FDA Defers Decision on Pembrolizumab for TNBC: Here's Why


Ahead of the Prescription Drug User Fee Act action date for the application, the regulatory agency’s Oncologic Drugs Advisory Committee voted 10 to 0 that a decision be deferred until further findings from KEYNOTE-522 trial become available.

The FDA has issued a complete response letter (CRL) to Merck stating that regulatory decision for the supplemental biologics license application (BLA) seeking approval for pembrolizumab (Keytruda) for use in patients with high-risk, early-stage triple-negative breast cancer (TNBC) plus chemotherapy as neoadjuvant treatment, then continuing as a single agent as adjuvant treatment following surgery, should be deferred.1

The BLA is based on data from the phase 3 KEYNOTE-522 trial (NCT03036488), which showed that the pathologic complete response (pCR) rate was 64.8% (95% CI, 59.9%-69.5%) with pembrolizumab/chemotherapy vs 51.2% (95% CI, 44.1%-58.3%) with placebo/chemotherapy; this translated to an estimated treatment difference of 13.6 percentage points (95% CI, 5.4-21.8; P <.001).2

Ahead of the Prescription Drug User Fee Act action date for the application, the regulatory agency’s Oncologic Drugs Advisory Committee voted 10 to 0 that a decision be deferred until further findings from KEYNOTE-522 trial become available. The next interim analysis from the trial is expected to occur in the third quarter of 2021.

Notably, the CRL does not impact any currently approved indications for the PD-1 inhibitor, such as its indication for use with chemotherapy in patients with locally recurrent unresectable or metastatic TNBC whose tumors have PD-L1 positivity.

In KEYNOTE-522, investigators set out to examine the safety and efficacy of neoadjuvant pembrolizumab plus chemotherapy vs neoadjuvant placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo in patients with TNBC.

To be eligible for enrollment, patients needed to be at least 18 years of age and have centrally confirmed TNBC; have newly diagnosed, previously untreated, nonmetastatic disease; an ECOG performance status of 0 or 1; and acceptable organ function. Notably, patients who had bilateral multifocal primary tumors and inflammatory breast cancers were permitted for inclusion.

If patients had autoimmune disease for which they received systemic treatment within the prior 2 years, a diagnosis of immunodeficiency or use of immunosuppressive therapy within the prior week, or a history of human immunodeficiency virus infection, they were excluded. Additional exclusion criteria included having a history of noninfectious pneumonitis for which the patient received glucocorticoids, current pneumonitis, active tuberculosis, active hepatitis B or C virus, or any active infection for which they are receiving systemic treatment, or clinically significant cardiovascular disease.

In the trial, a total of 1174 participants were randomized 2:1 to receive either pembrolizumab (n = 784) or placebo (n = 390). In the neoadjuvant phase of the trial, patients were given 4 cycles of an intravenous infusion of pembrolizumab at 200 mg or placebo once every 3 weeks plus paclitaxel at 80 mg/m2 and carboplatin at area under the curve of 5 mg/mL/min once every 3 weeks or 1.5 mg/mL/min once weekly within the first 12 weeks. This was followed by 4 cycles of pembrolizumab or placebo plus doxorubicin at 60 mg/m2 or epirubicin at 90 mg/m2 plus cyclophosphamide at 600 mg/m2 once every 3 weeks in the subsequent 12 weeks.

The co-primary end points of the trial were pCR and event-free survival (EFS) in the intent-to-treat population, while key secondary end points comprised pCR in all patients, pCR per all definitions in all patients with PD-L1–positive tumors, and EFS among those with PD-L1 positivity.

The median age of patients was 48.5 years, 56.3% of patients were postmenopausal, 82.5% had PD-L1–positive tumors, and 87.0% had an ECOG performance status of 0. About 80% of patients across the arms had a lactase dehydrogenase level less than the upper limit of normal, 57.3% received carboplatin on a weekly basis, and the majority of patients had a primary tumor classification of T1 to T2. Moreover, 51.5% had nodal involvement, 75.0% had stage II disease, and 74.6% had a HER2 status score of 0 to 1.

Additional results from the interim analysis of the trial indicated that the pCR benefit observed with pembrolizumab plus chemotherapy were generally consistent across subgroups analyzed, including those with PD-L1 expression. The percentage of PD-L1–positive patients with a pCR was 68.9% (n = 230/334) among those on the investigative arm vs 54.9% (n = 90/164) of those on the control arm; among those with PD-L1–negative tumors, these rates were 45.3% and 30.3%, respectively.

Moreover, Kaplan–Meier estimates of the percentage of patients at 18 months who were alive without disease progression that precluded definitive surgery, without local or distant recurrence, and without a second primary tumor was 91.3% (95% CI, 88.8%-93.3%) in the investigative arm vs 85.3% (95% CI, 80.3%-89.1%) in the control arm; the median had not yet been reached in either treatment arm. The hazard ratio for disease progression, local or distant recurrence or a second primary tumor, or death from any cause favored the pembrolizumab/chemotherapy arm (HR, 0.63; 95% CI, 0.43-0.93).

Regarding safety, in the neoadjuvant phase of the trial, any-grade adverse effects (AEs) determined to be associated with trial treatment by investigators were reported in 99.0% and 99.7% of those in the investigative and control arms, respectively. Treatment-related AEs (TRAEs) that were grade 3 or higher in severity were experienced by 76.8% of those who received pembrolizumab/chemotherapy vs 72.2% of those given placebo/chemotherapy.

Serious TRAEs were experienced by 32.5% and 19.5% of patients in the investigative and control arms, respectively. The most frequently reported serious TRAEs comprised febrile neutropenia (14.6% vs 12.1%, respectively), anemia (2.6% vs 2.1%), and pyrexia (2.6% vs 0.3%).

Toxicities of interest were reported in 38.9% and 18.3% in the pembrolizumab/chemotherapy and placebo/chemotherapy arms, respectively; these effects were grade 3 or higher in 12.9% and 1.8%, respectively. Specifically, 3.8% of patients in the investigative arm experienced severe skin reactions, 2.6% had infusion reactions, and 1.3% had adrenal insufficiency.

Moreover, 23.3% of those in the investigative arm experienced TRAEs that led to discontinuation vs 12.3% of those in the control arm. The majority of TRAEs were and AEs of interest were experienced in the neoadjuvant phase of the trial.

In the adjuvant phase, TRAEs were experienced in 48.1% and 43.0% of those in the investigative and control arms, respectively.


  1. Merck receives complete response letter from US FDA for supplemental biologics license application (sBLA) for KEYTRUDA (pembrolizumab) in high-risk early-stage triple-negative breast cancer (TNBC). News release. Merck. March 29, 2021. Accessed March 29, 2021. https://bwnews.pr/2PlIppT
  2. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549

This article was originally published on OncLive as, "FDA Issues Complete Response Letter for Neoadjuvant Pembrolizumab for High-Risk TNBC."

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