Addition of Atezolizumab to T-DM1 in Previously Treated Patients With HER2-Positive Advanced Breast Cancer

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In the phase II KATE2 trial reported in The Lancet Oncology, Leisha A. Emens, MD, and colleagues found that the addition of atezolizumab to ado-trastuzumab emtansine (T-DM1) did not improve progression-free survival in patients with advanced HER2-positive breast cancer progressing after previous treatment with trastuzumab and a taxane.

As stated by the investigators, “Addition of atezolizumab to [T-DM1] might potentiate anticancer immunity and enhance the HER2-targeted cytotoxic activity of [T-DM1].”

Leisha A. Emens, MD

Leisha A. Emens, MD

Study Details

In the double-blind trial, 202 patients from sites in nine countries were randomly assigned 2:1 between September 2016 and August 2017 to receive atezolizumab plus T-DM1 (n = 133) or placebo plus T-DM1 (n = 69). Treatments consisted of atezolizumab at 1,200 mg and T-DM1 at 3.6 mg/kg given every 3 weeks.

A total of 43% of the atezolizumab group vs 39% of the control group had PD-L1­–positive disease, defined as PD-L1 expression on tumor-infiltrating immune cells for ≥ 1% of the tumor area. The primary endpoint was investigator-assessed progression-free survival in the intent-to-treat population.

Progression-Free Survival

On the recommendation of the independent data monitoring committee, treatment assignment was unmasked in December 2017 due to futility and the greater frequency of adverse events among patients assigned to the atezolizumab group. This date served as the cutoff for the primary analysis.

Median follow-up was 8.5 months in the atezolizumab group and 8.4 months in the control group. Median progression-free survival was 8.2 months (95% confidence interval [CI] = 5.8–10.7 months) in the atezolizumab group vs 6.8 months (95% CI = 4.0–11.1 months) in the control group (stratified hazard ratio [HR] = 0.82, 95% CI = 0.55–1.23, P = .33).

Among patients with PD-L1–positive disease, median progression-free survival was 8.5 months (95% CI = 5.7 months–not estimable) in the atezolizumab group vs 4.1 months (95% CI = 2.7–11.1 months) in the control group (HR = 0.60, 95% CI = 0.32–1.11). Among patients with PD-L1–negative disease, median progression-free survival was 6.8 months (95% CI = 5.4 months–not estimable) in the atezolizumab group vs 8.2 months (95% CI = 4.2 months–not estimable) in the control group (HR = 1.02, 95% CI = 0.60–1.74).

At the cutoff date for the 12-month interim analysis of overall survival, median follow-up was 18 to 19 months. Median overall survival was not reached in either group (HR = 0.74, 95% CI = 0.42–1.30), with 12-month rates of 89% vs 89%. In post hoc analysis, median overall survival was not reached in either group in the PD-L1–positive population (HR = 0.55, 95% CI = 0.22–1.38) or in either group in the PD-L1–negative population (HR = 0.88, 95% CI = 0.43–1.80).

Adverse Events

The most common grade ≥ 3 adverse events in the atezolizumab group were thrombocytopenia (13% vs 4% in the control group), increased aspartate aminotransferase (AST; 8% vs 3%), anemia (5% vs 0%), neutropenia (5% vs 4%), and increased alanine aminotransferase (ALT; 5% vs 3%). Serious adverse events occurred in 33% vs 19% of patients; the most common was pyrexia leading to hospitalization, and this was observed only in patients in the atezolizumab group (n = 10).

Adverse events led to treatment discontinuation in 26% vs 15% of patients, with the most common in the atezolizumab group being increased AST (7% vs 4%), increased ALT (5% vs 4%), thrombocytopenia (5% vs 1%), and pneumonitis (4% vs 1%). One patient in the atezolizumab group died due to a treatment-related adverse event (hemophagocytic syndrome).

The investigators concluded, “Addition of atezolizumab to [T-DM1] did not show a clinically meaningful improvement in progression-free survival and was associated with more adverse events. Further study of [T-DM1] plus atezolizumab is warranted in a subpopulation of patients with PD-L1–positive, HER2-positive advanced breast cancer.”

Dr. Emens, of the University of Pittsburgh Medical Center, Hillman Cancer Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by F. Hoffman-La Roche. For full disclosures of the study authors, visit

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