Adding pembrolizumab to neoadjuvant chemotherapy improves pCR rates across diverse subgroups in ER+/HER2- breast cancer

The phase 3 KEYNOTE-756 study previously demonstrated that the addition of pembrolizumab to neoadjuvant chemotherapy leads to an improved pathologic complete response (pCR) in patients with ER+/HER2- breast cancer (BC). Subgroup analysis presented at SABCS 2023 revealed greater pCR benefits in patients with node-positive disease, higher PD-L1 CPS thresholds, and ER-low tumours (<10%). Interestingly, the addition of pembrolizumab resulted in a notable shift of patients towards lower residual cancer burden categories, and pCR rates were improved with pembrolizumab regardless of chemotherapy exposure.

Patients with early-stage ER+/HER2- breast cancer (BC) generally have a more favorable prognosis than other BC subtypes. Nevertheless, this BC subtype does include is a high-risk subpopulation for whom neoadjuvant chemotherapy is indicated. The phase 3 KEYNOTE-756 study previously demonstrated that the addition of pembrolizumab to neoadjuvant chemotherapy leads to a statistically significant increase in the pathologic complete response (pCR) rate in these patients, regardless of tumour PD-L1 expression status. At SABCS 2023, the additional pCR results from analyses of various subgroups in the KEYNOTE-756 study were presented.

Study design

The phase 3 KEYNOTE-756 included patients with T1c-2 (≥2 cm) cN1-2 or T3-4 cN0-2, invasive ductal ER+/HER2- BC. In total, 1,278 patients were randomly assigned (1:1) to receive neoadjuvant pembrolizumab 200 mg Q3W (n=635) or placebo (n=643), both given with paclitaxel QW for 12 weeks, followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide (neoadjuvant treatment). After surgery, patients received pembrolizumab or placebo for 6 months, along with standard endocrine therapy (ET). Dual primary endpoints were pCR  (ypT0/Tis ypN0) and event-free survival (EFS). Secondary endpoints included overall survival (OS), pCR defined as ypT0 ypN0 and ypT0/Tis and safety. Residual cancer burden (RCB) was an exploratory endpoint and was assessed by a local pathologist at the time of surgery. In this, RCB-0, -1, -2, and -3 denote an increasingly larger residual disease.

Results

After a median follow-up of 33.2 months, the first interim analysis revealed a statistically significant improvement in pCR with the addition of pembrolizumab compared to chemotherapy alone (24.3% vs. 15.6%; difference: 8.5%, p=0.00005). This benefit was observed in both stage II and III patients (difference: 9.1 and 8%, respectively). Notably, the benefit of pembrolizumab appeared to be more pronounced in patients with node-positive disease (25.1% vs. 15.8%: difference: 9.3%) than in those with a node-negative status (16.9% vs. 13.1%; difference: 3.8%). Geographic disparities were observed, with lower pCR rates in Chinese patients (12.5% vs. 9.9%; difference: 2.6%) compared to patients with an Eastern European origin (29.5% vs. 16.2%; difference: 13.3%) or other countries (25.0% vs. 16.6%; difference 8.4%). Increasing PD-L1 expression levels were associated with higher pCR rates and higher pCR benefit of pembrolizumab. This pCR benefit ranged from 4.5% in PD-L1 CPS <1 subgroup (7.2% vs. 2.6% in the pembrolizumab and placebo arms, respectively) to 17.4% in PD-L1 CPS ≥20 (53.6% vs. 36.4%). The analysis also revealed a greater pCR improvement in patients with PD-L1 CPS ≥ 1 and ER+ <10% (57.6% vs. 33.3%; difference: 24.2%) compared to ER+ ≥10% (27.6% vs. 18.4%; difference: 9.2%). The pCR rate was low in both arms (7.2% vs. 2.7%) in patients with PD-L1 CPS <1 and ER+ ≥10%, with a 4.6% improvement in patients treated with pembrolizumab. The addition of pembrolizumab also influenced the RCB, with more patients in the pembrolizumab group shifting to a lower RCB category after surgery (RCB-0-1, 35 vs. 23.6% of patients in the pembrolizumab and placebo arms, respectively) and fewer patients moving to a higher RCB category (RCB-2, 40.8% vs. 45.3%;  RCB-3, 20.5% vs. 28.9%). Patients who received less than the planned chemotherapy doses had lower pCR rates (13.2% vs. 6.4%; difference: 6.8%) than to those who received a full dose (26.2% vs. 16.9%; difference 9.3%). However, it is noteworthy that the addition of pembrolizumab improved pCR rates regardless of chemotherapy exposure.

As expected, immune-mediated  adverse events (AEs) were more frequent in the pembrolizumab arm (32.8% vs. 7.0%). Importantly, however, there were no AEs leading to death. The most common immune-related AEs in the pembrolizumab arm were hypothyroidism, hyperthyroidism and pneumonitis.

Conclusions

The addition of pembrolizumab to neoadjuvant chemotherapy led to a statistically significant increase in pCR rates across different subgroups. A larger magnitude of pCR benefit was observed in patients with node-positive disease, higher PD-L1 CPS thresholds, and ER-low tumours (<10%). Notably, patients who received less than the planned chemotherapy doses had lower pCR rates, although pCR rates were improved with pembrolizumab regardless of chemotherapy exposure. The addition of pembrolizumab to neoadjuvant chemotherapy also resulted in a shift of patients towards lower residual cancer burden categories (RCB 0–1). Immune-mediated AE rates were consistent with the known toxicity profile of pembrolizumab plus neoadjuvant chemotherapy and no new safety concerns were observed. EFS results are immature and continue to be evaluated.

Reference

Cardoso F, O’Shaughnessy J, McArthur H, et al. Phase 3 Study of Neoadjuvant Pembrolizumab or Placebo Plus Chemotherapy, Followed by Adjuvant Pembrolizumab or Placebo Plus Endocrine Therapy for Early-Stage High-Risk ER+/HER2− Breast Cancer: KEYNOTE-756. Presented at SABCS 2023; Abstract GS01-02.