FDA Approvals Sought for 2 Pembrolizumab Indications in TNBC

In Clinical Studies News by Barbara Jacoby

By: Kristi Rosa

From: onclive.com

The FDA has accepted 2 supplemental biologics applications (sBLAs) for pembrolizumab (Keytruda) in patients with triple-negative breast cancer (TNBC); these are the first US applications for the anti–PD-1 therapy in breast cancer, according to an announcement from Merck, the drug developer.1

Specifically, the regulatory agency has accepted and granted priority review to a new sBLA seeking accelerated approval for pembrolizumab in combination with chemotherapy for use in patients with locally recurrent or metastatic TNBC whose tumors express PD-L1 at a combined positive score (CPS) of 10 or higher. Under the Prescription Drug User Fee Act (PDUFA), the FDA is scheduled to make a decision on the sBLA by November 28, 2020.

Additionally, the FDA has accepted another sBLA for standard review for pembrolizumab in combination with chemotherapy as neoadjuvant treatment in patients with high-risk, early-stage TNBC, and then as single-agent adjuvant treatment following surgery. Under the PDUFA, the agency must make a decision on the application by March 29, 2021.

“There is a real need to advance new treatment options for TNBC, an aggressive form of the disease. The FDA’s acceptance of these Keytruda applications for review is an important step toward helping patients with both early-stage and metastatic disease,” Roy Barnes, MD, PhD, senior vice president and head of global clinical development and chief medical officer of Merck Research Laboratories, stated in a press release. “These acceptances mark the first US applications for Keytruda in breast cancer, and we look forward to working closely with the FDA to bring these new options to patients as quickly as possible.”

The applications are based on findings from the pivotal phase 3 KEYNOTE-355 (NCT02819518) and KEYNOTE-522 trials (NCT03036488), respectively.

In KEYNOTE-355, pembrolizumab in combination with various chemotherapy partners resulted in a statistically significant and clinically meaningful improvement in progression-free survival (PFS) versus chemotherapy alone in the frontline treatment of patients with locally recurrent, inoperable, or metastatic disease whose tumors a PD-L1 CPS of 10 or higher.2

Results presented during the 2020 ASCO Virtual Scientific Program showed that at a median follow-up of 26.1 months, treatment with the combination led to a median PFS of 9.7 months versus 5.6 months with chemotherapy alone in this patient population; this translated to a 35% reduction in the risk of disease progression or death(HR, 0.65; 95% CI, 0.49-0.86; one-sided P = .0012).

In patients with tumors that expressed a PD-L1 CPS of 1 or higher, the median PFS was 7.6 months with the pembrolizumab combination versus 5.6 months with chemotherapy by itself (HR, 0.74; 0.61-0.90; P = .0014); however, this benefit did not reach statistical significance.

Moreover, in the intent-to-treat (ITT) population, the addition of the anti–PD-1 therapy led to a median PFS of 7.5 months versus 5.6 months with chemotherapy alone, which translated to a 18% reduction in the risk of disease progression or death (HR, 0.82; 95% CI, 0.69-0.97). This population was not evaluated for statistical significance.

In the 2-part, randomized, phase 3 trial, pembrolizumab was evaluated in combination with investigator’s choice of nab-paclitaxel (Abraxane), paclitaxel, or gemcitabine/carboplatin versus placebo plus 1 of the 3 chemotherapy partners in previously untreated patients with locally recurrent inoperable or metastatic disease.

In the first portion of the trial, investigators examined the safety and tolerability of the PD-1 inhibitor in combination with 1 of the chemotherapy partners in a total of 30 patients. In the second portion, a total of 847 patients were randomized 2:1 to either placebo (n = 281) or pembrolizumab (n = 566) given at 200 mg intravenously (IV) on the first day of each 21-day cycle in combination with either IV nab-paclitaxel at 100 mg/m2 on days 1, 8, and 15 of each 28-day cycle; paclitaxel at 90 mg/m2 on days 1, 8, and 15 of each 28-day cycle; or 1000 mg/m2 of gemcitabine and area under the curve (AUC) or carboplatin on days 1 and 8 of each 21-day cycle. Patients continued on therapy until progressive disease or cessation of treatment.

The co-primary end points of the trial included PFS and overall survival (OS) in patients whose tumors had PD-L1 positivity as well as in the ITT population. Key secondary end points were comprised of objective response rate, duration of response, disease control rate, and safety.

With regard to safety, all-grade adverse effects (AEs) reported between the arms were comparable; rates of grade 3 to 5 AEs were 68.1% in the pembrolizumab arm versus 66.9% in the placebo arm. Two treatment-related AEs (TRAEs) on the pembrolizumab arm resulted in death versus no deaths on the control arm. Additionally, more patients on the investigational arm discontinued treatment compared with the control arm, at 18.1% versus 11.0%, respectively.

All-grade TRAES were reported in at least 20% of patients in either the pembrolizumab or placebo arms; these events included anemia (48.9% vs 45.9%, respectively), neutropenia (41.1% vs 38.1%), nausea (39.3% vs 40.9%), alopecia (33.1% vs 33.5%), fatigue (28.5% vs 29.5%), reduced neutrophil count (22.2% vs 26.3%) and increased alanine aminotransferase levels (20.5% vs 16.4%).

The trial will continue without changes to examine the co-primary end point of OS, according to Merck.

The KEYNOTE-522 trial was the first randomized trial to examine a PD-1 inhibitor in the neoadjuvant/adjuvant setting for TNBC. Results from this trial, published in the New England Journal of Medicine, showed that pembrolizumab plus neoadjuvant chemotherapy resulted in a higher percentage of patients achieving a pathologic complete response (pCR) compared with those who received placebo plus neoadjuvant chemotherapy.3

Results from the first interim analysis showed that in the first 602 patients who underwent randomization, 64.8% achieved a pCR on the pembrolizumab/chemotherapy arm (95% CI, 59.9-69.5) versus 51.2% (95% CI, 44.1-58.3) on the placebo/chemotherapy arm (95% CI, 5.4-21.8; P <.001).

At a median follow-up of 15.5 months, 7.4% of patients on the investigative arm versus 11.8% of those on the control arm experienced disease progression that precluded definitive surgery, local or distant recurrence or a second primary tumor, or died from any cause (HR, 0.63; 95% CI, 0.43-0.93).

In the phase 3 trial, treatment-naïve patients with stage II or stage III TNBC were randomly assigned in a 2:1 ratio to receive neoadjuvant treatment with 4 cycles of pembrolizumab at a dose of 200 mg every 3 weeks plus paclitaxel and carboplatin (n = 784) or placebo every 3 weeks plus paclitaxel and carboplatin (n = 390). Both groups were then given doxorubicin/cyclophosphamide or epirubicin/cyclophosphamide. Following definitive surgery, participants were then administered adjuvant treatment with either pembrolizumab or placebo every 3 weeks for up to 9 cycles.

The primary end points of the trial included pCR at the time of definitive surgery and event-free survival in the ITT population.

Regarding safety, the incidence of grade 3 or higher TRAEs, across all treatment phases, was 78.0% in the pembrolizumab/chemotherapy group versus 73.0% in the placebo/chemotherapy group; 3 patients versus 1 patient died, respectively.

Previously, in October 2019, pembrolizumab was granted a breakthrough therapy designation for use as a neoadjuvant treatment in patients with high-risk, early-stage TNBC, based on findings from the KEYNOTE-173 trial. Results from the trial showed that the PD-1 inhibitor elicited a pCR rate of 60%.4


  1. Merck announces two US regulatory milestones for Keytruda (pembrolizumab) in triple-negative breast cancer (TNBC). News release. Merck. July 30, 2020. Accessed July 30, 2020. https://bit.ly/30Zolvv.
  2. Cortes J, Cescon DW, Rugo HS. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol. 2020;38(suppl 15; abstr 1000). doi:10.1200/JCO.2020.38.15_suppl.1000
  3. 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
  4. Schmid P, Salgado R, Park YH. Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study. Ann Oncol. 2020;31(5):569-581. doi:10.1016/j.annonc.2020.01.072