Pembrolizumab Induces Modest Benefit in ER+/HER2- Advanced Breast Cancer

Pembrolizumab produced a &ldquo;modest but durable&rdquo; response in heavily pretreated women with PD-L1&ndash;positive, estrogen receptor-positive, HER2-negative advanced breast cancer, according to results from the KEYNOTE-028 trial which were recently published in <em>Clinical Cancer Research</em>.

Hope S. Rugo, MD

Pembrolizumab (Keytruda) produced a “modest but durable” response in heavily pretreated women with PD-L1—positive, estrogen receptor (ER)-positive, HER2-negative advanced breast cancer, according to results from the KEYNOTE-028 trial which were recently published inClinical Cancer Research.

There were no complete responses (CRs) and 3 of 25 patients had a partial response (PR) for an overall response rate (ORR) of 12% (95% CI, 2.5%-31.2%). Another 4 patients (16%) had stable disease (SD) for a median duration of 20 weeks (range, 15.7-37.4). The clinical benefit rate (CR + PR + SD for ≥24 weeks) was 20% (95% CI, 7%-41%), with a median duration of response of 12.0 months (range, 7.4-15.9).

KEYNOTE-028 (NCT02054806) is a nonrandomized, multicohort, open-label, phase Ib study evaluating the safety, tolerability, and antitumor activity of pembrolizumab in 20 cohorts of patients with PD-L1‒positive advanced solid tumors. For the breast cancer cohort, key eligibility requirements included age ≥18 years; ER-positive/HER2-negative tumor status; histologically or cytologically confirmed, locally advanced, or metastatic disease that had progressed on or after prior standard therapy; and an ECOG performance score 0 to 1.

Patients were enrolled from April 2014 to January 2015 at 11 investigational sites in Canada, France, Netherlands, Republic of Korea, and the United States. Including endocrine agents, the median number of prior therapies was 9 (range, 3-15).

All patients received 10 mg/kg of intravenous pembrolizumab every 2 weeks for 2 years or until unacceptable toxicity, disease progression, patient withdrawal of consent, or investigator decision to withdraw the patient. Patients who were clinically stable with initial radiographic evidence of disease progression based on RECIST v1.1 were allowed to remain on the study until confirmatory imaging was performed ≥4 weeks later.

Patients who interrupted treatment because of toxicity could resume pembrolizumab after resolution of toxic effects to grade ≤1 or baseline level. Treatment was discontinued if toxicity did not resolve within 12 weeks of the last pembrolizumab infusion. Patients experiencing stable disease (SD), partial response (PR), or complete response (CR) who discontinued pembrolizumab after 24 months of continuous treatment without evidence of disease progression were eligible for up to 1 year of additional pembrolizumab treatment after subsequent progression.

A total of 48 (19.4%) out of 248 evaluable tumor samples were PD-L1—positive. Twenty-three samples were excluded because of withdrawal of consent (n = 14), inadequate organ function (n = 4), or other reasons (n = 5). A total of 25 patients with PD-L1–positive tumors (52.1%) were enrolled and treated on-protocol.

The median patient age was 53 years (range, 36-79). Thirteen patients (52%) had ductal carcinoma, 3 (12%) had lobular carcinoma, 3 (12%) had carcinoid/neuroendocrine tumors, and 6 (24%) had adenocarcinoma not otherwise specified.

Eleven patients (44%) had elevated lactate dehydrogenase (LDH) levels; the median baseline LDH levels among 22 evaluable patients was 1.10 (range, 0.61-4.30).

Twelve patients (48%) had received ≥5 lines of prior therapy and 17 (68%) had prior adjuvant or neoadjuvant therapy for metastatic disease. Twenty-two patients (88%) had received prior endocrine therapy, and 7 (28%) had received a prior investigational agent.

The median follow-up was 9.7 months (range, 0.7-31.8). Twenty-one of 22 patients with ≥1 postbaseline tumor assessment had evaluable tumor lesions. Of those, 8 (35%) experienced a decrease in the size of target lesions from baseline. The median time to response was 1.7 months (range, 1.7-1.9), and the median duration of response was 12.0 months (range, 7.4-15.9).

All 3 patients who experienced PR had received ≥3 lines of chemotherapy for metastatic disease, and 2 had experienced progression on endocrine therapy in the metastatic setting.

Median progression-free survival (PFS) was 1.8 months (95% CI, 1.4-2.0), and the 6-month PFS rate was 16.7%. Median overall survival (OS) was 8.6 months (95% CI, 7.3-11.6). Six-month OS was 73.6% and 12-month OS rate was 29.5%.

Twenty-four patients (96%) discontinued pembrolizumab treatment, most due to adverse events (AEs; n = 5) or progressive disease (n = 15). No patient discontinued for treatment-related toxicities and there were no treatment-related deaths.

Treatment-related AEs were experienced by 64% of patients, most commonly nausea and fatigue. Four patients (16%) experienced grade 3/4 treatment-related AEs including nausea, autoimmune hepatitis, septic shock, increased γ-glutamyltransferase, and muscular weakness.

Five patients (20%) had AEs of special interest with a potential immune-mediated cause regardless of attribution to pembrolizumab by the investigator. These patients experienced grade 2 hypothyroidism, grade 2 hyperthyroidism, grade 3 autoimmune hepatitis, grade 2 infusion related reaction, and grade 1 pneumonitis.

The study authors, led by Hope S. Rugo, MD, considered that ER-positive, HER2-negative breast cancer tumors were immunologically “cold” compared with triple-negative and HER2-positive tumors due to lower levels of lymphocyte infiltration. The authors noted that further work is suggested to compare patients with PD-L1—positive and PD-L1–negative expression in ER-positive, HER2-negative breast cancer tumors to establish the responsiveness to pembrolizumab and the importance of PD-L1 expression as a biomarker.


Rugo HS, Delord JP, Im SA, et al. Safety and antitumor activity of pembrolizumab in patients with estrogen receptor‒positive/human epidermal growth factor receptor 2‒negative advanced breast cancer [published online March 20, 2018].Clin Cancer Res.doi: 10.1158/1078-0432.CCR-17-3452.