PD-1 Inhibitor Misses Primary OS Endpoint in Phase III Trial for Metastatic TNBC

Pembrolizumab monotherapy missed the prespecified primary endpoint of superior overall survival compared to chemotherapy in the phase III KEYNOTE-119 trial, in which the PD-1 inhibitor was being investigated as a second- or third-line treatment for patients with metastatic triple-negative breast cancer.

Roy Baynes, MD, PhD

Pembrolizumab (Keytruda) monotherapy missed the prespecified primary endpoint of superior overall survival (OS) compared to chemotherapy in the phase III KEYNOTE-119 trial, in which the PD-1 inhibitor was being investigated as a second- or third-line treatment for patients with metastatic triple-negative breast cancer (TNBC).1

As per study protocol, other endpoints were not formally tested because the primary endpoint was not met. The safety profile, however, of pembrolizumab was consistent with previous studies; no new safety signals were identified in this trial. The full findings will be presented at an upcoming medical meeting.

“Metastatic triple-negative breast cancer is an aggressive and challenging disease to treat, especially after progression on initial standard-of-care treatment,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “While we are disappointed by the outcome of this monotherapy trial, we are continuing to study Keytruda in earlier stages of the disease and in combination with chemotherapy to address the unmet medical need of patients with triple-negative breast cancer. We are grateful to the patients and investigators for their participation in this important study.”

In the phase III KEYNOTE-119 trial (NCT02555657), investigators randomized 622 patients 1:1 with metastatic TNBC to receive pembrolizumab monotherapy compared with single-agent physician’s choice chemotherapy, which included capecitabine, eribulin (Halaven), gemcitabine, or vinorelbine. The primary endpoint is OS; secondary endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and duration of response (DOR). Pembrolizumab was administered at a 200-mg fixed dose every 3 weeks for up to 2 years.

Prior phase II data with pembrolizumab had demonstrated clinical activity in this patient population. In the phase II KEYNOTE-086 trial (NCT02447003), results of which were presented at the 2017 ASCO Annual Meeting, the PD-1 inhibitor elicited a 4.7% (95% CI, 2.3-9.2) overall response rate in patients with heavily pretreated metastatic TNBC.2This included a 0.6% complete response (CR) rate and a 4.1% partial response (PR) rate, as well as a 20.6% stable disease (SD) rate. The median DOR was 6.3 months (range, 1.2+ to 10.3+).

In cohort A of KEYNOTE-086, 170 patients with metastatic TNBC who had received ≥1 prior line of chemotherapy for metastatic disease were enrolled. The median age was 54 years; 82.4% of patients were postmenopausal, 47.1% of patients had an ECOG performance status of 1, and 62% had PD-L1—positive disease. Elevated lactate dehydrogenase (LDH) was reported for 51% of patients, 74% had visceral metastases, and 44% had received ≥3 prior lines of treatment.

Pembrolizumab was administered at 200 mg every 3 weeks until disease progression, unacceptable toxicity, or a maximum of 2 years. The primary endpoint was ORR, and secondary endpoints included DOR, DCR, PFS, and OS.

The median follow-up was 10.9 months (range, 7.7-15.5) and 9 (5.3%) patients remained on pembrolizumab at the data cutoff of November 10, 2016. There was 1 CR and 7 PRs, and a total 27% of patients had a decrease in target lesion size from baseline, and progressive disease was reported for 60.6 % (n = 103) of patients.

PD-L1 status was not associated with response; the ORR was 4.8% in PD-L1—positive patients and 4.7% in PD-L1–negative patients.

The median time to response was 3.0 months (range, 1.9-8.1). The DCR was 7.6%, the median PFS was 2 months (95% CI, 1.9-2.0) and the median OS was 8.9 months (95% CI, 7.2-11.2). Additionally, 6-month PFS and OS rates were 12% and 69%, respectively. There was no significant difference in PFS or OS in the PD-L1—positive versus –negative cohorts.

In patients with poor prognostic factors, the ORR was 2% in patients with elevated LDH compared with 7% in patients with normal or low LDH. In patients with visceral metastases, the ORR was 2% compared with 11% in patients with no visceral metastases. No patients with liver metastases had a response.

The median time on therapy was 56.5 days and the median number of doses was 3. At the time of the analysis, 161 patients (94.7%) had discontinued treatment. The majority of patients discontinued due to disease progression; 7 patients (4.1%) discontinued due to adverse events (AEs).

Regarding safety, all-grade treatment-related adverse events (TRAEs) occurred in 60% of patients, with 12.4% of patients experiencing grade 3/4 TRAEs. The most common all-grade AEs were fatigue (20.6%) and nausea (10.6%). All-grade immune-mediated AEs occurred in 18.8% of patients, 1.2% of which were grade 3/4; none led to death. The most common all-grade immune-mediated AEs were hypothyroidism (11.2%), hyperthyroidism (4.7%), and pneumonitis (3.5%). There were no AE-related deaths.

Moreover, in the phase Ib KEYNOTE-012 study, in which 32 patients with PD-L1—positive heavily pretreated TNBC received pembrolizumab at 10 mg/kg every 2 weeks. Findings showed that the ORR was 18.5%, which included 1 CR (3.7%) and 4 partial PRs (14.8%).3Seven patients had SD (25.9%), 1 of which lasted for ≥24 months.

Additional ongoing clinical trials are continuing to evaluate pembrolizumab in TNBC, including the KEYNOTE-355 (NCT02819518) and KEYNOTE-522 (NCT03036488) studies.


  1. Merck Provides Update on Phase 3 KEYNOTE-119 Study of KEYTRUDA® (pembrolizumab) Monotherapy in Previously-Treated Patients with Metastatic Triple-Negative Breast Cancer. Merck. Published May 20, 2019. https://bit.ly/2WYCRjO. Accessed May 20, 2019.
  2. Adams S, Schmid P, Rugo HS, et al. Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mTNBC): KEYNOTE-086 cohort A.J Clin Oncol. 2017;35(suppl; abstr 1008).
  3. Nanda R, Specht J, Dees C, at al. KEYNOTE-012: Long-lasting responses in a phase Ib study of pembrolizumab for metastatic triple-negative breast cancer (mTNBC). Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract P6-10-03.