Pembrolizumab plus neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery as a standard of care for patients with early-stage TNBC

At SABCS 2023, updated event-free survival (EFS) results of the phase III KEYNOTE-522 study were presented. After a median follow-up of more than five years, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab continues to show a clinically meaningful improvement in EFS compared with neoadjuvant chemotherapy alone in patients with early-stage triple-negative breast cancer. Importantly, the benefit of pembrolizumab is seen across all subgroups and regardless of the pathological complete response outcome.

In KEYNOTE-522, neoadjuvant pembrolizumab plus chemotherapy (chemo) followed by adjuvant pembrolizumab led to a statistically significant and clinically meaningful improvement in pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant placebo plus chemo followed by adjuvant placebo in patients with early-stage triple-negative breast cancer (TNBC). At SABCS 2023, Prof. Schmid presented updated EFS results after a median follow-up of approximately five years.

Study design

KEYNOTE-522 is a randomized, placebo-controlled phase III trial of pembrolizumab for early-stage TNBC in the neoadjuvant and adjuvant settings. In total, 1,174 adult patients with newly diagnosed TNBC of either T1c N1–2 or T2–4 N0–2 were randomized (2:1) to neoadjuvant pembrolizumab 200 mg once every three weeks (Q3W) or placebo, both given with chemotherapy (4 cycles paclitaxel + carboplatin followed by 4 cycles doxorubicin–cyclophosphamide or epirubicin–cyclophosphamide). After definitive surgery, patients received adjuvant pembrolizumab or placebo (200 mg, Q3W) for up to nine cycles. The dual primary endpoints were pCR at the time of definitive surgery and EFS

Results

At SABCS 2023, updated EFS results after a median follow-up of 63.1 months were presented. With this longer follow-up, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab continues to show a clinically meaningful improvement in EFS compared to neoadjuvant chemotherapy alone (HR[95%CI]: 0.63[0.49-0.81]). The five-year EFS rate was reported at 81.3% in the pembrolizumab arm, as compared to 72.3% in the control arm. The benefit of neoadjuvant pembrolizumab + chemo followed by adjuvant pembrolizumab vs. neoadjuvant chemo alone was consistent with the primary EFS results in all five sensitivity analyses, including those defined by disease stage (HR, 0.59 for stage II and HR, 0.71 for stage III) nodal status (HR, 0.67 for positive nodal status and HR, 0.56 for negative nodal status) and T2N0 status (HR, 0.49). Within the disease stage and nodal status subgroups, the reduction in EFS events in the pembrolizumab groups was observed regardless of pCR outcome. Finally, there was a higher rate of distant recurrence as first EFS event with placebo vs. pembrolizumab (14.1% vs. 9.2%). The incidence of brain metastases as first EFS event was low in both treatment groups, with a numerically lower incidence in the pembrolizumab group as compared to the placebo group (2.3% vs. 3.3%). Follow-up for overall survival is ongoing.

Conclusion

After a median follow-up of more than five years, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab continues to show a clinically meaningful improvement in EFS compared to neoadjuvant chemo alone in patients with high-risk, early-stage TNBC. The EFS benefit with pembrolizumab was generally consistent in key subgroups, irrespective of disease stage, nodal status and T2N0 status.

Reference

Schmid P, et al. Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for early-stage triple-negative breast cancer: Updated event-free survival results from the phase 3 KEYNOTE-522 study. Presented at SABCS 2023; Abstract LB01-01.