Peter Schmid, MD, PhD
AS REPORTED in The New England Journal of Medicine by Peter Schmid, MD, PhD, of the Barts Cancer Institute, Queen Mary University of London, and colleagues, the phase III IMpassion130 trial has shown that the addition of atezolizumab to nanoparticle albumin-bound (nab)-paclitaxel significantly improved progression-free survival in patients with previously untreated advanced triple-negative breast cancer, particularly among those with programmed cell death ligand 1 (PD-L1) expression–positive tumors.1
IN THE DOUBLE-BLIND trial, 902 patients with previously untreated metastatic or unresectable locally advanced triple-negative breast cancer from 246 sites in 41 countries were randomly assigned between June 2015 and May 2017 to receive intravenous (IV) atezolizumab at 840 mg (n = 451) or placebo (n = 451) on days 1 and 15 and IV nab-paclitaxel at 100 mg/m2 on days 1, 8, and 15 of 28-day cycles. Treatment was continued until disease progression on Response Evaluation Criteria in Solid Tumors v1.1 or unacceptable toxicity.
Patients could have received radiation therapy and prior chemotherapy including a taxane in the setting of curative therapy if treatment was completed at least 12 months prior to randomization. Randomization stratification factors were receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and PD-L1 expression at baseline; PD-L1–positive status was defined as PD-L1 expression on tumor-infiltrating immune cells as a percentage of tumor area of at least 1%. The two primary endpoints were progression-free survival, in both the intent-to-treat population and PD-L1–positive subgroup, and overall survival tested in the intent-to-treat population and in the PD-L1–positive subgroup; formal overall survival analysis in the subgroup was to be performed only if the between-group difference was significant.
For the atezolizumab plus nab-paclitaxel group vs the control group: 185 vs 184 patients were PD-L1–positive; the median age was 55 vs 56 years (23% vs 26% aged ≥ 65 years); 68% vs 67% were white and 19% vs 17% were Asian; all but 1 patient in each group had Eastern Cooperative Oncology Group performance status of 0 or 1; 90% vs 91% had metastatic disease (liver metastases in 28% vs 26%); and 51% of patients in each group and 54% in each group had received prior taxane treatment and prior anthracycline treatment, respectively.
Progression-Free and Overall Survival
THE MEDIAN FOLLOW-UP was 12.9 months. Among all patients, the median progression-free survival was 7.2 months in the atezolizumab group vs 5.5 months in the control group (hazard ratio [HR] = 0.80, P = .002). Among patients with PD-L1–positive tumors, the median progression-free survival was 7.5 months vs 5.0 months (HR = 0.62, P < .001). Progression-free survival at 1 year was 29.1% vs 16.4%. A subgroup analysis showed that hazard ratios favored atezolizumab in nearly all subgroups, including patients with (HR = 0.80, 95% confidence interval [CI] = 0.62–1.04) and without (HR = 0.79, 95% CI = 0.66–0.94) liver metastases and among those with (HR = 0.80, 95% CI = 0.65–0.97) and without (HR = 0.81, 95% CI = 0.66–1.00) prior taxane treatment. Among patients with PD-L1–negative tumors, the median progression-free survival was 5.6 vs 5.6 months (HR = 0.95, 95% CI = 0.79–1.15).
At first interim analysis of overall survival among all patients, the median overall survival was 21.3 months vs 17.6 months (HR = 0.84, P = .08). Owing to the lack of significance in the intent-to-treat population, formal testing of survival in the PD-L1–positive subgroup was not performed; however, Kaplan–Meier analysis indicated a median overall survival of 25.0 months vs 15.5 months (HR = 0.62, 95% CI = 0.45–0.86).
After study therapy, subsequent anticancer therapy was received by 53.7% vs 60.3% of patients and was generally balanced between the groups, with most receiving chemotherapy and less than 4% receiving immunotherapy.
An objective response was observed in 56.0% vs 45.9% of all patients and in 58.9% vs 42.6% of PD-L1–positive patients.
THE MOST COMMON adverse event of any grade in the atezolizumab group was alopecia (56.4% vs 57.5% in the control group). Adverse events of any grade that occurred with at least 5% greater frequency in the atezolizumab group were nausea (46.0% vs 38.1%), cough (24.8% vs 18.9%), neutropenia (20.8% vs 15.3%), pyrexia (18.8% vs 10.7%), and hypothyroidism (13.7% vs 3.4%).
“A benefit with atezolizumab–nab-paclitaxel in patients with PD-L1–positive tumors that was shown in our trial provides evidence of the efficacy of immunotherapy in at least a subset of patients.”— Peter Schmid, MD, PhD, et al
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Grade 3 or 4 adverse events occurred in 48.7% vs 42.2% of patients, with the most common being neutropenia, decreased neutrophil count, peripheral neuropathy, fatigue, and anemia; the only grade 3 or 4 adverse event occurring with at least 2% greater frequency in the atezolizumab group was peripheral neuropathy (5.5% vs 2.7%). Adverse events of special interest of any grade (ie, those with a potential immune-related cause) occurred in 57.3% (grade 3 or 4 in 7.5%) vs 41.8% (grade 3 or 4 in 4.3%) of patients.
Serious adverse events occurred in 22.8% vs 18.3% of patients. Adverse events led to discontinuation of study treatment in 15.9% vs 8.2%. Adverse events led to death in 6 patients (1.3%) in the atezolizumab group and in 3 patients (0.7%) in the control group. Three deaths in the atezolizumab group (due to autoimmune hepatitis, mucosal inflammation, and septic shock) and one death in the control group (due to hepatic failure) were considered related to treatment.
The investigators concluded: “Atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in both the intent-to-treat population and the PD-L1–positive subgroup. Adverse events were consistent with the known safety profiles of each agent.”
They noted: “A benefit with atezolizumab–nab-paclitaxel in patients with PD-L1–positive tumors that was shown in our trial provides evidence of the efficacy of immunotherapy in at least a subset of patients. It is important for patients’ PD-L1 expression status on tumor-infiltrating immune cells to be taken into consideration to inform treatment choices for patients with metastatic triple-negative breast cancer.” ■
DISCLOSURE: The study was funded by F. Hoffmann–La Roche/Genentech. Dr. Schmid has an immediate family member employed by Roche; has received honoraria from AstraZeneca, Pfizer, Novartis, and Roche; is a consultant/advisor with Pfizer, Novartis, Eisai, Celgene, AstraZeneca, Merck, Boehringer Ingelheim, Bayer, Puma Biotechnology (immediate family member), Genentech/Roche; and has received institutional research funding from AstraZeneca, Astellas Pharma, Medivation, Oncogenex, Genentech, Novartis, Roche, and Merck.
1. Schmid P, Adams S, Rugo HS, et al: Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379:2108-2121, 2018.
Kevin Kalinsky, MD, MS
Dawn Hershman, MD, MS
THE IMPASSION130 trial—reported in The New England Journal of Medicine by Schmid et al1 and reviewed in this issue of The ASCO Post—was an eagerly awaited study in newly diagnosed metastatic triple-negative breast cancer. To briefly...!-->!-->!-->!-->