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Atezolizumab Plus Cobimetinib/Vemurafenib in BRAF V600–Positive Unresectable or Metastatic Melanoma


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On July 30, 2020, atezolizumab was granted approval for use in combination with cobimetinib and vemurafenib for patients with BRAF V600 mutation–positive unresectable or metastatic melanoma.1,2

Supporting Efficacy Data

Approval was based on findings from the phase III, double-blind IMspire150 trial (ClinicalTrials.gov identifier NCT02908672).2,3 In the trial, 514 patients were randomly assigned to receive atezolizumab plus cobimetinib/vemurafenib (n = 256) or placebo plus cobimetinib/vemurafenib (n = 258). After a 28-day cycle of cobimetinib and vemurafenib, patients received atezolizumab at 840 mg via intravenous (IV) infusion every 2 weeks in combination with cobimetinib at 60 mg orally once daily and vemurafenib at 720 mg orally twice daily or placebo in combination with cobimetinib at 60 mg orally once daily (21 days on/7 days off) and vemurafenib at 960 mg orally twice daily.

OF NOTE

Atezolizumab has warnings/precautions for immune-related pneumonitis, hepatitis, colitis, and endocrinopathies; infections; infusion-related reactions; and embryofetal toxicity.

The primary efficacy outcome measure was investigator-assessed, progression-free survival using Response Evaluation Criteria in Solid Tumors version 1.1. Median progression-free survival was 15.1 months (95% confidence interval [CI] = 11.4–18.4 months) in the atezolizumab group vs 10.6 months (95% CI = 9.3–12.7 months) in the control group (hazard ratio [HR] = 0.78, 95% CI = 0.63–0.97, P = .0249). An objective response was observed in 66% vs 65% of patients, with a complete response in 16% vs 18%. The median duration of response was 20.4 months (95% CI = 15.1 months to not estimable) vs 12.5 months (95% CI = 10.7–16.6 months).

How It Works

Atezolizumab is a monoclonal antibody that binds to PD-L1 and blocks its interactions with both PD-1 and B7.1 receptors. This activity releases the PD-L1/PD-1–mediated inhibition of immune response, including activation of antitumor immune response without inducing antibody-dependent cellular cytotoxicity. PD-L1 may be expressed on tumor cells or tumor-infiltrating immune cells and can contribute to inhibition of antitumor immune response in the tumor microenvironment. Binding of PD-L1 to PD-1 and B7.1 receptors on T cells and antigen-presenting cells results in suppression of cytotoxic T-cell activity, T-cell proliferation, and cytokine production. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.

In mouse models of cancer, dual inhibition of the PD-1/PD-L1 and MAPK pathways suppresses tumor growth and improves tumor immunogenicity through increased antigen presentation and T-cell infiltration and activation compared with targeted therapy alone.

How It Is Used

Prior to initiating atezolizumab, patients should receive a 28-day treatment cycle of cobimetinib at 60 mg orally once daily (21 days on and 7 days off) and vemurafenib at 960 mg orally twice daily from days 1 to 21 and vemurafenib at 720 mg orally twice daily from days 22 to 28. The recommended dose of atezolizumab is 840 mg via IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity, when administered with cobimetinib at 60 mg orally once daily (21 days on and 7 days off) and vemurafenib at 720 mg orally twice daily. If the first infusion of atezolizumab is tolerated, all subsequent infusions may be delivered over 30 minutes.

No dose reductions for atezolizumab are recommended. Infusion should be slowed or interrupted for grade 1 or 2 infusion reactions and permanently discontinued for grade 3 or 4 infusion reactions.

Product labeling provides instructions for atezolizumab interruption or discontinuation for adverse reactions including pneumonitis; hepatitis in patients with cancers other than hepatocellular carcinoma (HCC); hepatitis in patients with HCC; colitis or diarrhea; endocrinopathies including but not limited to hypophysitis, adrenal insufficiency, hyperthyroidism, and type 1 diabetes; other immune-mediated adverse reactions involving a major organ; infections; infusion-related reactions; persistent grade 2 or 3 adverse reactions (excluding endocrinopathies); inability to taper corticosteroid treatment; and recurrent grade 3 or 4 adverse reactions.

KEY POINTS

  • Atezolizumab was granted approval for use in combination with cobimetinib and vemurafenib for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.
  • The recommended dose of atezolizumab is 840 mg via IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity, when administered with cobimetinib at 60 mg orally once daily (21 days on and 7 days off) and vemurafenib at 720 mg orally twice daily.

Safety Profile

Safety data from the IMspire150 trial included 230 patients in the atezolizumab group who received at least one dose of atezolizumab and 281 patients who received cobimetinib/vemurafenib alone as a control group. In the trial, the most common adverse events of any grade (≥ 20%) in the atezolizumab group were rash (75% vs 72% in control group), musculoskeletal pain (62% vs 48%), fatigue (51% vs 45%), hepatotoxicity (50% vs 36%), pyrexia (49% vs 35%), nausea (30% vs 32%) pruritus (26% vs 17%), edema (26% vs 21%), stomatitis (23% vs 15%), hypothyroidism (22% vs 10%), and photosensitivity reaction (21% vs 25%). The most common grade 3 or 4 adverse events in the atezolizumab group included rash (27% vs 23%), hepatotoxicity (21% vs 13%), hypertension (10% vs 7%), and musculoskeletal pain (4% vs 3%). The most common grade 3 or 4 laboratory abnormalities were increased triacylglycerol lipase (46% vs 35%), decreased lymphocytes (24% vs 17%), decreased phosphorus (22% vs 14%), and increased alanine transaminase (ALT; 18% vs 12%).

Serious adverse events occurred in 45% of patients in the atezolizumab group, the most common being hepatotoxicity (7%), pyrexia (6%), pneumonia (4.3%), malignant neoplasms (2.2%), and acute kidney injury (2.2%). Adverse events led to interruption of atezolizumab treatment in 68% of patients, the most common causes being pyrexia (14%), increased ALT (13%), hyperthyroidism (10%), increased aspartate transaminase (10%), increased lipase (9%), increased amylase (7%), and pneumonitis (5%). Discontinuation of atezolizumab due to adverse events occurred in 21% of patients, the most common causes being pneumonitis (2.6%) and increased ALT (2.2%). Adverse events led to death in 3% of patients, with causes consisting of hepatic failure, fulminant hepatitis, sepsis, septic shock, pneumonia, and cardiac arrest.

Atezolizumab has warnings/precautions for immune-related pneumonitis, immune-related hepatitis, immune-related colitis, immune-related endocrinopathies, infections, infusion-related reactions, and embryofetal toxicity. Patients should be monitored for changes in liver function and changes in thyroid function. Patients should be advised not to breastfeed while receiving atezolizumab. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves atezolizumab for BRAF V600 unresectable or metastatic melanoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-braf-v600-unresectable-or-metastatic-melanoma. Accessed August 27, 2020.

2. Tecentriq (atezolizumab) injection, for intravenous use, Genentech, June 2018. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761034s028lbl.pdf. Accessed August 27, 2020.

3. Gutzmer R, Stroyakovskiy D, Gogas H, et al: Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): Primary analysis of the randomised, double-blind, placebo-controlled, phase III trial. Lancet 395:1835-1844, 2020.

 


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