De-Escalated Neoadjuvant Chemoimmunotherapy Shows Promise in Early TNBC

Use of nivolumab (Opdivo) before chemotherapy was not associated with improved pathologic complete response (pCR) rates among patients with early triple-negative breast cancer (TNBC), but a 12-week non-anthracycline regimen in combination with PD-1-targeted therapy showed promise, according to findings from the Neo-N trial.

In this non-comparative, open-label, randomized, phase II study, the pCR rate was 51% in the group who received nivolumab before chemotherapy compared with 55% in the group who received concurrent nivolumab, reported Sherene Loi, MD, PhD, of the University of Melbourne in Australia, and colleagues in Lancet Oncology.

The researchers had hypothesized that lead-in nivolumab before chemotherapy would be associated with a pCR advantage. While this was not borne out, Loi and colleagues said that the study showed pCR rates that were “clinically relevant” and comparable to similar studies, such as NeoPACT, “which suggests that shorter-duration neoadjuvant chemotherapy with PD-1 inhibition could be efficacious and associated with less toxic effects than the current 24-week standard of care, particularly in biomarker-selected populations independent of nivolumab sequencing,” they wrote.

In explaining the rationale behind the study, Loi and colleagues noted that neoadjuvant chemotherapy and PD-1-targeted immunotherapy became the standard of care in 2021 for patients with stage II or III TNBC based on results from the KEYNOTE-522 trial, in which improved pCR rates and event-free survival were observed.

However, “clinical uncertainty remains regarding the ideal sequencing strategy of PD-1 inhibitors with chemotherapy and whether shorter duration of non-anthracycline-based chemotherapy when combined with immunotherapy can be effective in biomarker-selected populations,” they wrote.

Loi and colleagues also conducted a prespecified subgroup biomarker analysis that showed pCR rates of 67% and 46% for high (≥30%) and low (<30%) stromal tumor-infiltrating lymphocyte status. In a PD-L1 subgroup analysis, the pCR rates were 71% for positive status versus 33% for negative status.

Patients with PD-L1-positive or high tumor-infiltrating lymphocyte status, performed by central pathology assessment, showed the highest pCR rate, at 75%. The second highest was PD-L1-positive or low tumor-infiltrating lymphocyte status, at 67%.

“These findings suggest that these biomarker-selected patients might be ideal candidates for de-escalated chemoimmunotherapy regimens, even though survival data from Neo-N remain immature,” wrote Anthony Gonçalves, MD, PhD, and Alexandre de Nonneville, PhD, both of Aix-Marseille University in Marseille, France, in a commentary accompanying the study.

“Showing the feasibility of an even more substantial de-escalation of neoadjuvant chemoimmunotherapy, as explored in the Neo-N study, will likely require stringent patient selection criteria, which could include limiting tumor burden to stage I-II or node-negative disease (or both) and incorporating biomarkers of baseline immune activation, DNA damage repair, and genomic signatures,” they added.

Neo-N was conducted at 12 hospitals in Australia, one in New Zealand, and one in Italy from July 2020 to April 2022 and included 110 women, 108 of whom were included in the modified intention-to-treat analysis (53 in the lead-in group and 55 in the concurrent group).

Median age was 49 years, 17% of patients had clinically node-positive disease, 34% had clinical stage I disease, 65% had stage II disease, and one had stage III disease.

Patients were assigned to lead-in nivolumab and carboplatin with paclitaxel or concurrent nivolumab and carboplatin with paclitaxel.

Treatment-related grade 3-4 adverse events occurred in 70% of patients — 60% in the lead-in group and 69% in the concurrent group — with the most common being decreased neutrophil count (47% vs 53%), anemia (11% vs 19%), and increased alanine aminotransferase (6% in both groups).

Serious adverse events were reported in 30% of patients in the lead-in group and 47% in the concurrent group. Treatment-related serious adverse events occurred in 13% and 36%, respectively. No treatment-related deaths occurred during the study.

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