Pembrolizumab Not So Hot (Yet) for Breast Cancer

Neil Osterweil

December 11, 2015

SAN ANTONIO, Texas — Now it's breast cancer's turn to see whether it will yield to the power of immune checkpoint inhibitors. Research is in its early days, but thus far, the numbers are underwhelming.

Results from a phase 1b "basket" (multidisease cohort) trial of pembrolizumab (Keytruda, Merck) for patients with advanced solid tumors expressing the programmed death 1 ligand (PD-L1) show that among 25 patients with estrogen receptor-positive (ER+), HER2-negative advanced breast cancer the overall response rate (ORR) was 12%, consisting entirely of three partial responses. An additional four patients (16%) had stable disease.

However, five (60%) patients had progressive disease, and three (22%) have not been assessed.

The investigators are not, however, discouraged.

"Based on these data, we believe that further investigation of immune therapies in HER-positive, ER-negative breast cancers, particularly using combination therapies that can expand the T-cell compartment, are warranted," said Hope Rugo, MD, director of the breast oncology clinical trials program at the University of California San Francisco.

The 12% ORR, while lackluster, was still well above the 2.8% ORR reported with the investigational PD-L1 inhibitor avelumab in locally advanced and metastatic disease (MSB0010718C; EMD Serono). Both studies were presented here at the 38th San Antonio Breast Cancer Symposium.

The difference in ORR between the studies may have been attributable to the use of different assays leading to marked differences in the rates of PD-L1 positivity detected, the fact that the avelumab trial included all comers (22% of whom were not evaluable for PD-L1), and the distinct possibility that not all immune checkpoint inhibitors are the same, Dr Rugo said.

"It's clear that as we move forward in this field of immunology, which we're all very excited about, that standardization of assays assessing PD-L1 positivity are going to be critical," she said.

The preliminary safety and efficacy results presented by Dr Rugo come from the ER+, HER2-negative cohort in the KEYNOTE 028 Trial. The 261 patients in this cohort were screened for PD-L1 expression, and 48 were found to have PD-L1 tumors. Dr Rugo presented data on 25 patients.

The patients had a mean age 53 (range 36 to 79), locally advanced or metastatic disease, were unable to receive standard therapy or had disease progression despite standard therapy, Eastern Cooperative Oncology Group performance status of 0 or 1, and one or more measurable lesions.

Two thirds of the patients had received four or five prior lines of therapy, all had undergone chemotherapy, 22 had received hormonal therapy, and six had received another investigational therapy.

­As in other studies of checkpoint inhibitors, patients appeared to tolerate the drug well, with grade 3 or 4 adverse events occurring in four patients. There were four treatment-related grade 3 events (autoimmune hepatitis, gamma-glutamyl transferase increase, muscular weakness, and nausea grade 3 in one patient each), and one grade 4 event (septic shock).

Immune-mediated adverse events included a grade 3 autoimmune hepatitis, grade 2 hyperthyroidism, three cases of grade 2 hypothyroidism, and one grade 1 pneumonitis.

At a median follow-up of 7.3 months there were no treatment-related deaths.

Responses were as noted before. The clinical benefit rate (a combination of partial responses and stable disease for at least 24 weeks) was 20%.

Among 22 patients who had at least one scan after baseline, the ORR was 14% and the clinical benefit rate was 23%. Among the patients with clinical responses, the change from baseline in target lesion size was "impressive," Dr Rugo said.

The three responders had all been on study treatment for 26 weeks or longer at the time of data cutoff. The median time to response was 8 weeks, with the median duration of response not yet reached (range 8.7+ to 44.3+ weeks).

The median duration of stable disease was 16 weeks (range 13.1+ to 24 weeks).

A breast cancer specialist who was not involved in the study told Medscape Medical News that the results are encouraging, given that the majority of patients in the study had been heavily pretreated.

"The fact that we're seeing a 12% response rate, 20% clinical benefit rate for a single-agent therapy, which has a relatively mild toxicity profile is quite encouraging," commented Carey Anders, MD, an oncologist at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill."Given the selection of the patients with the PD-L1 positivity by immunohistochemistry, I think we would have hoped to see a higher response rate," she added.

It will be important to see in the near future how pembrolizumab monotherapy compares with single-agent or doublet chemotherapy in this setting, Dr Anders said.

The KEYNOTE-028 study was funded by Merck.

Dr Rugo disclosed contracts with the company. Dr Anders disclosed receiving research funding from Merck, and is involved in an investigator-initiated study with pembrolizumab, but was not involved with this study.

San Antonio Breast Cancer Symposium (SABCS) 2015: Abstract S5-07. Presented December 11, 2015.


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