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Neoadjuvant, but not adjuvant, chemoimmunotherapy significantly improved key outcomes in certain patients with early breast cancer, according to a meta-analysis involving more than 5,000 patients.

Consistent with existing evidence, the addition of immune checkpoint inhibitors (ICIs) to neoadjuvant chemotherapy improved pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC) by an absolute difference of 13% versus chemotherapy alone, irrespective of PD-L1 expression status. And preoperative ICIs also improved pCR rates by 12% in hormone receptor (HR)-positive/HER2-negative breast cancer.

TNBC patients with pCRs had a 5-year event-free survival (EFS) rate of 92% with the addition of ICIs versus 88% without them. Five-year EFS rates also improved in patients with residual disease, from 56.1% without ICIs to 63.3% with them.

No numerical improvement was observed with the use of adjuvant ICI therapy regardless of pCR or presence of residual disease at surgery, reported Tomas Pascual, MD, of the Hospital Clinic of Barcelona in Spain, and co-authors in .

"Consistent with previous studies, this meta-analysis confirms that pCR status is associated with survival in patients with TNBC, with patients achieving pCR experiencing a 30% absolute increase in 5-year EFS rates," the authors wrote. "Importantly, the findings presented in this meta-analysis show that neoadjuvant ICI is not only associated with enhanced pCR rates but also extends its impact beyond pCR."

"Among patients with and without pCR at surgery, patients who had received neoadjuvant ICI therapy had better survival outcomes independent of administration of adjuvant ICI therapy," they added. "This finding suggests that the benefits of ICI therapy extend to various stages of disease response, reinforcing its potential utility in the management of TNBC and transcending the conventional parameters of tumor pathologic assessment."

Even in patients with residual disease after neoadjuvant therapy, a state of enhanced immunity exists -- possibly induced by ICI therapy -- that identifies , Pascual and team noted. Survival improvement beyond pCR status also has been demonstrated with pertuzumab (Perjeta) in .

Informing Ongoing Debate

The improved EFS rates in patients with pCR persisted when the investigators excluded studies that did not use adjuvant ICIs, noted Elizabeth A. Mittendorf, MD, PhD, and Sara Tolaney, MD, MPH, both of Dana-Farber Cancer Institute in Boston, in an . Pascual and colleagues noted that comparison of previous trials that used adjuvant ICIs and those that did not showed similar EFS rates among patients who achieved a pCR.

A recent update from the trial of adjuvant pembrolizumab (Keytruda) showed a 5-year EFS rate of 92.2% among patients who achieved pCR with the ICI versus 88.2% for placebo-treated patients who achieved a pCR.

This "difference in EFS is intriguing and suggests that all types of therapy that lead to pCRs are not the same," Mittendorf and Tolaney wrote. "The types of therapy that lead to pCR may impact long-term outcomes."

The ongoing OptimICE-PCR trial, which randomized patients who achieve a pCR to adjuvant pembrolizumab or placebo, will provide a definitive answer to the question of whether adjuvant ICIs should be given to patients who achieve pCR with neoadjuvant ICIs, they added.

Another notable finding of the meta-analysis was improved pCR in patients with HR-positive/HER2-negative breast cancers exhibiting PD-L1 expression. In contrast, PD-L1 expression has not proven useful as a marker for response in TNBC.

The investigators used "available data to begin to address the clinically important questions breast cancer clinicians are asking as we consider how to incorporate ICIs into our armamentarium to treat early-stage breast cancer," Mittendorf and Tolaney concluded. "Their data support and inform additional work that must be done in the form of clinical trials and correlative studies to better tailor the use of ICIs in clinical practice."

Key Findings

Pascual and colleagues performed the meta-analysis to help inform the ongoing debate over the optimal approach to integrate ICIs into treatment of early breast cancer. The debate comprises several unresolved issues: the prognostic role of PD-L1 expression, ICI efficacy in different molecular phenotypes, advantages (or lack thereof) of adjuvant ICI in patients with and without pCR, and potential safety implications.

The analysis included nine randomized trials and 5,114 patients. The breakdown by histologic subtype consisted of 2,097 patients with TNBC, 1,924 with HR-positive/HER2-negative tumors, and 1,115 with HER2-positive cancers. Co-primary endpoints were pCR (ypT0/is ypN0) in each breast cancer phenotype and EFS in patients with and without pCR.

In the TNBC subgroup, the addition of ICIs increased pCR rates from 46.6% to 59.9%, representing a 64% increase in the odds of achieving pCR (95% CI 1.19-2.25). The absolute benefit was similar in patients with PD-L1-positive tumors (13.3%) and PD-L1-negative tumors (10.9%).

Patients with HR-positive/HER2-negative cancers had an improvement in pCR rate from 14.8% to 24.6% with ICIs, an 87% increase in the odds ratio (95% CI 1.49-2.36). However, the overall difference was driven by a 12.2% absolute improvement in PD-L1-positive tumors (vs 4.1% in PD-L1-negative tumors).

Patients with HER2-positive tumors did not benefit significantly from adding an ICI to neoadjuvant chemotherapy, regardless of PD-L1 status.

With regard to survival, the overall cohort of patients with TNBC had a 5-year EFS rate of 80% with ICIs versus 71.8% without (HR 0.69, 95% CI 0.57-0.84). In the 997 patients who achieved pCR, the addition of ICIs reduced the hazard by 35% (95% CI 0.42-1.00). Patients with residual disease also had significantly better 5-year EFS rates with ICIs (HR 0.77, 95% CI 0.61-0.98).

As Mittendorf and Tolaney noted, an exploratory analysis of EFS by adjuvant therapy in the pCR subgroup showed no significant difference at 5 years with the addition of adjuvant ICI. The analysis also showed no significant benefit of ICIs among patients who had residual disease after surgery.

Use of ICIs was associated with an absolute 9.5% increase in grade ≥3 adverse events (AEs; 63.6% vs 54.1%). The most common AEs in patients who did and did not receive ICIs were nausea, fatigue, and neutropenia, which occurred at similar rates in both treatment arms. Overall, immune-related AEs occurred in 10.3% of patients who received ICIs.

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