Pembrolizumab Moving Forward in Triple-Negative Breast Cancer

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“Pembrolizumab ‘graduated’ in all HER2-negative signatures.”
— Rita Nanda, MD

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In the treatment of triple-negative breast cancer, checkpoint inhibition is making inroads in both early- and late-stage disease, and the line of treatment and expression of the programmed cell death ligand 1 (PD-L1) could be important in determining outcomes, according to studies reported at the 2017 ASCO Annual Meeting. 

In locally advanced breast cancer, the addition of pembrolizumab (Keytruda) to standard neoadjuvant therapy increased the rate of pathologic complete response approximately threefold in the I-SPY 2 trial, reported Rita Nanda, MD, of the University of Chicago.1 Overall, based on the Bayesian predictive probability of success in a confirmatory phase III trial, “Pembrolizumab ‘graduated’ in all HER2-negative signatures,” she revealed. 

In metastatic breast cancer, single-agent activity of pembrolizumab was observed but was higher in certain subsets, according to the results of the KEYNOTE-086 trial presented at the ASCO Meeting by Sylvia Adams, MD, of New York University School of Medicine.

I-SPY 2 Details 

I-SPY 2 is an ongoing phase II adaptively randomized multicenter study in newly diagnosed, locally advanced breast cancer. It is designed to screen promising drugs, select novel treatments based on patients’ molecular characteristics, and identify which drugs are most effective in specific subgroups. The primary endpoint is the rate of pathologic complete response in the breast and the lymph nodes. 


  • In the ongoing phase II I-SPY 2 trial, over 1,200 women have been randomized and 1,000 women have completed their surgical treatment. A total of 12 regimens are either being tested or have completed evaluation using the I-SPY 2 platform. For the pembrolizumab arm, only those with HER2- negative breast cancer were eligible for standard chemotherapy with or without pembrolizumab.
  • Pembrolizumab nearly tripled the rate of pathologic complete response, vs standard chemotherapy.
  • In patients with triple-negative disease, the rate of pathologic complete response was 40% absolute percentage points higher with pembrolizumab (60% vs 20%).

The I-SPY 2 team evaluated pembrolizumab in patients with locally advanced triple-negative or hormone receptor–positive/HER2-negative breast cancer. Patients were randomized to receive pembrolizumab (200 mg every 3 weeks for 4 weeks) in combination with paclitaxel followed by doxorubicin and cyclophosphamide (n = 69) or standard chemotherapy alone (n = 180). Patients were deemed at high risk of relapse based on hormone receptor status, HER2 status, and the MammaPrint 70-gene signature test. 

High Pathologic Complete Response Rates 

The estimated pathologic complete response rates for the various subgroups, for the pembrolizumab with chemotherapy arm vs chemotherapy alone arm, follow: 

  • All HER2-negative patients: 46% vs 16% 
  • Triple-negative patients: 60% vs 20% 
  • HER2-negative/hormone receptor–positive patients: 34% vs 13%. 

The “predictive probability of success” in phase III trials for pembrolizumab plus standard neoadjuvant chemotherapy was greater than 99% in the triple-negative breast cancer subgroup, and slightly less, 88%, for the hormone receptor–positive subgroup, Dr. Nanda reported. 

Laura J. Esserman, MD, MBA

Laura J. Esserman, MD, MBA

The I-SPY trials’ chief principal investigator, Laura J. Esserman, MD, MBA, Director of the Carol Franc Buck Breast Care Center at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, said the clear enhancement of pathologic complete responses in HER2-negative patients indicates “a new and important treatment pathway” and “gives us well-grounded hope for new options for patients with these aggressive breast cancers.” 

Immune-Related Events With Pembrolizumab 

The safety of pembrolizumab in patients with breast cancer was consistent with that observed in previously reported studies across tumors. The most common grade 3 to 5 treatment-related adverse events for the pembrolizumab and control arms, respectively, included neutropenia (1.4% vs 0.0%), febrile neutropenia (7.2% vs 6.7%), anemia (4.3% vs 3.9%), diarrhea (7.2% vs 2.2%), fatigue (5.8% vs 0.6%), and nausea (4.3% vs 0%). Immune-mediated adverse events of grade 3 to 5 occurred almost exclusively with pembrolizumab and included adrenal insufficiency (7.2%), hepatitis (2.9%), hypothyroidism (1.4%), and colitis (1.4%). 

Primary and secondary adrenal insufficiency are known toxicities of pembrolizumab. It occurred in six patients in the study, five of whom presented at least 21 weeks after starting pembrolizumab, and one developed 5 weeks after pembrolizumab was initiated. Presentation was variable, including nausea and vomiting, fatigue, and weakness. Patients were started on replacement therapy, and investigators have incorporated serial screening of morning cortisol levels in addition to ongoing serial thyroid function testing. 

Dr. Nanda concluded: “The results observed in this trial are not only encouraging, but demonstrate the potential for treatment combinations that can make a difference in patient outcomes.” 


  • In KEYNOTE-086, patients with metastatic breast cancer received pembrolizumab monotherapy. As first-line treatment for PD-L1–positive patients, the response rate was 23.1%. In the second-line or greater setting, in patients with any PD-L1 status, the response rate was 4.7%.

KEYNOTE-086 in Triple-Negative Disease 

KEYNOTE-086 is an international phase II study evaluating pembrolizumab monotherapy in metastatic triple-negative breast cancer. In an oral session at the 2017 ASCO Annual Meeting, results were presented for patients in cohort A who had been previously treated and 62% of whom expressed programmed cell death ligand 1 (PD-L1). Of the 170 patients, 8 (4.7%) responded and 13 (7.6%) achieved disease control for ≥ 24 weeks. One patient (0.6%) had a complete response to pembrolizumab monotherapy, and 27% had a reduction in target lesions. Patients with poor-prognosis factors were less likely to respond, and 14% could not be evaluated or assessed. (Of these patients, 2.9% had on-treatment scans that were not evaluable, but 11.2% never had the first study scan due to death or disease progression requiring change in therapy.) 

Response rates were approximately 5% regardless of PD-L1 expression, but the one complete responder had PD-L1–positive disease. In PD-L1–positive patients, the disease control rate was 9.5%, almost double that of PD-L1–negative patients. 

Median time to response was 3 months, and median duration of response was 6.3 months. The 1 complete responder has not had disease progression, nor have 5 of the 7 partial responders and 12 of the 35 patients with stable disease as best response. 

Sylvia Adams, MD

Sylvia Adams, MD

Median progression-free survival was 2.0 months overall and did not differ by PD-L1 expression. Although median overall survival was 8.9 months, it was longer (median not reached) among patients achieving a response or stable disease. At 9 months, 100% of responders were alive, as were 89.6% of stable patients, compared with 39.0% of patients failing to show a benefit. Grade 3/4 adverse events were observed in 12.4%, with only 1.2% of them immune-related. 

“At the time of data analysis (median, 10.9 months), median survival has not been reached for responders (and stable disease), which is encouraging,” Dr. Adams subsequently told The ASCO Post. 

Dr. Adams also presented a poster at the ASCO Meeting on the 52 patients in cohort B who were previously untreated and had PD-L1–positive disease.3 In this group, the response rate was 23.1%, with 4% being complete responses. Far more patients had a change in tumor size from baseline than was seen in the previously treated cohort A patients with any degree of PD-L1 status, she reported. ■

DISCLOSURE: Drs. Nanda and Esserman reported no conflicts of interest. Dr. Adams has received (institutional) research funding from Merck. 


1. Nanda R, Liu MC, Yau C, et al: Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer: Results from I-SPY 2. 2017 ASCO Annual Meeting. Abstract 506. Presented June 5, 2017. 

2. Adams S, Schmid P, Rugo HS, et al: Phase 2 study of pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: KEYNOTE-086 cohort A. 2017 ASCO Annual Meeting. Abstract 1008. Presented June 3, 2017. 

3. Adams S, Loi S, Toppmeyer D, et al: Phase 2 study of pembrolizumab as first-line therapy for PD-L1–positive metastatic triple-negative breast cancer: Preliminary data from KEYNOTE-086 cohort B. 2017 ASCO Annual Meeting. Abstract 1088. Presented June 4, 2017.

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