Immune-checkpoint inhibitors (ICIs) have the potential to induce long-term remission of cancer, but have disappointing efficacy in patients with breast cancer, at least as monotherapy for advanced-stage disease. Now, new data from two trials indicate that ICIs might be more effective if combined with neoadjuvant chemotherapy.

As part of the adaptively randomized phase II I-SPY2 trial, 40 women with high-risk HER2-negative and hormone receptor-positive disease (HER2−/HR+) and 29 with triple-negative breast cancer (TNBC) received pembrolizumab added to neoadjuvant chemotherapy (paclitaxel then doxorubicin and cyclophosphamide). The pathological complete response (pCR) rates in the HER2− population overall, the HER2–/HR+ subgroup and the TNBC subgroup were more than double those observed in a total of 181 women treated with chemotherapy alone: 44% versus 17%, 30% versus 13% and 60% versus 22%, respectively. In all three settings, the probability of success in a 300-patient, subtype-specific phase III trial of the pembrolizumab combination was >85%. In an immature exploratory analysis of event-free survival (EFS), patients with a pCR faired very well, regardless of which treatment they received (hazard ratios <0.4 relative to their counterparts without a pCR).

Immune-related adverse events, particularly thyroid and adrenal endocrinopathies (frequency of 15.9% and 8.7%, respectively), occurred with pembrolizumab, but not with chemotherapy alone. Thus, identifying predictive biomarkers will be important to avoid potentially unnecessary and toxic treatment of patients who often have excellent outcomes with current therapies.

The pathological complete response (pCR) rates … were more than double those observed … with chemotherapy alone

In the ongoing phase III KEYNOTE-522 trial, patients with TNBC are being randomly assigned (2:1) to receive neoadjuvant chemotherapy (paclitaxel and carboplatin then cyclophosphamide plus either epirubicin or doxorubicin) plus either pembrolizumab or placebo, with stratification by PD-L1 status. In an interim analysis of data from 602 patients, the pCR rates were 64.8% with the ICI versus 51.2% with placebo (P < 0.001); the rates were 68.9% versus 54.9% and 45.3% versus 30.3% in the PD-L1+ and PD-L1– subgroups, respectively, suggesting a similar degree of benefit (~15%). At a median follow-up duration of 15.5 months, pembrolizumab was also associated with a trend towards improved EFS (hazard ratio 0.63, 95% CI 0.43–0.93). The toxicity profiles were as expected for each treatment, with similar rates of grade ≥3 treatment-related adverse events (78% versus 73%).

These promising results warrant further evaluation of the potential long-term survival benefits.