As reported in the Journal of Clinical Oncology by Jens Huober, MD, and colleagues, the phase III IMpassion050 trial showed no significant improvement in pathologic complete response rate with the addition of atezolizumab to neoadjuvant pertuzumab/trastuzumab and chemotherapy in patients with HER2-positive breast cancer, including those with PD-L1–positive tumors.
Jens Huober, MD
In the double-blind trial, 454 patients from sites in 12 countries with a primary tumor larger than 2 cm and positive lymph node status were randomly assigned between January 2019 and August 2020 to the atezolizumab group (n = 226) or placebo group (n = 228). Patients received four 2-week cycles of atezolizumab at 840 mg or placebo with doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2, followed by four cycles of atezolizumab at 1,200 mg/placebo once every 3 weeks, paclitaxel at a80 mg/m2 once weekly, trastuzumab at 6 mg/kg (after an 8-mg/kg loading dose) once every 3 weeks, and pertuzumab at 420 mg (after an 840-mg loading dose) once every 3 weeks.
PD-L1–positive status was defined as tumor-infiltrating immune cells ≥ 1%. The PD-L1–positive population included 109 evaluable patients in the atezolizumab group and 109 in the placebo group.
The primary endpoints were pathologic complete response among all patients and in the PD-L1–positive population.
In the adjuvant phase, patients continued atezolizumab/placebo with pertuzumab/trastuzumab to complete 1 year of HER2-targeted therapy. Patients with residual disease at surgery could switch to ado-trastuzumab emtansine (3.6 mg/kg every 3 weeks for 14 cycles) while maintaining atezolizumab/placebo.
Pathologic Complete Response Rates
At clinical cutoff (in February 2021), pathologic complete response rates were 62.4% (141 of 226) in the atezolizumab group vs 62.7% (143 of 228) in the placebo group among all patients (difference = –0.33%, 95% confidence interval [CI] = –9.2% to 8.6%, P = .9551). Rates were 64.2% (70 of 109) in the atezolizumab group vs 72.5% (79 of 109) in the placebo group in the PD-L1–positive population (difference = –8.26%, 95% CI = –20.6% to 4.0%, P = .1846). Among patients with PD-L1–negative tumors, pathologic complete response rates were 60.7% (71 of 117) in the atezolizumab group vs 53.8% (64 of 119) in the placebo group (difference = 6.90%, 95% CI = –5.69% to19.49%).
Median duration of follow-up was 15.7 months in the atezolizumab group and 15.9 months in the placebo group. Event-free survival events occurred in 12 patients (5.3%) in the atezolizumab group vs 7 (3.1%) in the placebo group (P = .2084). Overall, 13 events were disease recurrences; 5 were fatal adverse events, and 1 was death due to gastric cancer.
After review of unblinded data in January 2021, the independent Data Monitoring Committee recommended stopping randomized atezolizumab/placebo treatment due to an unfavorable benefit-risk profile, with patients continuing standard-of-care treatment through the completion of adjuvant treatment per study protocol. Only three patients who had received neoadjuvant treatment had yet to undergo surgery at the time of clinical cutoff.
Treatment-related grade 3 or 4 adverse events occurred in 47.3% of patients in the atezolizumab group vs 42.2% of the placebo group during neoadjuvant treatment, and in 13.4% of 216 patients in the atezolizumab group vs 9.8% of 215 patients in the placebo group who entered the adjuvant treatment phase. Adverse events led to atezolizumab withdrawal in 8.4% of patients and to placebo withdrawal in 5.8% during neoadjuvant treatment. Serious treatment-related adverse events occurred in 15.0% vs 10.7% of patients during neoadjuvant treatment and in 5.1% vs 3.3% during adjuvant treatment. Adverse events led to death in four (1.8%) vs zero patients during neoadjuvant therapy, with two deaths considered related to treatment (due to alveolitis and septic shock), and in one (considered unrelated to treatment) vs zero patients during adjuvant treatment. Adverse events of special interest of any grade occurred in 72.6% vs 61.3% of patients (grade 3 or 4 in 10.6% vs 6.7%) during neoadjuvant treatment and in 56.5% vs 42.8% (grade 3 or 4 in 6.5% vs 2.3%) during adjuvant treatment.
The investigators concluded, “Atezolizumab with neoadjuvant dose-dense doxorubicin/cyclophosphamide/paclitaxel and pertuzumab/trastuzumab for high-risk, HER2-positive early breast cancer did not increase [pathologic complete response] rates vs placebo in the intention-to-treat or PD-L1–positive populations. Pertuzumab/trastuzumab and chemotherapy remains standard of care; longer follow-up may help to inform the long-term impact of atezolizumab.”
Dr. Huober, of Cantonal Hospital, Breast Center St. Gallen, St. Gallen, Switzerland, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was sponsored by F. Hoffmann-La Roche Ltd. For full disclosures of the study authors, visit ascopubs.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.