Hope Rugo on Pembrolizumab's Potential in ER+/HER2- Breast Cancer

Hope Rugo, MD, discusses the phase Ib KEYNOTE-028 trial and the impact of its results thus far, as well as the design, findings, and next steps for the trial.

Hope Rugo, MD

Pembrolizumab (Keytruda) may have similar potential in ER-positive/HER2-negative advanced breast cancer as was previously shown in triple-negative breast cancer (TNBC), says 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.

Rugo was the lead investigator on the phase Ib KEYNOTE-028 trial, a basket trial that demonstrated an overall response rate (ORR) of 12% (n = 3; 95% CI, 2.5-31.2) in PD-L1—positive patients with ER-positive/HER2-negative breast cancer.1

Previously reported data from the phase Ib KEYNOTE-012 trial showed that pembrolizumab had an ORR of 18.5% in patients with PD-L1—positive TNBC.2

“I think we are seeing the same durability we saw in triple-negative breast cancer,” says Rugo, who presented the phase Ib KEYNOTE-028 trial at the San Antonio Breast Cancer Symposium in December 2015. “There was a lower percent of PD-L1 positivity and a lower response rate, but the results were still very reasonable in patients with ER-positive disease treated with a single immunotherapy.”

OncLive: How was the KEYNOTE-028 trial designed?

To better understand the phase Ib KEYNOTE-028 trial and the impact of its results thus far, OncLive spoke with Rugo about the design, findings, and next steps for the trial.Rugo: The KEYNOTE-028 trial is a basket or multi-cohort phase Ib trial. It is certainly not by any means the first-in-human study. However, the reason why these types of trials are often called phase I trials is because many different cancers are included. Only phase I units have the capability of taking care of patients with so many different kinds of cancer.

How was this cohort selected?

This trial included 20 cancers. Six patients have reported response rates from 11.5% up to 30%. The ER-positive/HER2-negative breast cancer cohort is the seventh cohort to report. At the 2014 San Antonio Breast Cancer Symposium, data were presented on ER-negative/HER2-negative breast cancer—known as triple-negative disease—that showed that pembrolizumab resulted in a response rate of 18%. In some of these patients, the response rate was very durable.We did this cohort of ER-positive/HER2-negative breast cancer, which we know has a PD-L1 expression rate of somewhere between 4% and 20%. Previous studies have suggested that expression is more common in women who have more proliferative luminal B type disease. We tested women with PD-L1—expressing metastatic ER-positive breast cancer who had received chemotherapy in some setting.

What were the most significant findings?

How was the drug tolerated?

What should oncologists take away from these results?

Do you think immunotherapy has as much potential in breast cancer as we’ve seen in melanoma or lung cancer?

One hundred percent of patients had received chemotherapy previously, despite the fact that they had ER-positive breast cancer. Patients had to have at least one measurable lesion and their tumor had to be documented to have at least 1% or higher PD-L1 expression. We screened over 240 patients and we found a positive rate of just over 19%, which amounted to 48 people. Of those 48, 25 patients started therapy because some of them continued to get sicker. Or, they couldn’t go on while they were waiting for their results or waiting to start another treatment. Of those 25 patients, 22 of them had at least one scan after starting treatment.We saw an ORR of 12% and a clinical benefit of 20% that included stable disease for at least 6 months. When we analyzed the 22 patients who had 1 follow-up scan so we knew what was going on with them, the response rate increased to 14% with a clinical benefit rate of 23%. Overall, the patients who continued had durable responses. They have continued to stay on treatment for many, many weeks.If you look at all 25 patients, the tolerability was very good. We had 1 case of grade 3 autoimmune hepatitis, which was resolved. Other significant toxicities included hypothyroidism, hyperthyroidism, and 1 case of grade 1 asymptomatic pneumonitis. No one died on the study, and our median follow-up was over 7 months.We know now that pembrolizumab has limited activity but, sometimes, it is durable activity in ER-positive/HER2-negative breast cancer. It is just a little bit lower than what we saw with a single agent in triple-negative disease. Now, we have to design the next set of combination studies that will enhance upon what pembrolizumab has added to therapy for ER-positive breast cancer, rather than using it as a single agent.It’s different. We don’t see that kind of level or response, but I think it may help chemotherapy to work better in a subset of patients who have a big role of their T-cell compartment in terms of the cancer. For it to work properly the cancer has to be more proliferative. Slow-growing cancers won’t benefit. It will be interesting to see.

Another trial was recently presented, called the JAVELIN trial, which looked at avelumab in more than 160 patients who were not selected by PD-L1 positivity. Here, researchers found a much lower response rate. Even though only eligible patients were treated and a subset of patients who were PD-L1—positive was examined, a lower response rate was still reported. In that trial, the response rate for ER-positive disease was only 2.8%.

What are the next steps in this research?

The problem is, in the patient population that they treated, 22% were not evaluable to assess PD-L1 at all, and the PD-L1 expression rate was 50%. This suggests that, if we had 19% in our trial, this was just a different tumor group or perhaps the assays need to be standardized. There is an international group working on standardization of assays.There are a lot of trials ongoing in triple-negative disease and there are also a lot of trials being planned and discussed in ER-positive disease, so stay tuned.


  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. Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. Paper presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S1-09.