In patients with early-stage triple-negative breast cancer, the addition of atezolizumab to standard adjuvant chemotherapy provided no benefit over chemotherapy alone in the final analysis of the phase III ALEXANDRA/IMpassion030 trial. The results were presented at the 2024 European Breast Cancer Conference by Heather McArthur, MD, MPH, Professor in the Department of Internal Medicine and Clinical Director of the Breast Cancer Program, Harold C. Simmons Comprehensive Cancer Center, at The University of Texas Southwestern Medical Center, Dallas.
“The final analysis of the primary endpoint together with secondary efficacy endpoints do not support the addition of atezolizumab to adjuvant chemotherapy in patients who have undergone primary surgery for early triple-negative breast cancer,” Dr. McArthur said.
Heather McArthur, MD, MPH
As Dr. McArthur pointed out, previous studies have established the benefit of immunotherapy in the neoadjuvant treatment of triple-negative breast cancer, and in other solid tumors adjuvant immunotherapy has improved outcomes. “When ALEXANDRA/IMpassion030 was designed,” she said, “the optimal timing of PD-1/PD-L1–inhibitor administration in combination with chemotherapy in early triple-negative disease was unknown.”
The ALEXANDRA/IMpassion030 trial was the first study to look at the role of atezolizumab added to chemotherapy after surgery. Although the primary endpoint of the study was not met, Dr. McArthur emphasized, “The ALEXANDRA/IMpassion030 trial contributes to an improved understanding about the optimal use of immunotherapy in patients with early-stage triple-negative breast cancer.”
About ALEXANDRA/IMpassion030
The phase III ALEXANDRA/IMpassion030 study included 2,199 patients from 31 countries with stage II or III triple-negative breast cancer. Following resection, patients were randomly assigned to standard chemotherapy with paclitaxel, anthracycline, and cyclophosphamide or to chemotherapy plus atezolizumab at 840 mg given concomitantly, followed by maintenance atezolizumab at 1,200 mg for 1 year of treatment. The primary endpoint was invasive disease–free survival in the intention-to-treat population.
Recruitment stopped after 2,199 of the planned 2,300 patients were enrolled on the recommendation of the independent data monitoring committee. In the final cohort, 71% had PD-L1–positive tumors and 48% had node-positive disease. Most patients had stage pT1–pT2 poorly differentiated ductal carcinoma.
At the interim analysis, with a median of approximately 25 months of follow-up and 239 disease-free survival events, the hazard ratio (HR) crossed the prespecified futility boundary. The final analysis—with a median of about 32 months of follow-up and 266 events—was reported at the meeting by Dr. McArthur.
No Benefit for Adjuvant Atezolizumab
No disease-free or overall survival benefit was demonstrated with the addition of atezolizumab to adjuvant chemotherapy. Recurrences were noted for 141 patients (12.8%) receiving atezolizumab/chemotherapy and 125 (11.4%) receiving chemotherapy alone (HR = 1.11; P = .38). Overall survival events (deaths) were recorded for 6.5% and 5.3%, respectively (HR = 1.23), she reported.
Researchers also found no invasive disease–free survival benefit in any prespecified subgroup, including patients with node-positive disease (HR = 1.32) and those with PD-L1–expressing tumors (HR = 1.00). In the PD-L1–expressing group, recurrence rates were 10.6% in the atezolizumab arm and 10.4% in the control arm.
The safety of atezolizumab was consistent with other trials of the treatment. Grade ≥ 3 toxicities were noted for 54.3% receiving atezolizumab and chemotherapy and for 44.1% receiving chemotherapy alone.
EXPERT POINT OF VIEW
The invited discussant of the phase III ALEXANDRA/IMpassion030 trial was Marleen Kok, MD, PhD, a medical oncologist and group leader of the Netherlands Cancer Institute, Amsterdam. “This is a negative study, and we can only speculate as to why it is negative, but I want to highlight that negative studies are just as important as positive studies,” Dr. Kok said.
Marleen Kok, MD, PhD
As she pointed out, the negative findings for atezolizumab stand in contrast to the benefit seen for pembrolizumab in KEYNOTE-522.2 “Is it about atezolizumab, an anti–PD-L1 agent, vs pembrolizumab, an anti–PD-1 drug? Probably not. We saw big changes in pathologic complete response with atezolizumab in the IMpassion031 study.3 The patient selection was more or less similar, so that’s not a good explanation either. The main difference is that the ALEXANDRA/IMpassion030 study lacked the neoadjuvant immunotherapy component,” Dr. Kok said.
Studies, primarily in melanoma, have revealed that the presence of the primary tumor and lymph nodes (with their T cells, dendritic cells, and other key immune cells) helps boost the effect of immunotherapy. These entities “help the body recognize the cancer … and help train the T cells to fight the cancer,” she explained. “Adjuvant immunotherapy alone is not as effective as neoadjuvant immunotherapy. So, in contrast to lung cancer, renal cell cancer, and melanoma, so far we do not have a place for adjuvant immunotherapy in triple-negative breast cancer.”
Remaining Questions
The important question now is this: what is the contribution of adjuvant anti–PD-1/PD-L1 after neoadjuvant immunotherapy? Pivotal trials have not yet included a second randomization that might shed light on this issue. For example, looking at past studies for guidance, GeparNUEVO4 and NeoPACT5 demonstrated excellent outcomes without adjuvant immunotherapy in patients who achieved a pathologic complete response. An exploratory study6,7 from the Netherlands Cancer Institute indicates that patients with high levels of tumor-infiltrating lymphocytes treated with short-term immunotherapy alone can achieve pathologic complete responses.
Such observations, Dr. Kok said, beg the question, “Why do we need this whole year of immunotherapy?” The evidence to date suggests, she said, “the neoadjuvant portion of immunotherapy is the most important.”
DISCLOSURE: Dr. McArthur has consulted for Amgen, AstraZeneca, Bristol Myers Squibb, Calithera, Celgene, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Peregrine, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Daiichi Sankyo, Seattle Genetics, Gilead, Crown Bioscience, and TapImmune. Dr. Kok reported institutional research funding from Natera, Alderaan, AstraZeneca, Bristol Myers Squibb, Daiichi-Sankyo, Domain Therapeutics, MSD, Roche, and Gilead Sciences.
REFERENCE
1. McArthur H, Bailey A, Saji S, et al: Adjuvant chemotherapy with or without atezolizumab for stage II and III triple-negative breast cancer: Final analysis of the ALEXANDRA/IMpassion030 phase 3 trial. 2024 European Breast Cancer Conference. Abstract 1LBA. Presented March 20, 2024.
2. Schmid P, Cortes J, Pusztai L, et al: Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382:810-821, 2020.
3. Mittendorf EA, Zhang H, Barrios CH, et al: Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): A randomised, double-blind, phase 3 trial. Lancet 396:1090-1100, 2020.
4. Loibl S, Untch M, Burchardi N, et al: A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: Clinical results and biomarker analysis of GeparNuevo study. Ann Oncol 30:1279-1288, 2019.
5. Sharma P, Stecklein SR, Yoder R, et al: Clinical and biomarker findings of neoadjuvant pembrolizumab and carboplatin plus docetaxel in triple-negative breast cancer: NeoPACT phase 2 clinical trial. JAMA Oncol 10:227-235, 2024.
6. Kok M, Nederlof I, Isaeva OI, et al: Nivolumab and ipilimumab in early-stage triple negative breast cancer with tumor-infiltrating lymphocytes: First results from the BELLINI trial. ESMO Congress 2022. Abstract LBA13. Presented September 10, 2022.
7. Nederlof I, et al: Neoadjuvant nivolumab/relatlimab or nivolumab/ipilimumab in triple negative breast cancer with high tumor-infiltrating lymphocytes. ESMO Congress 2024. Abstract LBA11. Presented September 16, 2024.
