to 5 years | OS is defined as the time from randomization into the MTP to time of death from any cause. |
| Duration of Response | From first objective response until disease progression or death from any cause, up to 5 years | Defined as the time from the first assessment of CR or PR until disease progression or death from any cause, whichever occurs first. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. |
| Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | From baseline until end of study (up to 5 years) | — |
| Time to Treatment Response | From randomization until disease progression or death from any cause, up to 5 years | Calculated as the time from randomization to the first Occurrence of a documented Objective Response (CR or PR) determined according to RECIST 1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. |
Countries
Argentina, Belgium, Bosnia and Herzegovina, Brazil, Denmark, Egypt, France, Germany, Greece, Italy, Mexico, Netherlands, Poland, Portugal, Russia, Serbia, Slovakia, Slovenia, South Korea, Spain, Sweden, Turkey (Türkiye), United Kingdom
Participant flow
Pre-assignment details
Participants initially received study treatment during the Induction Phase. Next, participants within each cohort based on biomarker status were randomized to either an experimental arm or control arm per cohort in the Maintenance Phase. BRAFmut participants experiencing early disease progression during induction treatment had the option of proceeding immediately to receive second-line treatment and were followed during the study, but were not part of the Maintenance Phase study objectives.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Induction Phase (IP) Included participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt). All study participants received either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab during Induction Treatment. | 93 |
| Cohort 2 (IP) Included participants with BRAFwt. All study participants received either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab during Induction Treatment. | 635 |
| Cohort 3 (IP) Included participants with human epidermal growth factor receptor 2 positive (HER2+). All study participants received either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab during Induction Treatment. | 6 |
| Cohort 4 (IP) Included participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut). All study participants received either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab during Induction Treatment. | 310 |
| Total | 1,044 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Early Disease Progression | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 10 |
| Early Disease Progression | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Induction Treatment | Adverse Event | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Induction Treatment | Death | 25 | 0 | 0 | 111 | 0 | 0 | 1 | 0 | 0 | 82 | 0 | 0 | 0 |
| Induction Treatment | Lost to Follow-up | 1 | 0 | 0 | 12 | 0 | 0 | 0 | 0 | 0 | 9 | 0 | 0 | 0 |
| Induction Treatment | Missing | 4 | 0 | 0 | 14 | 0 | 0 | 0 | 0 | 0 | 54 | 0 | 0 | 0 |
| Induction Treatment | Non-Compliance | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Induction Treatment | Physician Decision | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Induction Treatment | Protocol Violation | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 |
| Induction Treatment | Reason Not Specified | 0 | 0 | 0 | 4 | 0 | 0 | 0 | 0 | 0 | 7 | 0 | 0 | 0 |
| Induction Treatment | Withdrawal by Subject | 0 | 0 | 0 | 24 | 0 | 0 | 0 | 0 | 0 | 18 | 0 | 0 | 0 |
| Maintenance Treatment Phase | Adverse Event | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Maintenance Treatment Phase | Death | 0 | 29 | 16 | 0 | 188 | 107 | 0 | 1 | 1 | 0 | 46 | 19 | 0 |
| Maintenance Treatment Phase | Lost to Follow-up | 0 | 1 | 0 | 0 | 15 | 4 | 0 | 1 | 0 | 0 | 3 | 3 | 0 |
| Maintenance Treatment Phase | Non-Compliance | 0 | 1 | 0 | 0 | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Maintenance Treatment Phase | Not Treated | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Maintenance Treatment Phase | Physician Decision | 0 | 2 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 |
| Maintenance Treatment Phase | Reason Not Specified | 0 | 0 | 0 | 0 | 7 | 2 | 0 | 1 | 0 | 0 | 1 | 0 | 0 |
| Maintenance Treatment Phase | Study Ended by Sponsor | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Maintenance Treatment Phase | Withdrawal by Subject | 0 | 0 | 0 | 0 | 15 | 12 | 0 | 0 | 0 | 0 | 2 | 3 | 0 |
Baseline characteristics
| Characteristic | Cohort 2 (IP) | Cohort 3 (IP) | Cohort 1: Induction Phase (IP) | Cohort 4 (IP) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 60.9 years STANDARD_DEVIATION 12.6 | 48.0 years STANDARD_DEVIATION 7.7 | 59.5 years STANDARD_DEVIATION 12 | 60.1 years STANDARD_DEVIATION 10.3 | 60.5 years STANDARD_DEVIATION 11.9 |
| Age, Customized 85 years and over | 5 Participants | 0 Participants | 0 Participants | 1 Participants | 6 Participants |
| Age, Customized Adolescents (12-17 years) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adults (18-64 years) | 351 Participants | 6 Participants | 58 Participants | 199 Participants | 614 Participants |
| Age, Customized Children (2-11 years) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized From 65-84 years | 279 Participants | 0 Participants | 35 Participants | 110 Participants | 424 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized In utero | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 52 Participants | 1 Participants | 5 Participants | 49 Participants | 107 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 494 Participants | 4 Participants | 75 Participants | 247 Participants | 820 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 89 Participants | 1 Participants | 13 Participants | 14 Participants | 117 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 9 Participants | 0 Participants | 1 Participants | 14 Participants | 24 Participants |
| Race (NIH/OMB) Asian | 15 Participants | 0 Participants | 5 Participants | 16 Participants | 36 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 0 Participants | 0 Participants | 5 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 62 Participants | 0 Participants | 11 Participants | 9 Participants | 82 Participants |
| Race (NIH/OMB) White | 539 Participants | 6 Participants | 76 Participants | 264 Participants | 885 Participants |
| Sex: Female, Male Female | 247 Participants | 4 Participants | 49 Participants | 123 Participants | 423 Participants |
| Sex: Female, Male Male | 388 Participants | 2 Participants | 44 Participants | 187 Participants | 621 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 | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 25 / 93 | 29 / 40 | 16 / 20 | 111 / 635 | 188 / 297 | 107 / 148 | 1 / 6 | 1 / 3 | 1 / 2 | 82 / 310 | 46 / 65 | 19 / 34 | 10 / 11 |
| other Total, other adverse events | 91 / 93 | 40 / 40 | 17 / 18 | 608 / 632 | 270 / 293 | 120 / 143 | 6 / 6 | 3 / 3 | 2 / 2 | 298 / 309 | 61 / 64 | 29 / 34 | 11 / 11 |
| serious Total, serious adverse events | 44 / 93 | 15 / 40 | 5 / 18 | 232 / 632 | 76 / 293 | 20 / 143 | 1 / 6 | 0 / 3 | 0 / 2 | 93 / 309 | 26 / 64 | 3 / 34 | 3 / 11 |
Outcome results
Primary
Progression-Free Survival (PFS)
PFS is defined as the time from randomization to the first occurrence of disease progression 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: From randomization until disease progression or death from any cause, up to 5 years
Population: Participants that were in the Maintenance Phase of the study, which included the experimental and control arms of Cohorts 1-4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib | Progression-Free Survival (PFS) | 9.99 months |
| Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Progression-Free Survival (PFS) | 11.60 months |
| Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab | Progression-Free Survival (PFS) | 7.13 months |
| Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Progression-Free Survival (PFS) | 7.36 months |
| Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab | Progression-Free Survival (PFS) | 4.44 months |
| Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Progression-Free Survival (PFS) | 4.04 months |
| Cohort 4 (MP): Cobimetinib,Atezolizumab | Progression-Free Survival (PFS) | 3.75 months |
| Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Progression-Free Survival (PFS) | 7.79 months |
p-value: =0.87295% CI: [0.5, 1.82]Log Rank
p-value: =0.66695% CI: [0.77, 1.18]Log Rank
p-value: =0.12895% CI: [0.9, 2.29]Log Rank
Secondary
Disease Control Rate (DCR)
DCR is defined as the percentage of participants with CR, PR, or stable disease (SD) at 16 weeks. Per RECIST v1.1, CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum on study. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline, or the appearance of one or more new lesions.
Time frame: From randomization until disease progression, up to 5 years
Population: Participants that were in the Maintenance Phase of the study, which included the experimental and control arms of Cohorts 1-4.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib | Disease Control Rate (DCR) | 36 Participants |
| Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Disease Control Rate (DCR) | 15 Participants |
| Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab | Disease Control Rate (DCR) | 227 Participants |
| Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Disease Control Rate (DCR) | 111 Participants |
| Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab | Disease Control Rate (DCR) | 1 Participants |
| Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Disease Control Rate (DCR) | 0 Participants |
| Cohort 4 (MP): Cobimetinib,Atezolizumab | Disease Control Rate (DCR) | 44 Participants |
| Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Disease Control Rate (DCR) | 26 Participants |
p-value: =0.125Chi-squared
p-value: =0.739Chi-squared
p-value: 0.362Chi-squared
Secondary
Duration of Response
Defined as the time from the first assessment of CR or PR until disease progression or death from any cause, whichever occurs first. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time frame: From first objective response until disease progression or death from any cause, up to 5 years
Population: Participants that were in the Maintenance Phase of the study, which included the experimental and control arms of Cohorts 1-4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib | Duration of Response | 11.50 months |
| Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Duration of Response | 8.74 months |
| Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab | Duration of Response | 9.30 months |
| Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Duration of Response | 7.59 months |
| Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab | Duration of Response | 9.205 months |
| Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Duration of Response | 0 months |
| Cohort 4 (MP): Cobimetinib,Atezolizumab | Duration of Response | 7.11 months |
| Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Duration of Response | 6.06 months |
p-value: =0.421Log Rank
p-value: =0.495Log Rank
p-value: 0.357Log Rank
Secondary
Overall Response
Calculated as the number of participants with a best overall response of CR or PR according to RECIST 1.1. CR: disappearance of all target lesions. 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. OR= CR + PR.
Time frame: From randomization until disease progression, up to 5 years
Population: Participants that were in the Maintenance Phase of the study, which included the experimental and control arms of Cohorts 1-4.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib | Overall Response | 20 Participants |
| Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Overall Response | 5 Participants |
| Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab | Overall Response | 49 Participants |
| Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Overall Response | 22 Participants |
| Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab | Overall Response | 1 Participants |
| Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Overall Response | 0 Participants |
| Cohort 4 (MP): Cobimetinib,Atezolizumab | Overall Response | 7 Participants |
| Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Overall Response | 8 Participants |
p-value: =0.064Chi-squared
p-value: =0.658Chi-squared
p-value: 0.093Chi-squared
Secondary
Overall Survival (OS)
OS is defined as the time from randomization into the MTP to time of death from any cause.
Time frame: From randomization until death from any cause, up to 5 years
Population: Participants that were in the Maintenance Phase of the study, which included the experimental and control arms of Cohorts 1-4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib | Overall Survival (OS) | 24.02 months |
| Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Overall Survival (OS) | 21.73 months |
| Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab | Overall Survival (OS) | 22.54 months |
| Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Overall Survival (OS) | 22.24 months |
| Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab | Overall Survival (OS) | NA months |
| Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Overall Survival (OS) | 14.59 months |
| Cohort 4 (MP): Cobimetinib,Atezolizumab | Overall Survival (OS) | 22.60 months |
| Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Overall Survival (OS) | 25.17 months |
p-value: =0.27695% CI: [0.39, 1.32]Log Rank
p-value: =0.07695% CI: [0.64, 1.02]Log Rank
p-value: =0.157Log Rank
p-value: =0.41595% CI: [0.73, 2.14]Log Rank
Secondary
Percentage of Participants With Adverse Events
Time frame: From baseline until end of study (up to 5 years)
Population: Safety population: all participants who received an intervention during the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib | Percentage of Participants With Adverse Events | 98.9 percentage of participants |
| Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Percentage of Participants With Adverse Events | 100 percentage of participants |
| Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab | Percentage of Participants With Adverse Events | 94.4 percentage of participants |
| Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Percentage of Participants With Adverse Events | 96.0 percentage of participants |
| Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab | Percentage of Participants With Adverse Events | 95.6 percentage of participants |
| Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Percentage of Participants With Adverse Events | 88.1 percentage of participants |
| Cohort 4 (MP): Cobimetinib,Atezolizumab | Percentage of Participants With Adverse Events | 100 percentage of participants |
| Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Percentage of Participants With Adverse Events | 100 percentage of participants |
| Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Percentage of Participants With Adverse Events | 100 percentage of participants |
| Cohort 4 (IP) | Percentage of Participants With Adverse Events | 97.4 percentage of participants |
| Cohort 4 (MP): Cobimetinib,Atezolizumab | Percentage of Participants With Adverse Events | 98.4 percentage of participants |
| Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Percentage of Participants With Adverse Events | 88.2 percentage of participants |
| Early Progressing BRAFmut Cohort | Percentage of Participants With Adverse Events | 90.9 percentage of participants |
Secondary
Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score
Time frame: From baseline until end of study (up to 5 years)
Population: Participants that were in the Maintenance Phase of the study, which included the experimental and control arms of Cohorts 1-4.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved or stayed the same | 75.0 percentage of participants |
| Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved | 10.0 percentage of participants |
| Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved | 5.0 percentage of participants |
| Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved or stayed the same | 85.0 percentage of participants |
| Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved or stayed the same | 76.7 percentage of participants |
| Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved | 10.4 percentage of participants |
| Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved | 5.4 percentage of participants |
| Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved or stayed the same | 82.5 percentage of participants |
| Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved | 0 percentage of participants |
| Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved or stayed the same | 100 percentage of participants |
| Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved | 0 percentage of participants |
| Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved or stayed the same | 100 percentage of participants |
| Cohort 4 (MP): Cobimetinib,Atezolizumab | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved | 7.7 percentage of participants |
| Cohort 4 (MP): Cobimetinib,Atezolizumab | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved or stayed the same | 63.1 percentage of participants |
| Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved | 5.9 percentage of participants |
| Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score | Improved or stayed the same | 79.4 percentage of participants |
Secondary
Time to Treatment Response
Calculated as the time from randomization to the first Occurrence of a documented Objective Response (CR or PR) determined according to RECIST 1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time frame: From randomization until disease progression or death from any cause, up to 5 years
Population: Participants that were in the Maintenance Phase of the study, which included the experimental and control arms of Cohorts 1-4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib | Time to Treatment Response | 3.943 months |
| Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Time to Treatment Response | 5.552 months |
| Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab | Time to Treatment Response | 5.224 months |
| Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Time to Treatment Response | 4.616 months |
| Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab | Time to Treatment Response | 5.490 months |
| Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Time to Treatment Response | 0 months |
| Cohort 4 (MP): Cobimetinib,Atezolizumab | Time to Treatment Response | 3.745 months |
| Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab | Time to Treatment Response | 2.530 months |