Neoadjuvant pembrolizumab in combination with chemotherapy followed by adjuvant pembrolizumab monotherapy resulted in a significant improvement in event-free survival and pathologic complete response vs neoadjuvant chemotherapy alone in patients with high-risk, early-stage triple-negative breast cancer.
Neoadjuvant pembrolizumab (Keytruda) in combination with chemotherapy followed by adjuvant pembrolizumab monotherapy resulted in a significant improvement in event-free survival (EFS) and pathologic complete response (pCR) vs neoadjuvant chemotherapy alone in patients with high-risk, early-stage triple-negative breast cancer (TNBC), meeting the dual primary end points of the phase 3 KEYNOTE-522 trial (NCT03036488).1
The toxicity profile of the PD-1 therapy was found to be consistent with what has been previously reported with the agent, with no new signals observed.
“[Pembrolizumab] is the first immunotherapy to show positive results for EFS in patients with high-risk early-stage TNBC, a particularly aggressive form of breast cancer,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, as well as chief medical officer of Merck Research Laboratories, stated in a press release. “The improvement in pCR rates initially observed following preoperative treatment was encouraging, and now that we are seeing the data mature after 4 years to include a statistically significant improvement in EFS, we look forward to working with the FDA and other global authorities to bring this new option to patients as quickly as possible.”
Earlier data from KEYNOTE-522 presented during the ESMO Congress 2019 showed that neoadjuvant treatment with pembrolizumab plus chemotherapy extended pCR rates by 13.6 percentage points (CI, 5.4-21.8) vs chemotherapy alone in patients with TNBC.2 In the pembrolizumab/chemotherapy arm, the pCR rate was 64.8% vs 51.2% in the chemotherapy-alone arm (P = .00055).
Notably, the benefit with the PD-1 inhibitor proved to be consistent, irrespective of pCR definition. Using the ypT0 ypN0 definition, the pCR rates in the investigative and control arms were 59.9% and 45.3%, respectively. By the ypT0/Tis definition, the pCR rates with pembrolizumab/chemotherapy and chemotherapy alone were 68.6% and 53.7%, respectively.
Following neoadjuvant treatment, patients on the pembrolizumab arm went on to receive adjuvant single-agent pembrolizumab, which was compared with a matched placebo arm. At a median of 15.2 months of follow-up, pembrolizumab resulted in an EFS rate of 91.3% vs 85.3% with placebo. At the time, the benefit was not determined to be of statistical significance (HR, 0.63; 95% CI, 0.43-0.93).
In the trial, patients with TNBC were randomized 2:1 to receive pembrolizumab at a dose of 200 mg every 3 weeks (n = 784) or placebo (n = 390). All participants were given 4 cycles of carboplatin plus paclitaxel, which was followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide. After surgery, adjuvant pembrolizumab was given for 9 cycles or until disease recurrence or intolerable toxicity.
The dual primary end points of the trial were EFS and pCR, and pCR was defined as ypT0/Tis or ypN0.
Patients with node-negative and -positive disease were permitted to enroll to the trial. Tumor stage ranged from T1c N1/N2 to T2 to T4 and N0 to N2, per American Joint Committee on Cancer criteria. Study participants had an ECOG performance status of either 0 or 1, and they were evenly stratified between the arms based on nodal status, tumor size, and carboplatin schedule (weekly vs every 3 weeks).
Additional data from the trial showed that in the PD-L1–positive group who had a combined positive score of 1 or greater (n = 498), the pCR rate in the investigational arm was 68.9% vs 54.9% in the control arm; this translated to 14.2-increase in percentage points (CI, 5.3-23.1). In the PD-L1–negative subgroup (n = 97), the pCR rates in the investigational and control arms were 45.3% and 30.3%, respectively; this was an 18.3 percentage point increase (CI, 3.3-36.8).
Regarding safety, at least 1 treatment-related toxicity was reported by patients in both treatment arms during the neoadjuvant phase of treatment. Treatment-related adverse effects (TRAEs) that were grade 3 to 5 in severity were reported at similar frequencies between the 2 arms; these rates were 76.8% and 72.2% in the pembrolizumab and placebo arms, respectively. Moreover, 24.5% of those in the investigative arm discontinued treatment due to toxicity vs 13.1% of those in the control arm.
The most frequently reported TRAEs in the pembrolizumab and placebo arms during the neoadjuvant phase of the trial included nausea (62.7% vs 63.2%, respectively), alopecia (60.3% vs 56.6%), anemia (55.1% vs 55.3%), neutropenia (46.7% vs 47.0%), fatigue (41.1% vs 37.8%), diarrhea (29.4% vs 23.7%), alanine aminotransferase increase (25.5% vs 24.7%), vomiting (25.5% vs 21.9%), asthenia (24.5% vs 25.4%), constipation (23.7% vs 21.1%), decreased neutrophil count (23.7% vs 28.8%), rash (21.8% vs 15.2%), and peripheral neuropathy (19.7% vs 21.1%).
In the adjuvant phase of treatment, less TRAEs were reported. Specifically, 5.7% of those on the investigative arm experienced TRAEs that were grade 3 to 5 vs 1.9% of those on the control arm. The most frequently reported TRAEs comprised arthralgia (7.9% in investigative arm vs 6.7% in control arm), rash (4.9% vs 2.2%, respectively), and pruritus (4.2% vs 2.2%).
In March 2021, the FDA issued a complete response letter (CRL) to Merck stating that the regulatory decision for the supplemental biologics license application seeking approval for pembrolizumab for use in patients with high-risk, early-stage TNBC plus chemotherapy as neoadjuvant treatment, then continuing as a single agent as adjuvant therapy following surgery, should be deferred.3
The CRL followed a 10 to 0 vote by the Oncologic Drug Advisory Committee that was in favor of deferring review until further findings from KEYNOTE-522 became available.