When or Whether to Give Immunotherapy in Early Breast Cancer

Which patients with early-stage breast cancer will benefit most from immunotherapy, and at what point is immunotherapy most useful?

This question spans neoadjuvant and adjuvant settings.

In the neoadjuvant setting, solid data exist demonstrating a benefit of pembrolizumab in patients with triple-negative breast cancer (TNBC), but evidence of a benefit in other subgroups is more limited.

In the adjuvant setting, among patients who received immunotherapy and chemotherapy before surgery, it’s unclear whether continuing immunotherapy after surgery provides a survival benefit or simply leads to greater treatment-related and financial toxicities.

Results of a recent meta-analysis, published in JAMA Oncology, help address some of the uncertainty surrounding whether, and in whom, to use immune checkpoint inhibitor (ICI) therapy in early-stage breast cancer.

The study included data from nine randomized clinical trials that assessed neoadjuvant and adjuvant ICI plus chemotherapy in 5114 patients with early breast cancer, including 2097 with TNBC, 1924 with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative disease, and 1115 with HER2–positive tumors.

Overall, 2802 (54.8%) patients received an ICI with chemotherapy, and 2312 (45.2%) received treatment without an ICI. The trials spanned four ICI therapies: Atezolizumab, pembrolizumab, durvalumab, and nivolumab.

In the neoadjuvant setting, the meta-analysis supported the use of an ICI alongside chemotherapy in patients with TNBC and HR–positive, HER2–negative disease, but not among patients with HER2–positive disease.

In patients with TNBC, adding an ICI to chemotherapy led to a significant improvement in pathologic complete response (pCR) rates — 46.6%-59.9% — regardless of programmed death-ligand 1 (PD-L1) status (odds ratio [OR], 1.64). Patients who received ICI therapy also demonstrated an event-free survival benefit (hazard ratio [HR], 0.69), with 5-year event-free survival rates at 80.0% vs 71.8% in those not receiving neoadjuvant ICI therapy.

Among patients who achieved a pCR, neoadjuvant ICI therapy was associated with significantly improved event-free survival (hazard ratio [HR], 0.65), with 5-year event-free survival rates at 92.0% vs 88.0%. And among patients who had residual disease, those receiving neoadjuvant ICIs demonstrated better event-free survival (HR, 0.77), with 5-year rates at 63.3% vs 56.1%.

In patients with HR–positive, HER2–negative disease, neoadjuvant immunotherapy also led to better overall pCR rates — 24.6% vs 14.8% (OR, 1.87). However, the benefit was largely observed in PD-L1–positive tumors — with rates increasing from about 19% to 31% — with only a marginal benefit noted in PD-L1–negative tumors — an increase from about 6% to 10%.

Not everyone benefited from neoadjuvant ICIs. Patients with HER2–positive tumors did not achieve a significant benefit from the additional therapy.

On the toxicity front, adding neoadjuvant ICI therapy to chemotherapy for early breast cancer did not appear to significantly increase traditional chemotherapy-associated adverse events, such as gastrointestinal symptoms or hematologic complications. However, in patients receiving ICIs, immune-related adverse events were “noteworthy,” with 10.3% being severe (grade 3 or higher), the study team said.

No Support for Adjuvant Immunotherapy

In the adjuvant setting, the analysis revealed no significant survival advantage among patients who continued ICI therapy after surgery, regardless of whether patients achieved a pCR or had residual disease.

In an exploratory analysis, when comparing two trials that provided adjuvant ICIs (KEYNOTE-522 and IMpassion031) and two that did not (GeparNuevo and I-SPY2), patients with TNBC who achieved a pCR demonstrated similar event-free survival outcomes (92.1% vs 92.8%). Similarly, among patients with TNBC who had residual disease, continuing ICI therapy in the adjuvant setting did not lead to significantly better survival outcomes (HR, 1.23; 95% CI, 0.60-2.53).

The lack of benefit in the adjuvant setting suggests that the therapeutic impact of ICIs in TNBC may be confined to the neoadjuvant setting.

“This finding calls into question whether patients with residual disease should complete the year of pembrolizumab in the adjuvant setting,” Elizabeth A. Mittendorf, MD, PhD, and Sara Tolaney, MD, MPH, both from Dana-Farber Cancer Institute in Boston, wrote in an accompanying editorial.

Considering these findings and given the financial and toxicity issues associated with immunotherapy, the study authors agreed that “it is crucial to investigate whether adjuvant therapy could be safely omitted, potentially redefining treatment paradigms in early breast cancer.”

However, because the current analysis relies on cross-trial comparisons, “the results could be biased and should be interpreted with caution,” the research team added. It’s also possible that certain populations may benefit from continuing ICI therapy in the adjuvant setting.

The editorialists “congratulated” the investigators for beginning 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 added that these “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.”

This research had no commercial funding. The authors and editorial writers disclosed various relationships with industry. All are listed with the original articles.