Pembrolizumab added to chemotherapy increases pCR in triple-negative breast cancer
A phase III randomized placebo-controlled trial has shown a higher rate of pathological complete response (pCR) among patients with previously untreated stage II/III triple-negative breast cancer who received pembrolizumab and chemotherapy vs chemotherapy alone.
“At the first interim analysis … the pCR rate was 64.8 percent in the pembrolizumab-chemotherapy group and 51.2 percent in the placebo-chemotherapy group [estimated treatment difference, 13.6 percentage points; 95 percent confidence interval (CI), 5.4 to 21.8; p<0.001],” reported the investigators of the KEYNOTE-522 study. [N Engl J Med 2020;382:810-821]
At 18 months, the Kaplan-Meier estimate of the percentage of patients alive without disease progression that precluded definitive surgery, without local or distant recurrence, and without a second primary tumour was 91.3 percent in the pembrolizumab-chemotherapy group vs 85.3 percent in the placebo-chemotherapy group.
“The hazard ratio [HR] for disease progression precluding definitive surgery, local or distant recurrence or a second primary tumour, or death from any cause favoured the pembrolizumab-chemotherapy group [HR, 0.63; 95 percent CI, 0.43 to 0.93],” wrote the investigators.
The pCR benefits of pembrolizumab-chemotherapy were consistent across PD-L1–expression subgroups. In the PD-L1–positive population, the pCR rate was 68.9 percent in the pembrolizumab-chemotherapy arm vs 54.9 percent among placebo-chemotherapy recipients, while in the PD-L1–negative population, the rates were 45.3 percent and 30.3 percent, respectively.
“These findings differ from the results of the IMpassion130 trial, which showed efficacy of a PD-L1 inhibitor only in patients with PD-L1–positive metastatic triple-negative breast cancer,” noted the investigators. [N Engl J Med 2018;379:2108-2121] “The inconsistent results may be related to the different drugs or inhibition pathways, disease stages [early vs late], PD-L1 assays, or all of these factors.”
While generally consistent across the key analyzed subgroups, pembrolizumab’s pCR benefit was not observed among patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 1 (pCR rate, 61.6 percent in pembrolizumab-chemotherapy arm vs 64.3 percent in placebo-chemotherapy arm). Among patients with an ECOG of 0, pCR rates were 65.5 percent and 49.1 percent, respectively.
Patients in the KEYNOTE-522 study were randomized 2:1 to receive neoadjuvant therapy with four intravenous cycles of pembrolizumab 200 mg (784 patients) or placebo (390 patients) every 3 weeks plus paclitaxel and carboplatin, followed by a second neoadjuvant treatment consisting of four cycles of pembrolizumab or placebo plus doxorubicin or epirubicin plus cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles.
Serious treatment-related adverse events (TRAEs) occurred in 32.5 percent of patients treated with pembrolizumab-chemotherapy vs 19.5 percent of patients in the placebo-chemotherapy group, with febrile neutropenia (14.6 percent vs 12.1 percent), anemia (2.6 percent vs 2.1 percent), and pyrexia (2.6 percent vs 0.3 percent) being the most common. The addition of pembrolizumab did not increase chemotherapy-related toxic effects such as myelosuppression, nausea and vomiting, renal insufficiency, and neuropathy.
“[Although] most TRAEs and adverse events of interest occurred during the neoadjuvant phase, the higher incidence of serious TRAEs [in the pembrolizumab arm] did not hamper the ability to administer neoadjuvant chemotherapy, which is important, since administration of fewer doses of neoadjuvant chemotherapy than planned is associated with worse long-term outcomes,” commented the investigators. [J Clin Oncol 2019;37(Suppl):abstract 591]
Overall, TRAEs led to discontinuation of any trial drug in 23.3 percent of patients in the pembrolizumab-chemotherapy group vs 12.3 percent in the placebo-chemotherapy group.