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NCT02788279

A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma (COTEZO IMblaze370)

Completed Phase 3 Results posted Last updated 11 December 2019
What this trial tests

Phase 3 trial testing Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody in Colorectal Cancer in 363 participants. Completed in 26 December 2018.

Timeline
5 July 2016
Primary endpoint
9 March 2018
26 December 2018

Quick facts

Lead sponsorHoffmann-La Roche
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment363
Start date5 July 2016
Primary completion9 March 2018
Estimated completion26 December 2018
Sites73 locations across Hong Kong, Italy, Russia, Belgium, United Kingdom, Poland, South Korea, Canada

Drugs / interventions tested

Conditions studied

Sponsor

Hoffmann-La Roche — full company profile →

Who can join

18 and older, any sex, with Colorectal Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Overall Survival (OS) Primary · From randomization up to death due to any cause (up to approximately 20 months)

Overall survival is defined as the time (in months) between the date of randomization and the date of death due to any cause. Participants who were not reported as having died at the date of analysis were censored at the date when they were last known to be alive. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.

GroupValue95% CI
Regorafenib8.516.41 – 10.71
Cobimetinib + Atezolizumab8.877.00 – 10.61
Atezolizumab7.106.05 – 10.05
Progression-Free Survival (PFS) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Secondary · From randomization up to disease progression or death due to any cause (up to approximately 20 months)

PFS was defined as the time from randomization to disease progression as determined by the investigator with the use of RECIST v1.1 or death due to any cause, whichever occurred earlier. Disease progression was 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. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). For non-target lesions, disease progression was defined as unequivocal progression of existing lesions. The appearan

GroupValue95% CI
Regorafenib2.001.87 – 3.61
Cobimetinib + Atezolizumab1.911.87 – 1.97
Atezolizumab1.941.91 – 2.10
Percentage of Participants With Investigator-Assessed Objective Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.1 Secondary · From randomization up to death due to any cause (up to approximately 20 months)

PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions). Objective response and its 95% CI were calculated using the Clopper-Pearson method.

GroupValue95% CI
Regorafenib2.20.27 – 7.80
Cobimetinib + Atezolizumab2.70.89 – 6.26
Atezolizumab2.20.27 – 7.80
Duration of Response (DOR) According to RECIST Version 1.1 Secondary · From first occurrence of CR or PR up to disease progression or death due to any cause (up to approximately 20 months)

DOR is defined as the period measured from the date of the first occurrence of a CR or PR (whichever status is recorded first) until the first date that progressive disease or death is documented. Disease progression was determined on the basis of investigator assessment with use of RECIST v1.1. Median DOR was estimated using the Kaplan-Meier method, and the 95% CI was calculated using the method of Brookmeyer and Crowley.

GroupValue95% CI
Regorafenib4.503.61 – 5.39
Cobimetinib + Atezolizumab1.971.77 – 3.81
Atezolizumab2.811.84 – 3.78
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire (EORTC QLQ-C30) Physical Functioning Sub-scale Score Secondary · Baseline, end of the study (up to approximately 2.5 years)

The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functionin

Week 3
GroupValue95% CI
Atezolizumab-1.50± 10.56
Week 4
GroupValue95% CI
Regorafenib-6.52± 13.90
Cobimetinib + Atezolizumab-3.92± 11.05
Week 6
GroupValue95% CI
Atezolizumab-0.14± 12.49
Week 8
GroupValue95% CI
Regorafenib-8.97± 13.95
Cobimetinib + Atezolizumab-3.23± 16.15
Week 9
GroupValue95% CI
Atezolizumab-6.67± 17.19
Week 12
GroupValue95% CI
Regorafenib-7.78± 13.57
Cobimetinib + Atezolizumab-5.10± 15.54
Atezolizumab-6.40± 16.61
Week 15
GroupValue95% CI
Atezolizumab-7.08± 14.90
Week 16
GroupValue95% CI
Regorafenib-9.12± 17.10
Cobimetinib + Atezolizumab-5.11± 16.67
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire (EORTC QLQ-C30) Global Quality of Life Sub-scale Score at the End of the Study Secondary · Baseline, end of the study (up to approximately 2.5 years)

The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functionin

Week 3
GroupValue95% CI
Atezolizumab-1.70± 17.76
Week 4
GroupValue95% CI
Regorafenib-6.44± 18.84
Cobimetinib + Atezolizumab-7.00± 21.24
Week 6
GroupValue95% CI
Atezolizumab-4.86± 17.43
Week 8
GroupValue95% CI
Regorafenib-8.05± 15.98
Cobimetinib + Atezolizumab-4.38± 22.58
Week 9
GroupValue95% CI
Atezolizumab-4.84± 15.78
Week 12
GroupValue95% CI
Regorafenib-1.04± 18.60
Cobimetinib + Atezolizumab-4.25± 18.51
Atezolizumab-3.67± 15.42
Week 15
GroupValue95% CI
Atezolizumab-4.69± 12.16
Week 16
GroupValue95% CI
Regorafenib-4.39± 18.08
Cobimetinib + Atezolizumab-1.94± 23.64
Percentage of Participants With Adverse Events (AEs) Secondary · Baseline, end of the study (up to approximately 2.5 years)
Serious AEs
GroupValue95% CI
Regorafenib23.8
Cobimetinib + Atezolizumab39.7
Atezolizumab16.7
Non-serious AEs
GroupValue95% CI
Regorafenib97.5
Cobimetinib + Atezolizumab97.8
Atezolizumab93.3
Plasma Concentration of Cobimetinib Secondary · Predose (0 hours) and 3 to 6 hours after dose on Day 15 of Cycles 1 and 4 (1 cycle = 28 days) (up to approximately 2.5 years).
Cycle 1 Day 15 - Predose
GroupValue95% CI
Cobimetinib + Atezolizumab195± 190.0
Cycle 1 Day 15 - Postdose
GroupValue95% CI
Cobimetinib + Atezolizumab362± 89.4
Cycle 4 Day 15 - Predose
GroupValue95% CI
Cobimetinib + Atezolizumab94.3± 741.9
Cycle 4 Day 15 - Postdose
GroupValue95% CI
Cobimetinib + Atezolizumab210± 273.4
Serum Concentration of Atezolizumab Secondary · Pre-infusion (0 hours) on Day 1 of Cycle 1 up to approximately 2.5 years. Detailed time frame is explained in the outcome measure description field.

Pre-infusion (0 hours) on Day 1 of Cycles 1 to 4; 30 minutes post-infusion on Day 1 of Cycles 1 and 4; pre-infusion (0 hours) on Day 1 of Cycle 8 and every 8 cycles thereafter; at treatment discontinuation; 120 days after treatment discontinuation (up to approximately 2.5 years) (1 cycle = 28 days)

Cycle 1 Day 1 - Predose
GroupValue95% CI
AtezolizumabNA± NA
Cobimetinib + AtezolizumabNA± NA
Cycle 1 Day 1 - 30 min post dose
GroupValue95% CI
Atezolizumab348± 150.0
Cobimetinib + Atezolizumab259± 141.0
Cycle 2 Day 1 - Predose
GroupValue95% CI
Atezolizumab81.5± 35.7
Cobimetinib + Atezolizumab68.2± 191.2
Cycle 2 Day 1 - 30 min post dose
GroupValue95% CI
Atezolizumab56.2± NA
Cycle 3 Day 1 - Predose
GroupValue95% CI
Atezolizumab118± 45.4
Cobimetinib + Atezolizumab133± 51.2
Cycle 4 Day 1 - Predose
GroupValue95% CI
Atezolizumab146± 52.4
Cobimetinib + Atezolizumab167± 48.4
Cycle 4 Day 1 - 30 min post dose
GroupValue95% CI
Atezolizumab487± 41.5
Cobimetinib + Atezolizumab415± 37.2
Cycle 5 Day 1 - Predose
GroupValue95% CI
Atezolizumab155± NA
Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab Secondary · Pre-infusion (0 hours) on Day 1 of Cycles 1 to 4, 8, and every 8 cycles thereafter; at treatment discontinuation; 120 days after treatment discontinuation (up to approximately 2.5 years) (1 cycle = 28 days)
GroupValue95% CI
Cobimetinib + Atezolizumab43.8
Atezolizumab41.3

Adverse events — posted to ClinicalTrials.gov

Time frame: From baseline to end of study (approximately 2.5 years).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Regorafenib
Serious: 19/90 (21%)
Deaths: 62/90
Cobimetinib + Atezolizumab
Serious: 71/183 (39%)
Deaths: 136/183
Atezolizumab
Serious: 15/90 (17%)
Deaths: 72/90

Serious adverse events (89 terms)

ReactionSystemRegorafenibCobimetinib + AtezolizumabAtezolizumab
PYREXIAGeneral disorders
DIARRHOEAGastrointestinal disorders
ANAEMIABlood and lymphatic system disorders
SEPSISInfections and infestations
INFUSION RELATED REACTIONInjury, poisoning and procedural complications
ABDOMINAL PAINGastrointestinal disorders
COLITISGastrointestinal disorders
INTESTINAL PERFORATIONGastrointestinal disorders
PNEUMONIAInfections and infestations
URINARY TRACT INFECTIONInfections and infestations
BLOOD CREATINE PHOSPHOKINASE INCREASEDInvestigations
HYPONATRAEMIAMetabolism and nutrition disorders
MUSCULAR WEAKNESSMusculoskeletal and connective tissue disorders
CEREBROVASCULAR ACCIDENTNervous system disorders
SYNCOPENervous system disorders
ATRIAL FIBRILLATIONCardiac disorders
LEFT VENTRICULAR DYSFUNCTIONCardiac disorders
ADRENAL INSUFFICIENCYEndocrine disorders
MACULOPATHYEye disorders
ANAL HAEMORRHAGEGastrointestinal disorders
COLONIC FISTULAGastrointestinal disorders
CONSTIPATIONGastrointestinal disorders
GASTROINTESTINAL HAEMORRHAGEGastrointestinal disorders
ILEUSGastrointestinal disorders
LOWER GASTROINTESTINAL HAEMORRHAGEGastrointestinal disorders
Other adverse events (57 terms — click to expand)

ReactionSystemRegorafenibCobimetinib + AtezolizumabAtezolizumab
DIARRHOEAGastrointestinal disorders
RASHSkin and subcutaneous tissue disorders
NAUSEAGastrointestinal disorders
FATIGUEGeneral disorders
PYREXIAGeneral disorders
VOMITINGGastrointestinal disorders
DECREASED APPETITEMetabolism and nutrition disorders
DERMATITIS ACNEIFORMSkin and subcutaneous tissue disorders
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROMESkin and subcutaneous tissue disorders
ASTHENIAGeneral disorders
DYSPNOEARespiratory, thoracic and mediastinal disorders
CONSTIPATIONGastrointestinal disorders
COUGHRespiratory, thoracic and mediastinal disorders
ABDOMINAL PAINGastrointestinal disorders
OEDEMA PERIPHERALGeneral disorders
ANAEMIABlood and lymphatic system disorders
HYPERTENSIONVascular disorders
BLOOD CREATINE PHOSPHOKINASE INCREASEDInvestigations
PRURITUSSkin and subcutaneous tissue disorders
DYSPHONIARespiratory, thoracic and mediastinal disorders
STOMATITISGastrointestinal disorders
WEIGHT DECREASEDInvestigations
BACK PAINMusculoskeletal and connective tissue disorders
HEADACHENervous system disorders
MUCOSAL INFLAMMATIONGeneral disorders
ASPARTATE AMINOTRANSFERASE INCREASEDInvestigations
CHILLSGeneral disorders
BLOOD ALKALINE PHOSPHATASE INCREASEDInvestigations
HYPOKALAEMIAMetabolism and nutrition disorders
ARTHRALGIAMusculoskeletal and connective tissue disorders
DRY SKINSkin and subcutaneous tissue disorders
PAIN IN EXTREMITYMusculoskeletal and connective tissue disorders
HYPOPHOSPHATAEMIAMetabolism and nutrition disorders
RASH MACULO-PAPULARSkin and subcutaneous tissue disorders
THROMBOCYTOPENIABlood and lymphatic system disorders
DYSPEPSIAGastrointestinal disorders
FACE OEDEMAGeneral disorders
ALANINE AMINOTRANSFERASE INCREASEDInvestigations
DIZZINESSNervous system disorders
DRY MOUTHGastrointestinal disorders

Most-reported serious reactions: PYREXIA, DIARRHOEA, ANAEMIA, SEPSIS, INFUSION RELATED REACTION, ABDOMINAL PAIN, COLITIS, INTESTINAL PERFORATION.

Data from ClinicalTrials.gov NCT02788279 adverse events section.

Sponsor's own description

This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Immunotherapy in colorectal cancer: rationale, challenges and potential.
    Ganesh K, Stadler ZK, Cercek A, Mendelsohn RB, et al · · 2019 · cited 1407× · PMID 30886395 · DOI 10.1038/s41575-019-0126-x
  2. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome.
    Alsaab HO, Sau S, Alzhrani R, Tatiparti K, et al · · 2017 · cited 1206× · PMID 28878676 · DOI 10.3389/fphar.2017.00561
  3. Comprehensive review of targeted therapy for colorectal cancer.
    Xie YH, Chen YX, Fang JY. · · 2020 · cited 1162× · PMID 32296018 · DOI 10.1038/s41392-020-0116-z
  4. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions.
    Yi M, Zheng X, Niu M, Zhu S, et al · · 2022 · cited 1018× · PMID 35062949 · DOI 10.1186/s12943-021-01489-2
  5. Angiogenic signaling pathways and anti-angiogenic therapy for cancer.
    Liu ZL, Chen HH, Zheng LL, Sun LP, et al · · 2023 · cited 808× · PMID 37169756 · DOI 10.1038/s41392-023-01460-1
  6. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial.
    Eng C, Kim TW, Bendell J, Argilés G, et al · · 2019 · cited 439× · PMID 31003911 · DOI 10.1016/s1470-2045(19)30027-0
  7. Drug resistance and new therapies in colorectal cancer.
    Van der Jeught K, Xu HC, Li YJ, Lu XB, et al · · 2018 · cited 424× · PMID 30228778 · DOI 10.3748/wjg.v24.i34.3834
  8. Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation.
    Wu M, Huang Q, Xie Y, Wu X, et al · · 2022 · cited 336× · PMID 35279217 · DOI 10.1186/s13045-022-01242-2

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