FDA CRL Issued to Pembrolizumab Developer for Early-Stage TNBC Application

The FDA has issued a complete response letter (CRL) to Merck’s supplemental Biologics License Application (BLA) which sought FDA approval of pembrolizumab (Keytruda) for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, then as a single agent as adjuvant treatment due to a need to more data, announced Merck, in a press release.¹

The FDA followed guidance from the Oncologic Drug Advisory Committee, which during a vote held on February 9, 2021, voted unanimously not move forward with the pembrolizumab BLA. Merck submitted the application based on early interim event-free survival (EFS) findings from the phase 3 KEYNOTE-522 (NCT03036488). The study is ongoing, and the next interim analysis is expected in the third quarter of 2021.

The KEYNOTE-522 trial evaluates the safety and efficacy of pembrolizumab plus chemotherapy versus placebo plus chemotherapy as neoadjuvant therapy. It will also evaluate pembrolizumab versus a placebo as adjuvant therapy in patients with TNBC. It has an actual enrollment of 1174 participants. Primary outcomes include pathological complete response rate (pCR) and event-free survival (EFS). Secondary outcomes include overall survival (OS), percentage of patients who experience adverse events (AE), and the percentage of patients who discontinue treatment due to AE’s.²

Patients were randomized into one of two arms. In the experimental arm, participants received pembrolizumab every 3 weeks plus chemotherapy for 4 21-day cycles prior to surgery. Patients will then receive pembrolizumab for 9 cycles post-surgery. In arm two, patients will follow the same regiment except for the fact that pembrolizumab will be replaced by a placebo.

At the first interim-analysis, 602 patients underwent randomization. In the pembrolizumab plus chemotherapy group, the pCR was 64.8% (95% confidence interval [CI], 59.9 to 69.5) and 51.2% (95% CI, 44.1 to 58.3) for the placebo plus chemotherapy. At the median follow-up of 15.5 months, 7.4% of patients in the experimental group had disease progression that precluded definitive surgery, had local or distant recurrence or a secondary tumor, or died from any cause while 11.8% of those in the placebo group did (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). In the pembrolizumab group, the rate of grade 3 or higher AE’s was 78% and 73% in the placebo group.

In order to participate, patients must be 18 years old or older, has newly diagnosed, locally advanced, and centrally confirmed TNBC or has previously untreated locally advanced non-metastatic TNCB. The patient must also demonstrate adequate organ function. Patients who have a history of an invasive malignancy less than 5 years prior to singing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer an ineligible. Additionally, patient who have received prior chemotherapy, targeted therapy, and radiation therapy within the past 12 months cannot participate.

Merck is currently reviewing the FDA’s CRL and will work with them regarding next steps. The FDA’s decision does not impact any of the current indications for pembrolizumab. This includes the indication with it in combination with chemotherapy for patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1.

Pembrolizumab has been approved across a number of cancer types, including melanoma, non-small cell lung cancer, small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, primary mediastinal Large B-Cell Lymphoma, urothelial carcinoma, and others. It has been approved both as a combination and a monotherapy.³

_REFERENCE:

_{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/2Pjc57c}

_{2.Schmid, P., Carotes, J., Pusztai, L., et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020; 382(9):810-821 February 27, 2020 Accessed March 30, 2021. DOI: 10.1056/NEJMoa1910549}

_{3.Highlights of prescribing information. Merck .Accessed March 30, 2021 https://bit.ly/3sOdD7u.}