NCT01689519: coBRIM

A Study Comparing Vemurafenib Versus Vemurafenib Plus Cobimetinib in Participants With Metastatic Melanoma

Completed Phase 3 Results posted Last updated 2 May 2022

What this trial tests

Phase 3 trial testing Placebo in Malignant Melanoma in 495 participants. Completed in 21 July 2019.

Timeline

8 January 2013

Primary endpoint
9 May 2014

21 July 2019

Quick facts

Lead sponsor	Hoffmann-La Roche
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	triple
Primary purpose	treatment
Enrollment	495
Start date	8 January 2013
Primary completion	9 May 2014
Estimated completion	21 July 2019
Sites	156 locations across Italy, New Zealand, Netherlands, Russia, Belgium, Sweden, United States, France

Drugs / interventions tested

• Placebo
• Vemurafenib (vemurafenib) — full drug profile →
• Cobimetinib (cobimetinib) — full drug profile →

Conditions studied

• Malignant Melanoma — all drugs for Malignant Melanoma →

Sponsor

Hoffmann-La Roche — full company profile →

Who can join

18 and older, any sex, with Malignant Melanoma. 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.

Progression-free Survival Primary · Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)

Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.

Primary Analysis: 9 May 2014

Group	Value	95% CI
Cobimetinib + Vemurafenib	9.90	9.00 – NA
Placebo + Vemurafenib	6.20	5.55 – 7.39

Post hoc Efficacy Analysis: 16 January 2015

Group	Value	95% CI
Cobimetinib + Vemurafenib	12.30	9.50 – 13.40
Placebo + Vemurafenib	7.20	5.60 – 7.50

Extended 5-Year Analysis: 21 July 2019

Group	Value	95% CI
Cobimetinib + Vemurafenib	12.60	9.50 – 14.80
Placebo + Vemurafenib	7.20	5.60 – 7.50

Overall Survival Secondary · Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)

Overall survival was defined as the time from randomization until the date of death from any cause.

Primary Analysis 9 May 2014

Group	Value	95% CI
Cobimetinib + Vemurafenib	NA	NA – NA
Placebo + Vemurafenib	NA	NA – NA

Post hoc Analysis 16 January 2015

Group	Value	95% CI
Cobimetinib + Vemurafenib	NA	20.70 – NA
Placebo + Vemurafenib	17.00	15.00 – NA

Final Analysis 28 August 2015

Group	Value	95% CI
Cobimetinib + Vemurafenib	22.30	20.3 – NA
Placebo + Vemurafenib	17.40	15.00 – 19.8

Extended 5-year Analysis 21 July 2019

Group	Value	95% CI
Cobimetinib + Vemurafenib	22.50	20.30 – 28.80
Placebo + Vemurafenib	17.40	15.00 – 19.80

Percentage of Participants With an Objective Response Secondary · Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)

An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart. Responses were determined by Response Evaluation Criteria in Solid Tumors v1.1. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions.

Primary Analysis: 9 May 2014

Group	Value	95% CI
Cobimetinib + Vemurafenib	67.60	61.39 – 73.41
Placebo + Vemurafenib	44.80	38.46 – 51.18

Post hoc Efficacy Analysis: 16 January 2015

Group	Value	95% CI
Cobimetinib + Vemurafenib	69.60	63.50 – 75.30
Placebo + Vemurafenib	50.00	43.60 – 56.40

Extended 5-Year Analysis: 21 July 2019

Group	Value	95% CI
Cobimetinib + Vemurafenib	69.60	63.49 – 75.31
Placebo + Vemurafenib	49.60	43.21 – 55.99

Duration of Response Secondary · Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)

Duration of response was defined as the time from first occurrence of a documented confirmed objective response until the time of disease progression, as determined by investigator review of tumor assessments using Response Evaluation Criteria in Solid Tumors v1.1 or death from any cause during the study. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance o

Primary Analysis: 9 May 2014

Group	Value	95% CI
Cobimetinib + Vemurafenib	NA	9.30 – NA
Placebo + Vemurafenib	7.29	5.78 – NA

Extended 5-Year Analysis: 21 July 2019

Group	Value	95% CI
Cobimetinib + Vemurafenib	14.65	12.90 – 19.30
Placebo + Vemurafenib	9.23	7.50 – 12.90

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months).. Reporting threshold: 0.05%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Cobimetinib + Vemurafenib

Serious: 105/248 (42%)

Deaths: 160/247

Placebo + Vemurafenib

Serious: 71/245 (29%)

Deaths: 164/248

Serious adverse events (180 terms)

Reaction	System	Cobimetinib + Vemurafenib	Placebo + Vemurafenib
PYREXIA	General disorders	—	—
PNEUMONIA	Infections and infestations	—	—
DEHYDRATION	Metabolism and nutrition disorders	—	—
ATRIAL FIBRILLATION	Cardiac disorders	—	—
PERICARDIAL EFFUSION	Cardiac disorders	—	—
ALANINE AMINOTRANSFERASE INCREASED	Investigations	—	—
KERATOACANTHOMA	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
RASH	Skin and subcutaneous tissue disorders	—	—
CHORIORETINOPATHY	Eye disorders	—	—
DIARRHOEA	Gastrointestinal disorders	—	—
SMALL INTESTINAL OBSTRUCTION	Gastrointestinal disorders	—	—
HYPERSENSITIVITY	Immune system disorders	—	—
ERYSIPELAS	Infections and infestations	—	—
ASPARTATE AMINOTRANSFERASE INCREASED	Investigations	—	—
GAMMA-GLUTAMYLTRANSFERASE INCREASED	Investigations	—	—
SEIZURE	Nervous system disorders	—	—
ACUTE KIDNEY INJURY	Renal and urinary disorders	—	—
PLEURAL EFFUSION	Respiratory, thoracic and mediastinal disorders	—	—
PULMONARY EMBOLISM	Respiratory, thoracic and mediastinal disorders	—	—
RASH MACULO-PAPULAR	Skin and subcutaneous tissue disorders	—	—
CARDIAC FAILURE	Cardiac disorders	—	—
MYOCARDIAL INFARCTION	Cardiac disorders	—	—
SEROUS RETINAL DETACHMENT	Eye disorders	—	—
PANCREATITIS	Gastrointestinal disorders	—	—
VOMITING	Gastrointestinal disorders	—	—

Other adverse events (70 terms — click to expand)

Reaction	System	Cobimetinib + Vemurafenib	Placebo + Vemurafenib
DIARRHOEA	Gastrointestinal disorders	—	—
NAUSEA	Gastrointestinal disorders	—	—
ARTHRALGIA	Musculoskeletal and connective tissue disorders	—	—
RASH	Skin and subcutaneous tissue disorders	—	—
FATIGUE	General disorders	—	—
BLOOD CREATINE PHOSPHOKINASE INCREASED	Investigations	—	—
PHOTOSENSITIVITY REACTION	Skin and subcutaneous tissue disorders	—	—
PYREXIA	General disorders	—	—
ALOPECIA	Skin and subcutaneous tissue disorders	—	—
HYPERKERATOSIS	Skin and subcutaneous tissue disorders	—	—
VOMITING	Gastrointestinal disorders	—	—
ALANINE AMINOTRANSFERASE INCREASED	Investigations	—	—
ASPARTATE AMINOTRANSFERASE INCREASED	Investigations	—	—
GAMMA-GLUTAMYLTRANSFERASE INCREASED	Investigations	—	—
DECREASED APPETITE	Metabolism and nutrition disorders	—	—
ANAEMIA	Blood and lymphatic system disorders	—	—
ASTHENIA	General disorders	—	—
PRURITUS	Skin and subcutaneous tissue disorders	—	—
HEADACHE	Nervous system disorders	—	—
HYPERTENSION	Vascular disorders	—	—
BLOOD ALKALINE PHOSPHATASE INCREASED	Investigations	—	—
SUNBURN	Injury, poisoning and procedural complications	—	—
BLOOD CREATININE INCREASED	Investigations	—	—
DRY SKIN	Skin and subcutaneous tissue disorders	—	—
MYALGIA	Musculoskeletal and connective tissue disorders	—	—
PAIN IN EXTREMITY	Musculoskeletal and connective tissue disorders	—	—
OEDEMA PERIPHERAL	General disorders	—	—
DERMATITIS ACNEIFORM	Skin and subcutaneous tissue disorders	—	—
RASH MACULO-PAPULAR	Skin and subcutaneous tissue disorders	—	—
ERYTHEMA	Skin and subcutaneous tissue disorders	—	—
SQUAMOUS CELL CARCINOMA OF SKIN	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
VISION BLURRED	Eye disorders	—	—
COUGH	Respiratory, thoracic and mediastinal disorders	—	—
EJECTION FRACTION DECREASED	Investigations	—	—
CHORIORETINOPATHY	Eye disorders	—	—
ABDOMINAL PAIN	Gastrointestinal disorders	—	—
SKIN PAPILLOMA	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
CONSTIPATION	Gastrointestinal disorders	—	—
DYSGEUSIA	Nervous system disorders	—	—
INSOMNIA	Psychiatric disorders	—	—

Most-reported serious reactions: PYREXIA, PNEUMONIA, DEHYDRATION, ATRIAL FIBRILLATION, PERICARDIAL EFFUSION, ALANINE AMINOTRANSFERASE INCREASED, KERATOACANTHOMA, RASH.

Data from ClinicalTrials.gov NCT01689519 adverse events section.

Sponsor's own description

To evaluate the efficacy of vemurafenib in combination with cobimetinib (GDC-0973), compared with vemurafenib and placebo, in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced or metastatic melanoma, as measured by progression-free survival (PFS), assessed by the study site investigator.

Publications & conference data

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

1. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.
   Larkin J, Ascierto PA, Dréno B, Atkinson V, et al · · 2014 · cited 1516× · PMID 25265494 · DOI 10.1056/nejmoa1408868
2. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.
   Ascierto PA, McArthur GA, Dréno B, Atkinson V, et al · · 2016 · cited 705× · PMID 27480103 · DOI 10.1016/s1470-2045(16)30122-x
3. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies.
   Bahar ME, Kim HJ, Kim DR. · · 2023 · cited 519× · PMID 38105263 · DOI 10.1038/s41392-023-01705-z
4. Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine.
   Cheng L, Lopez-Beltran A, Massari F, MacLennan GT, et al · · 2018 · cited 265× · PMID 29148538 · DOI 10.1038/modpathol.2017.104
5. Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy.
   Eroglu Z, Ribas A. · · 2016 · cited 223× · PMID 26753005 · DOI 10.1177/1758834015616934
6. MEK and the inhibitors: from bench to bedside.
   Akinleye A, Furqan M, Mukhi N, Ravella P, et al · · 2013 · cited 218× · PMID 23587417 · DOI 10.1186/1756-8722-6-27
7. Pathways and therapeutic targets in melanoma.
   Shtivelman E, Davies MQ, Hwu P, Yang J, et al · · 2014 · cited 163× · PMID 24743024 · DOI 10.18632/oncotarget.1892
8. Tumor-intrinsic signaling pathways: key roles in the regulation of the immunosuppressive tumor microenvironment.
   Yang L, Li A, Lei Q, Zhang Y. · · 2019 · cited 153× · PMID 31775797 · DOI 10.1186/s13045-019-0804-8