Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab for early-stage triple-negative breast cancer
Keynote-522 is the first prospective, randomised placebo-controlled phase III trial of pembrolizumab in early triple negative breast cancer (TNBC) in the neoadjuvant and adjuvant settings. In prior interim analyses, pembrolizumab plus chemotherapy demonstrated a significant improvement in pathological complete response and a favourable trend in event-free survival. At ESMO 2021, results from a prespecified interim analysis of Keynote-522 were presented.
Keynote-522 study design
In total, 1174 adult patients with previously untreated, non-metastatic, centrally confirmed TNBC (stage T1c N1-2 or T2-4 N0-2 per AJCC) were randomised 2:1 to neoadjuvant pembrolizumab 200 mg Q3W or placebo, both given with 4 cycles of paclitaxel plus carboplatin, followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide. The trial was designed to demonstrate a possible benefit of pembrolizumab on top of the most effective platinum-containing chemotherapy regimen. After definitive surgery, patients received adjuvant pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. Patients were stratified by nodal status (positive vs. negative), tumour size (T1/T2 vs. T3/T4), and carboplatin schedule (Q3W vs. QW). Dual primary endpoints are pathological complete response (pCR, ypT0/Tis ypN0) and event-free survival (EFS).
After a median follow-up of 37.8 months, 123 patients (15.7%) in the pembrolizumab group and 93 patients (23.8%) in the placebo group had an EFS event (i.e. disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause). The 36-month EFS rate was 84.5% in the pembrolizumab group vs. 76.8% in the placebo group (HR[95%CI]: 0.63[0.48-0.82], p= 0.00031), median EFS was not reached in either group. Fifty percent of first events were distant events. The benefit of pembrolizumab was consistent across all subgroups, with a similar benefit for N0/N+ patients (despite a larger relative pCR benefit for N+ patients [Δ6.3% vs. Δ20.6%]), and in patients with PD-L1 positive or negative tumours. In general, obtaining a pCR is predictive of better outcome, regardless of the addition of pembrolizumab. EFS in patients with pCR after pembrolizumab is better than in patients with pCR without pembrolizumab (HR: 0.73). However, also in patients with residual disease, EFS is better with pembrolizumab than without (HR: 0.70). At this early time point, pembrolizumab demonstrated a favourable trend in OS but further follow-up is ongoing.
No new safety signals were identified and adverse events were consistent with the known safety profiles. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 77.1% of patients in the pembrolizumab group and in 73.3% of patients in the placebo group. Treatment-related deaths were reported in 0.5% and 0.3% of patients, respectively. Immune-mediated AEs of any grade occurred in 43.6% and 21.9% of patients in the pembrolizumab and chemotherapy arms, respectively. Immune-mediated AEs mostly occurred during the neoadjuvant phase with a very low incidence during the adjuvant phase.
Keynote-522 met its dual primary endpoints. Neoadjuvant pembrolizumab plus chemotherapy resulted in a statistically significant and clinically meaningful increase in pCR. In addition, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in EFS. At this early time point, there was a favourable trend for OS in the pembrolizumab group, further follow-up is ongoing. Safety was consistent with the known profiles of each regimen, with no new safety concerns.
Schmid P, Cortes J, Dent R, et al. KEYNOTE-522: Phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early stage TNBC. Presented at ESMO 2021; Abstract VP7_2021.