Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Atezolizumab

Vemurafenib

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Immunologic Factors

Protein Kinase Inhibitors

Enzyme Inhibitors

Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.

Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.

Will be administered as per the schedule described in individual arm.

Atezolizumab Placebo

Cobimetinib

Vemurafenib Placebo

Clinical Trials

This is a Phase III, double-blinded, placebo-controlled, randomized, multicenter study designed to evaluate the efficacy, safety, and pharmacokinetics of atezolizumab + cobimetinib + vemurafenib compared with placebo + cobimetinib + vemurafenib in patients with previously untreated BRAFv600 mutation-positive metastatic or unresectable locally advanced melanoma.

A Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFv600 Mutation-Positive Patients With Metastatic or Unresectable Locally Advanced Melanoma

A Phase III, Double-Blinded, Randomized, Placebo-Controlled Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFV600 Mutation-Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma

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

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

Objective response is defined as a CR or PR on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1

DOR, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first

OS is defined as the time from randomization to death from any cause

2-year landmark survival, defined as survival at 2 years

Time to deterioration in global health status/healthrelated quality of life (GHS/HRQoL), defined as the time from randomization to first observed ≥ 10-point decrease in EORTC QLQ-C30 linearly transformed GHS/HRQoL scale score that is sustained for two consecutive assessments or followed by death while the participant is on treatment.

The score range for each EORTC QLQ-C30 scale is from 0 to 100, with higher scores indicating better functioning and better GHS/HRQoL.

Time to deterioration in physical functioning, defined as the time from randomization to first observed ≥ 10-point decrease in EORTC QLQ-C30 linearly transformed physical functioning scale score that is sustained for two consecutive assessments or followed by death while the participant is on treatment.

The score range for each EORTC QLQ-C30 scale is from 0 to 100, with higher scores indicating better functioning and better GHS/HRQoL.

Presence of ADAs against atezolizumab during the study relative to the presence of ADAs at baseline

Hoffmann-La Roche

22 participants in the atezo+cobi+vem arm stopped treatment during the run-in period and received no atezo and 4 more in the atezo+cobi+vem arm completed the run-in period but did not receive atezolizumab. These 26 participants were included in the placebo+cobi+vem arm for safety evaluation. 3 participants from the placebo+cobi+vem arm were not treated with either cobimetinib or vemurafenib.

Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 only followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.

Atezolizumab Placebo + Cobimetinib + Vemurafenib

Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 only followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.

Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Medical Communications

Progression-Free Survival (PFS), as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Progression-Free Survival (PFS), as Determined by Independent Review Committee Using RECIST v1.1

Responders

Non-Responders

ITT Population with measurable disease at baseline

Percentage of Participants With Objective Response, as Determined by Investigator Using RECIST v1.1

Duration of Response, as Determined by Investigator Using RECIST v1.1

Overall Survival

Percentage of Participants Who Have Survived at 2 Years

Time to Deterioration in Global Health Status Using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status Scale Score

Time to Deterioration in Physical Functioning Using EORTC QLQ-C30 Physical Functioning Scale Score

Percentage of Participants With Adverse Events and Serious Adverse Events

Cycle 1 Day 1/30 Min Postdose

Cycle 2 Day 1/Predose

Cycle 3 Day 1/Predose

Cycle 4 Day 1/Predose

Cycle 4 Day 1/30 Min Postdose

Study Drugs Discontinuation Visit

Serum Concentration of Atezolizumab

Cycle 1 Day 15/Predose

Cycle 1 Day 15/3-6 Hr Postdose

Cycle 4 Day 15/Predose

Cycle 4 Day 15/3-6 Hr Postdose

The PK-evaluable population is defined as all participants who have received any dose of Cobimetinib 20/40 mg and for whom at least one evaluable PK sample is collected.

Plasma Concentration of Cobimetinib Dose: 20/40 mg

The PK-evaluable population is defined as all participants who have received any dose of Cobimetinib 60 mg and for whom at least one evaluable PK sample is collected.

Plasma Concentration of Cobimetinib Dose: 60 mg

Cycle 1 Day 15/ predose

Cycle 1 Day 15/ 3-6 hr

Cycle 4 Day 15/ predose

Cycle 4 Day 15/ 3-6 hr postdose

Vemurafenib PK was characterized in the PK-evaluable population, of 218 out of 255 treated in the placebo+cobi+vem arm and 209 out of 256 treated in the atezo+cobi+vem arm.

Plasma Concentration of Vemurafenib

Baseline evaluable participants

Post-baseline evaluable participants

The ADA-evaluable population was defined as participants who received at least one dose of Atezolizumab and had ≥ 1 post-baseline ADA result.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFv600 Mutation-Positive Patients With Metastatic or Unresectable Locally Advanced Melanoma	NCT02908672	Melanoma	Atezolizumab Atezolizumab Pl... Cobimetinib Vemurafenib Vemurafenib Pla...	18 Years -	Hoffmann-La Roche
A Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFv600 Mutation-Positive Patients With Metastatic or Unresectable Locally Advanced Melanoma	NCT02908672	Melanoma	Atezolizumab Atezolizumab Pl... Cobimetinib Vemurafenib Vemurafenib Pla...	18 Years -	Hoffmann-La Roche

Spots Global Cancer Trial Database for vemurafenib placebo