Early Trial Yields Promising Data for Pemrolizumab in Breast Cancer


The immunotherapy pembrolizumab (Keytruda) demonstrated on overall response rate (ORR) of 12% in patients with ER-positive, HER2-negative advanced breast cancer in the phase 1b KEYNOTE-028 trial, marking the second early-stage trial to show antitumor activity with this agent in breast cancer.



Hope S. Rugo, MD

The immunotherapy pembrolizumab (Keytruda) demonstrated on overall response rate (ORR) of 12% in patients with ER-positive, HER2-negative advanced breast cancer in the phase 1b KEYNOTE-028 trial, marking the second early-stage trial to show antitumor activity with this agent in breast cancer. In previously reported data, pembrolizumab demonstrated an ORR of 18.5% in patients with PD-L1­—positive triple-negative breast cancer.

“Based on these data, we believe that further investigation of immune therapies in ER+/HER- breast cancer, particularly using combination therapies that can expand the T-cell compartment, is warranted," lead researcher Hope S. Rugo, MD, professor of Medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, said when presenting the data at the 2015 San Antonio Breast Cancer Symposium.

The ongoing, multicohort, open-label phase Ib KEYNOTE-028 basket trial is evaluating pembrolizumab in patients with PD-L1—positive advanced solid tumors. The breast cancer cohort from KEYNOTE-028 discussed at SABCS included 25 patients with ER+/HER2- tumors, locally advanced or metastatic disease, and progression on or an inability to receive standard therapy.

PD-L1 levels were measured at a central laboratory using a prototype immunohistochemistry assay with the 22C3 antibody from Merck, the manufacturer of pembrolizumab.

“All 25 patients had either membranous PD-L1 expression on at least 1% of tumor cells or any staining in stroma,” said Rugo.

The median patient age was 53 years (range, 36-79). Forty-four percent (n = 11) of patients had an ECOG performance status of 1, 52% (n =13) had a status of 0, and the status was unknown for 1 patient (4%). Sixty-four percent of patients (n = 16) were white, 16% (n = 4) were Asian, 4% (n = 1) were black, and race was not specified for 16% (n = 4). Ten patients (40%) had elevated LDH.

Sixteen percent of patients (n = 4) had received 3 prior lines of therapy, with 20% (n = 5) and 44% (n = 11) of patients having received 4 and ≥5 lines of therapy, respectively. Types of prior therapy included chemotherapy, hormonal therapy, and other investigational therapies in 100% (n = 25), 88% (n = 22), and 24% (n = 6) of patients, respectively.

Patients received pembrolizumab at 10 mg/kg every 2 weeks for up to 24 months or until disease progression or unacceptable toxicity. Responses were measured using RECIST v1.1 criteria every 8 weeks for 6 months and then every 12 weeks. ORR was the primary outcome measure.

At a median follow-up of 7.3 months, the ORR was 12% (n = 3; 95% CI, 2.5-31.2), comprising all partial responses and no complete responses. The median time to response was 8 weeks and the median duration of response has not yet been reached, ranging from 8.7 to >44 weeks.

“All 3 responders remained on study for 26 or more weeks at the time of our data cutoff in July 2015,” said Rugo.

Four patients (16%) had stable disease, with a median duration of 16 weeks. The clinical benefit rate, defined as partial response plus stable disease for ≥24 weeks, was 20% (n = 5). Fifteen patients (60%) had progressive disease. Among 22 patients who had at least 1 scan following baseline, ORR was 14% and the clinical benefit rate was 23%.

Regarding toxicities, Rugo said, “Treatment-related adverse events were generally modest, with most in the grade 1/2 range. We saw no new unexpected adverse events,” said Rugo.

Sixty percent of patients experienced at least 1 adverse event (AE). The most common AEs across all grades were nausea (20%), fatigue (12%), and 8% each for arthralgia, decreased appetite, mucosal inflammation, pruritus, rash, and blurred vision.

Grade 3/4 AEs occurred in 16% of patients and included 1 case each of grade 3 autoimmune hepatitis, grade 3 increased gamma glutamyl transferase, grade 3 muscular weakness, grade 3 nausea, and grade 4 septic shock.

The AEs of interest based on immune etiology included 3 cases (12%) of grade 2 hypothyroidism and 1 case each of grade 2 hyperthyroidism, grade 3 autoimmune hepatitis, and grade 1 pneumonitis. Only the autoimmune hepatitis resulted in treatment interruption. There were no treatment-related deaths.

Rugo discussed the KEYNOTE-028 data in the context of a separate abstract presented at SABCS that examined the PD-L1 inhibitor avelumab in more than 160 patients with mixed phenotypes of breast cancer.2

“They reported an overall response rate in 72 patents with ER-positive disease of 2.8% compared to our response rate of 12%," said Rugo.

Rugo suggested reasons for why these results varied, including differences in the assays used to measure PD-L1 levels in patients enrolled in the two trials. Also, the avelumab trial included all comers and 22% of patients were not evaluable for PD-L1 expression.

It is also possible, Rugo said, “that all checkpoint inhibitors are not the same, and that it makes a difference whether you are targeting the receptor, PD-1, as we do with pembrolizumab, or PD-L1, [as is done with avelumab]."

“It’s clear that as we move forward in this field of immunotherapy, standardization of assays assessing PD-L1 positivity is going to be critical,” said Rugo.


1. Rugo HS, Delord J-P, Im S-A, et al. Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1—positive, estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer enrolled in KEYNOTE-028. Presented at the 2015 San Antonio Breast Cancer Symposium; San Antonio, TX; December 8-12, 2015. Abstract S5-07.

2. Dirix LY, Takacs I, Nikolinakos P, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial. Presented at: 2015 San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract: S1-07.

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