Since the approval of immune checkpoint inhibitors (ICIs) for the treatment of patients with triple-negative breast cancer (TNBC), there has been some debate about the optimal approach to early-stage disease (ie, neoadjuvant or adjuvant administration). Published in JAMA Oncology, a large systematic review and meta-analysis of 9 randomized trials and more than 5,000 patients treated with ICIs was conducted to provide insights into early breast cancer treatment. The objectives were to evaluate the association of neoadjuvant ICIs with pathologic complete response (pCR) across molecular phenotypes, to quantify the survival benefits of ICIs beyond pCR status, and to estimate the incidence of specific adverse events. Four types of ICI treatments were identified: atezolizumab, pembrolizumab, durvalumab, and nivolumab.
The analysis found that neoadjuvant ICI therapy was associated with improved outcomes in early-stage TNBC and programmed cell death ligand 1-positive (PD-L1+)/ERBB2-negative tumors with an acceptable safety profile. The addition of ICIs to neoadjuvant chemotherapy improved pCR rates in TNBC by 13% vs chemotherapy alone, irrespective of PD-L1 expression. The analysis also demonstrated that the benefits of neoadjuvant immunotherapy in breast cancer extend beyond triple-negative disease. Preoperative ICIs also improved pCR rates by 12% in hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, driven by an absolute improvement in PD-L1+ tumors. Patients with HER2+ tumors did not benefit significantly from neoadjuvant ICI, regardless of PD-L1 status.
Five-year event-free survival rates improved with the addition of ICIs in patients with TNBC, both for those with pCRs and those with residual disease. Use of adjuvant ICI therapy did not improve event-free survival in either patient group. A linked editorial noted that this difference suggests that not all pCRs are the same, and the types of therapy that lead to pCR may impact long-term outcomes.
Consistent with prior studies, there was an increase in grade 3 or higher adverse events, and immune-related adverse events occurred in approximately 10% of patients who received ICIs.
According to the authors, this meta-analysis confirms that pCR status is associated with survival in patients with TNBC, with patients in pCR experiencing a 30% increase in 5-year event-free survival rates. Patients in the analysis who received neoadjuvant ICI therapy had better survival outcomes, independent of administration of adjuvant ICI therapy, reinforcing its potential utility in the management of TNBC in patients with various stages of disease response.
High level
The insights into early breast cancer identified in this meta-analysis should be used to support and inform additional clinical trials and correlative studies to better tailor the use of ICIs in clinical practice. Emerging insights into comprehensive molecular classifications may help to better personalize treatment and improve patient selection in future trials. Given the financial and toxicity costs associated with ICIs, identification and validation of biomarkers of response to ICIs added to neoadjuvant chemotherapy should also be prioritized in future research to help support decision-making. On the basis of this meta-analysis’ findings, it is crucial to investigate whether adjuvant therapy could be safely omitted and potentially redefine treatment paradigms in early breast cancer.
Ground level
These insights into early breast cancer are based on cross-trial comparisons, so they could be biased and should be interpreted with caution. Clinicians should review the results of the ongoing OptimICE-PCR trial when available, which will provide a definitive answer to the question of whether adjuvant ICIs should be given to patients who have a pCR with neoadjuvant ICIs. Given the potential for serious immune-related adverse events affecting various organs with ICIs, careful monitoring is required when using ICIs in early treatment. The lack of survival advantage with adjuvant ICI therapy in patients with residual disease raises the question of whether these patients should complete the year of pembrolizumab in the adjuvant setting. Such patients should be considered for clinical trials evaluating other strategies, including antibody-drug conjugates.