Adding pembrolizumab to platinum-based neoadjuvant chemotherapy leads to an increase in the pathological response rate in early triple negative breast cancer

Results of the phase III Keynote-522 trial demonstrate that the addition of the PD-1 inhibitor pembrolizumab to neoadjuvant chemotherapy results in a significant improvement in the pathological complete response rate (pCR) in patients with early-stage triple negative breast cancer. This is the first study evaluating an immune checkpoint inhibitor in this type of early stage breast cancer. The results indicate that this higher pCR rate with the pembrolizumab-containing treatment regimen translates into fewer recurrences. Surprisingly, PD-L1 expression had a poor predictive value in this trial, as the effect of adding pembrolizumab to neoadjuvant chemotherapy was seen irrespective of PD-L1 expression.

Background

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and predominantly affects young women. Patients typically receive chemotherapy, followed by surgery to remove the tumor. This provides women the best chance of achieving a pCR. If women obtain a pCR, they have a 85-90% likelihood of being cured. Patients with residual viable tumor tissue, however, face a 40-50% probability of recurrence, which often occurs within three years. Based on these findings, regulatory authorities support the use of pCR as an endpoint for accelerated approval of neoadjuvant treatment in early TNBC.

Last year, results of the phase III IMpassion-123 trial demonstrated that atezolizumab plus nab-paclitaxel prolonged the progression-free survival (PFS) in patients with metastatic TNBC. Furthermore, pembrolizumab showed promising activity in the treatment of metastatic TNBC, especially in the first-line setting. These findings formed the basis to also evaluate immune checkpoint inhibition in earlier TNBC disease stages. In this setting, neoadjuvant pembrolizumab + chemotherapy showed manageable safety and antitumor activity. Based on the results of the phase I KEYNOTE-173 and the phase II I-SPY2 trials, pembrolizumab plus chemotherapy was granted a breakthrough therapy designation by the FDA for the neoadjuvant treatment of patients with high-risk, early-stage TNBC.

In KEYNOTE-522, adult patients with newly diagnosed TNBC (T1c N1-2 or T2-4 N0-2) and an ECOG performance status of 0 or 1 were randomly assigned (2:1) to receive neoadjuvant chemotherapy (carboplatin + paclitaxel in cycles 1-4, doxorubicin/epirubicin + cyclophosphamide in cycles 5-8) in combination with pembrolizumab or placebo followed by surgery and maintenance therapy with either pembrolizumab (200 mg q3w for 9 cycles), or placebo. The co-primary endpoints of this trial were pCR rate and event free survival (EFS).

Results

In total, 1174 patients were randomized in the trial of which 1.3% and 2.3% discontinued the neoadjuvant treatment due to progression in the experimental arm and the control arm, respectively. In the pembrolizumab arm, 69.8% of patients started adjuvant therapy, while this was 80.5% in the control arm. The median age of patients in the trial was 49 years, about 13% had an ECOG performance status of 1 and 83% had PD-L1 positive disease. Three quarters of patients had T1/T2 disease, with 51% having nodal involvement.

The analysis presented at the ESMO 2019 was performed after a median follow-up of 15.5 months. The pCR, assessed in the first 602 patients, significantly increased from 51.2% in the placebo group to 64.8% in the pembrolizumab group (p= 0.00055), representing a clinically meaningful 13.6% increase. Interestingly, this pCR benefit was seen irrespective of PD-L1 expression level. In PD-L1 positive patients, the pCR rate was 68.9% with pembrolizumab and chemotherapy as compared to 54.9% with chemotherapy alone. In PD-L1 negative patients, the pCR rates were lower, but in that population as well, the addition of pembrolizumab to neoadjuvant chemotherapy led to a significant increase in pCR from 30.3% to 45.3%.

Given the fact that recurrences in TNBC often occur early on, the investigators conducted an interim analysis of the EFS at this early time point. Also with respect to this endpoint the outcome was positive, with a favorable trend for the pembrolizumab-treated patients with a hazard ratio of 0.63 (95% CI: 0.43–0.93). At 18 months, the predicted EFS rate with chemotherapie + pembrolizumab was 91.3% as compared to 85.3% with chemotherapy alone. These are very preliminary data, but provide a strong sign that the addition of immune therapy to neoadjuvant chemotherapy does prevent breast cancer recurrence.

The safety profile of the pembrolizumab-containing regimen was consistent with the known toxicity profile of each agent. Grade 3 or higher treatment-related adverse events in the pembrolizumab and placebo groups occurred in 78.0% and 73.0%, respectively. Side effects with a potential link to immune therapy occurred in 42% of study participants taking pembrolizumab as compared to 21% on placebo.

Conclusions

KEYNOTE-522 is the first prospective randomized placebo controlled phase III trial of pembrolizumab as a treatment for early TNBC in the neoadjuvant/adjuvant setting. The addition of pembrolizumab to platinum-containing neoadjuvant chemotherapy resulted in a statistically significant and clinically meaningful increase in pCR. This pCR benefit was consistently seen with pCR defined as ypT0 ypN0 and ypT0/Tis and was seen irrespective of PD-L1 expression. At this early time point, there was already a favorable trend for EFS in the pembrolizumab arm. Safety was consistent with the known profiles of each regimen.

Reference

Schmid P, Cortés J, Dent R, et al. KEYNOTE-522: Phase 3 study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC). Presented at ESMO 2019; Abstract LBA9_PR.