FDA Approves Neoadjuvant Pembrolizumab Combination for Early TNBC Indication

Based on results of the KEYNOTE-522 trial, the FDA approved pembrolizumab, the first immunotherapy for this indication, plus chemotherapy as neoadjuvant treatment for patients with early-stage triple-negative breast cancer.

The FDA granted approval to the supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) as neoadjuvant therapy for patients with high-risk early-stage triple-negative breast cancer (TNBC) when given in combination with chemotherapy followed by single-agent use after surgery, according to the company responsible for the PD-1 inhibitor, Merck.1

This decision by the FDA was supported by data from the phase 3 KEYNOTE-522 trial (NCT03036488) which examined the neoadjuvant regimen in the indicated patient population versus matched placebo and demonstrated a statistically significant event-free survival (EFS) benefit (HR, 0.63; 95% CI, 0.48-0.82; P = .00031) with active versus control therapy.

“Even when TNBC is diagnosed early, 30% to 40% of patients will suffer cancer recurrence after standard neoadjuvant chemotherapy and surgery,” Joyce O’Shaughnessy, MD, chair of Breast Cancer Research at Baylor University Medical Center of Texas Oncology, U.S. Oncology in Dallas, Texas, said in a press release. “Therefore, there is a high unmet need for new treatment options. Today’s approval is very welcome news and has the potential to change the treatment paradigm by now including an immunotherapy as part of the regimen for patients with high-risk early-stage TNBC.”

The original sBLA for this indication was accepted by the FDA in July 2020 with a prescription drug user fee act date set for March 2021.2 However, the agency decided to defer a decision regarding approval until data regarding EFS, one of 2 dual primary end points, were more mature.3 At that time, the other primary end point of pathologic complete response (pCR) had shown a statistically significant benefit of using pembrolizumab versus the control arm, with pCR rates of 64.8% versus 51.2%, respectively (HR, 0.63; 95% CI, 0.43-0.93).

At the median follow-up of 39 months, EFS data were made available showing that pembrolizumab produced a statistically significant EFS benefit compared with chemotherapy alone. For patients who were in the PD-L1–positive group, defined as those with a combined positive score of 1 or higher, there was a 33% reduced risk of EFS events with pembrolizumab compared with the placebo group (HR, 0.67; 95% CI, 0.49-0.92). In the PD-L1–negative group, patients receiving the pembrolizumab regimen had a reduced risk for EFS events by 52% compared with the placebo-chemotherapy group (HR, 0.48; 95% CI, 0.28-0.85).

Additionally, the accelerated approval of pembrolizumab plus chemotherapy for patients with locally advanced unresectable or metastatic PD-L1–positive TNBC was converted to regular approval based on confirmatory data in KEYNOTE-522. The data originally supporting this approval were from the double-blind, randomized, placebo-controlled phase 3 KEYNOTE-355 trial (NCT02819518).4 According to Merck, KEYNOTE-355 recently demonstrated that first-line treatment with pembrolizumab in combination with chemotherapy results in a statistically significant and clinically meaningful improvement in overall survival compared with chemotherapy alone in patients with metastatic TNBC whose tumors expressed PD-L1.5

“Triple-negative is a difficult-to-treat type of breast cancer that unfortunately is more common in the US in younger women and in Black women,” Vicki Goodman, MD, vice president of clinical research at Merck Research Laboratories, said in a press release. “We are proud to offer a new treatment option for patients faced with this challenging cancer. This neoadjuvant and adjuvant combination with Keytruda is the first immunotherapy regimen to be approved in high-risk early-stage TNBC, marking a meaningful milestone for the breast cancer community.”

In the KEYNOTE-522 trial, patients received pembrolizumab 200 mg every 3 weeks plus carboplatin and paclitaxel for 4 cycles followed by 4 additional cycles of preoperative pembrolizumab in combination with either doxorubicin or epirubicin plus cyclophosphamide every 3 weeks. After surgery, 9 cycles of pembrolizumab were administered every 3 weeks.


1. FDA Approves KEYTRUDA (pembrolizumab) for Treatment of Patients With High-Risk Early-Stage Triple-Negative Breast Cancer in Combination With Chemotherapy as Neoadjuvant Treatment, Then Continued as Single Agent as Adjuvant Treatment After Surgery. News release. Merck. Published July 27, 2021. Accessed July 27, 2021. https://bit.ly/2Vc0rgX

2. Merck Announces Two US Regulatory Milestones for KEYTRUDA (pembrolizumab) in Triple-Negative Breast Cancer (TNBC). News release. Merck. Published July 30, 2020. Accessed July 27, 2021. https://bwnews.pr/3f0tH1j

3. 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 July 27, 2021. https://bit.ly/2QT45dx

4. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. News release. FDA. Published November 13, 2020. Accessed July 27, 2021. https://bit.ly/3zxmBt0

5. Merck Announces Phase 3 KEYNOTE-355 Trial Met Primary Endpoint of Overall Survival (OS) in Patients with Metastatic Triple-Negative Breast Cancer Whose Tumors Expressed PD-L1 (CPS ≥10). News release. Merck. Published July 27, 2021. Accessed July 27, 2021. https://bit.ly/3i5yb8E

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