Conclusion. The combination of neoadjuvant chemotherapy and pembrolizumab in patients with newly diagnosed, early-stage, triple-negative breast cancer yielded a higher percentage of patients achieving a pCR as compared with chemotherapy plus placebo.
Commentary
The current study adds to the growing body of literature outlining the efficacy of immune checkpoint inhibition in triple-negative breast cancer. The previously published IMpassion130 trial showed that the addition of the PD-L1 antibody atezolizumab to nab-paclitaxel improved progression-free survival in patients with PD-L1–positive (1% or greater), metastatic triple-negative breast cancer.1 Similarly, in the phase 2 I-SPY2 trial, the addition of pembrolizumab to standard neoadjuvant chemotherapy led to a near tripling of the pCR rates in triple-negative breast cancer.2 While the current study demonstrated improved pCR rates with pembrolizumab, no difference in EFS has yet been demonstrated; however, longer-term follow-up will be required. There certainly are numerous studies documenting an association between pCR and improved disease-free survival and possibly overall survival. Cortazar and colleagues performed a pooled analysis of 12 international trials, which demonstrated an association between pCR and improved EFS (hazard ratio [HR], 0.24) and overall survival (HR, 0.16) in patients with triple-negative breast cancer.3 The results of the current study will require longer-term follow-up to confirm such an association.
The current study appears to have demonstrated a benefit with the addition of pembrolizumab across treatment subgroups, particularly in the PD-L1–positive and PD-L1–negative populations. While this differs from the findings of the IMpassion130 trial, it is quite difficult to draw definitive conclusions because the 2 trials studied different antibodies, and thus used a different assay to define PD-L1 positivity. Notable differences exist in determination of PD-L1 status across assays, and it is important for providers to use the appropriate assay for each antibody. These differences highlight the need for more informative biomarkers to predict a benefit from immune checkpoint inhibition.
It is also noteworthy that the control arm in the current trial was a platinum-based regimen. Platinum-based neoadjuvant regimens previously have been shown to induce higher pCR rates in triple-negative breast cancer; however, the incorporation of carboplatin as standard of care remains a topic of debate.4 Nevertheless, a similar trial evaluating the efficacy of atezolizumab combined with platinum-based neoadjuvant chemotherapy in triple-negative breast cancer, NSABP B-59 (NCT03281954), is underway, with the control arm also incorporating carboplatin. The results of this study will also help validate the role of checkpoint inhibitors in the neoadjuvant setting in triple-negative breast cancer. Of note, this trial did not allow for the use of adjuvant capecitabine, which has been previously shown in the CREATE-X trial to prolong survival in this population.5 How the use of adjuvant capecitabine would impact these results is completely unknown.6 The incidence of grade 3 or higher toxicities in the current trial appeared to be similar in both groups. There did appear to be a higher incidence of infusion reactions and skin reactions in the pembrolizumab groups. Immune-related adverse events were consistent with prior pembrolizumab data.
Applications for Clinical Practice
KEYNOTE-522 adds to the growing evidence suggesting that incorporation of immune checkpoint inhibitors into neoadjuvant therapy in patients with triple-negative breast cancer can improve pCR rates; however, its use as a standard of care will require longer-term follow-up to ensure the noted findings translate into improvement in EFS and, ultimately, overall survival.
– Daniel Isaac, DO, MS