Two Studies of Atezolizumab-Based Regimens in Early-Stage, Triple-Negative and HER2-Positive Breast Cancers
Immunotherapy regimens involving the PD-L1 monoclonal antibody atezolizumab have demonstrated promising results in patients with early-stage, triple-negative breast cancer and HER2-positive breast cancer, according to a pair of studies presented at the European Society for Medical Oncology (ESMO) Breast Cancer Annual Congress 2023,1,2 but additional evidence on the use of this agent in the early setting is still needed.
Carlos H. Barrios, MD
Final analysis of the phase III IMpassion031 trial showed that the addition of atezolizumab to neoadjuvant chemotherapy led to numerical improvements in event-free, disease-free, and overall survival in patients with early-stage, triple-negative breast cancer compared with chemotherapy plus placebo. Data from the randomized phase II ATHENE trial showed high pathologic complete response rates in patients with early-stage, HER2-positive breast cancer with a chemotherapy de-escalation immunotherapy regimen, including trastuzumab, pertuzumab, atezolizumab, and epirubicin. Authors of both studies highlighted the significance of these findings, which showcase potential new treatment approaches for patients with these breast cancer subtypes.
“Pathologic complete response continues to be a prognostically favorable variable for long-term outcomes at individual-patient levels,” said lead author of the IMpassion031 trial, Carlos H. Barrios, MD, of the Latin American Cooperative Oncology Group and Hospital São Lucas, Brazil. “Further research and longer follow-up will help determine the full extent of the benefits of this combination therapy in triple-negative breast cancer.”
As Dr. Barrios reported, IMpassion031 was designed to evaluate the addition of atezolizumab to neoadjuvant chemotherapy in patients with untreated stage II or III triple-negative breast cancer, with a primary tumor greater than 2 cm and cT2 to cT4, cN0 to cN3, or cM0 disease. The primary endpoint of the study was pathologic complete response, with secondary endpoints including event-free survival, overall survival, and disease-free survival in the intent-to-treat and PD-L1–positive populations, as well as safety and patient-reported outcomes.
The trial enrolled 333 patients who were randomly assigned 1:1 to receive either atezolizumab plus chemotherapy or chemotherapy alone. The experimental arm received atezolizumab every 2 weeks, plus nab-paclitaxel, followed by atezolizumab plus doxorubicin and cyclophosphamide, prior to surgery. Adjuvant atezolizumab was given once every 3 weeks for 11 cycles. The control arm was given placebo plus nab-paclitaxel followed by placebo plus doxorubicin and cyclophosphamide for 8 weeks prior to surgery.
- In the phase III IMpassion031 trial, atezolizumab plus chemotherapy demonstrated numerical improvements in event-free survival, disease-free survival, and overall survival in early-stage, triple-negative breast cancer.
- In the randomized phase II ATHENE trial, a neoadjuvant chemotherapy “de-escalation” immunotherapy regimen showed high rates of pathologic complete response in early-stage, HER2-positive breast cancer.
The final analysis showed a trend for improved event-free survival favoring neoadjuvant atezolizumab plus chemotherapy compared with chemotherapy alone (hazard ratio [HR] = 0.76; 95% confidence interval [CI] = 0.47–1.21).
“These results suggest a potential benefit of adding atezolizumab to neoadjuvant chemotherapy in patients with this aggressive cancer subtype, particularly in PD-L1–positive patients,” said Dr. Barrios.
No new safety signals or treatment-related deaths were reported with atezolizumab. Grade 3 or 4 adverse events occurred in 63% of patients in the atezolizumab arm and 60% in the placebo arm. Rates of grade 3 or 4 -treatment-related adverse events were 57% and 53%, respectively. Adverse events of special interest occurred in 81% of patients in the atezolizumab arm, including 17% with grade 3 or 4 events, compared with 61% in the placebo arm, including 13% with grade 3 or 4 events.
An exploratory analysis showed that circulating tumor DNA (ctDNA) clearance was 89% at surgery in the atezolizumab arm, compared with 86% in the placebo arm. The pathologic complete response rate for patients who achieved ctDNA clearance was 62% in the experimental arm vs 41% in the control arm.
For most patients with HER2-positive early breast cancer, neoadjuvant dual HER2 blockade with trastuzumab and pertuzu-mab plus polychemotherapy is standard of care. The open-label, two-arm, single-stage phase II ABCSG-52/ATHENE trial investigated a monochemotherapy regimen in combination with dual HER2 blockade and atezolizumab. Investigators hypothesized that the immunogenic properties of epirubicin and atezolizumab would promote synergistic activity and improve outcomes.
The ABCSG-52/ATHENE trial enrolled 58 treatment-naive patients with early-stage, HER2-positive breast cancer. Patients were randomly assigned 1:1 to either (A) two 3-weekly cycles of a chemotherapy-free induction phase (part 1) with atezolizu-mab and dual HER2 blockade with trastuzumab and pertuzumab or (B) dual HER2 blockade alone. Afterward, all patients received four cycles of atezolizumab and dual HER2 blockade in combination with epirubicin (part 2). The primary endpoint of the study was pathologic complete response, which was defined as no evidence of invasive tumor or lymph nodes after neoadjuvant therapy.
Gabriel Rinnerthaler, MD
The overall pathologic complete response rate in the trial was 60.3%. In an exploratory analysis breaking down responses by treatment arm, the addition of atezolizumab in part 1 was shown to increase the pathologic complete response rate to 65.5%, whereas it dropped to 55.2% without atezolizumab in the induction phase. A complete or by near complete remission (residual cancer burden class 0 or 1) was achieved in 80%—85.7% in the atezolizumab group and 74.1% without atezolizumab.
“Interestingly, highest response rates were observed in PD-L1–negative patients treated with atezolizumab in the induction phase with a pathologic complete response rate of 73.3%, compared to 52.9% in PD-L1–positive patients without atezolizumab in part 1,” said lead study author Gabriel Rinnerthaler, MD, Associate Professor, Department of Internal Medicine III, University Hospital Salzburg, Austria.
“In HER2-positive early breast cancer patients, PD-L1 positivity can be understood as a surrogate for trastuzumab sensitivity rather than a biomarker for atezolizumab effectivity. According to previous findings, trastuzumab-resistant tumors have lower PD-L1 expression. In this subset, the addition of atezolizumab seems to improve outcome. This is in line with the findings from our trial and the results from the phase III IMpassion050 study,” said Dr. Rinnerthaler.
“These results suggest a potential benefit of adding atezolizumab to neoadjuvant chemotherapy in patients with this aggressive cancer subtype [early-stage, triple-negative breast cancer].”— Carlos H. Barrios, MD
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The safety profile of the immunotherapy regimen was considered acceptable, with no new safety signals identified. Grade 3 or higher adverse events occurred in 29.3% of patients: 31.0% in the atezolizumab arm and 27.6% in the trastuzumab/pertuzumab arm. No grade 3 or higher adverse events of special interest, defined as immune-related adverse events, cardiac disorders, or infusion--related reactions, were reported.
“For HER2-positive, early-stage breast cancer, a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzu-mab, pertuzumab, atezolizumab, and epirubicin is highly effective and safe and merits further investigation,” Dr. Rinnerthaler concluded.
DISCLOSURE: Dr. Barrios has received consulting fees from Roche and Genentech, which sponsored the study. Dr. Rinnerthaler reported financial relationships with Daiichi Sankyo, Eli Lilly, Gilead Sciences, MSD, Novartis, Pfizer, Roche, Seagen, Amgen, AstraZeneca, Merck, MSD, and Pierre Fabre.
1. Barrios CH, Harbeck N, Zhang HA, et al: Final analysis of the placebo-controlled randomized phase 3 IMpassion031 trial evaluating neoadjuvant atezolizumab plus chemotherapy followed by open-label adjuvant atezolizumab in patients with early-stage triple-negative breast cancer. ESMO Breast Cancer Annual Congress 2023. Abstract LBA1. Presented May 12, 2023.
2. Rinnerthaler G, Egle D, Bartsch R, et al: Randomized phase II trial of neoadjuvant atezolizumab in early HER2-positive breast cancer (ABCSG-52/ATHENE). ESMO Breast Cancer Annual Congress 2023. Abstract 123O. Presented May 12, 2023.
Matteo Lambertini, MD, PhD
Invited discussant of these two trials, Matteo Lambertini, MD, PhD, Associate Professor at the University of Genova–IRCCS Policlinico San Martino Hospital Genoa, Italy, emphasized the importance of longer follow-up periods for both these clinical trials and the need ...