FDA Issues Complete Response Letter for Pembrolizumab as Neoadjuvant Therapy in Early TNBC


The FDA’s Oncologic Drugs Advisory Committee voted in favor of waiting for additional event-free survival data to become available before making a regulatory decision regarding a biologics license application for pembrolizumab in early triple-negative breast cancer.

A complete response letter from the FDA has been issued to Merck, the company responsible for developing and manufacturing pembrolizumab (Keytruda), about a biologics license application for the PD-1 inhibitor as neoadjuvant treatment in combination with chemotherapy followed by adjuvant monotherapy for patients with high-risk early-stage triple-negative breast cancer (TNBC).1

The company is reviewing the letter so that the next steps can be reviewed in tandem with FDA guidance.

Notably, the response letter does not impact any current indications for pembrolizumab, which includes its use in combination with chemotherapy for patients with locally advanced unresectable metastatic TNBC with tumor expression PD-L1 with a combined positive score (CPS) of 10 or greater.

The application garnering a response letter was supported by results from the phase 3 KEYNOTE-522 trial (NCT03036488), in which pathological complete response (pCR) and event-free survival (EFS) data are dual primary end points. In the trial, pembrolizumab was evaluated in combination with chemotherapy compared with placebo plus chemotherapy as neoadjuvant therapy, followed by pembrolizumab monotherapy compared with placebo as adjuvant therapy in patients with TNBC.

The investigators enrolled 1174 patients to the study and randomized them 2:1 to either the experimental or control arms. Pembrolizumab was administered every 3 weeks plus paclitaxel weekly and carboplatin (weekly or every 3 weeks) for 4 cycles, followed by pembrolizumab plus cyclophosphamide every 3 weeks and either doxorubicin or epirubicin for 4 cycles as neoadjuvant therapy prior to surgery, followed by 9 cycles of pembrolizumab every 3 weeks as adjuvant therapy post-surgery. Those in the control arm received matching placebo and the same regimen of chemotherapy.

Patients in the experimental arm achieved pCR at a rate of 64.8% versus 51.2%, resulting in a statistically significant improvement with pembrolizumab (P <.001). Disease progression precluding definitive surgery, local or distant recurrence or a second primary tumor, or death from any cause occurred in 7.4% and 11.8% of patients, respectively (HR, 0.63; 95% CI, 0.43-0.93).2

Secondary end points include the pCR rate using alternative definitions of no invasive or noninvasive residual cancer in breast or nodes at the time of definitive surgery, overall survival, EFS in patients whose tumors express PD-L1 with a CPS of 1 or greater, safety, and patient-reported outcomes.

The trial continues to evaluate for EFS, which led the FDA’s Oncologic Drugs Advisory Committee to vote 10 to 0 in favor of deferring regulatory decision until more data are available. The next interim analysis will occur at the end of the third quarter of 2021. Originally, the FDA accepted this BLA in July 2020 and set a prescription drug user fee act (PDUFA) date of March 29, 2021.


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 30, 2021. https://bit.ly/2QT45dx

2. Schmid P, Cortes J, Pusztai L; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020;382(9):810-821. doi: 10.1056/NEJMoa1910549

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