SAN ANTONIO—Breast cancer is not known as a particularly immunogenic malignancy, but a Phase Ib trial of the anti-PD-1 agent pembrolizumab (MK-3475) has shown durable responses in patients with advanced triple-negative disease.
In a presentation at the San Antonio Breast Cancer Symposium, Rita Nanda, MD, Assistant Professor of Medicine and Associate Director of the Breast Medical Oncology Program at the University of Chicago, explained that PD-1 is expressed primarily on activated T cells. Binding of PD-1 to its ligands PD-L1 and PD-L2 impairs T-cell function, and tumors co-opt the PD-1 pathway to evade immune surveillance.
Pembrolizumab is a humanized anti-PD-1 antibody which binds with very high affinity to its PD-1 receptor. It has demonstrated clinical activity in a variety of cancer types, including Hodgkin lymphoma, and was granted accelerated approval in September 2014 for the treatment of patients with unresectable or metastatic melanoma with disease progression (OT 10/10/14 issue).
Nanda reported on the KEYNOTE-12 study of pembrolizumab in women with ER-, PR-, HER2-negative tumors that were positive for PD-1. A total of 58 percent of women screened for the study who had triple-negative breast cancer had PD-L1-positive tumors.
The 32 women in the study had a median age of 52. They were all heavily pretreated, half had received three or more lines of prior therapies, and 90 percent had received chemotherapy in the adjuvant or neoadjuvant setting—mainly capecitabine, taxane, anthracycline, and platinum.
Among 27 evaluable patients, five (18.5%) had a response to therapy, including one complete response and four partial responses. Two of those responses were in patients who had undergone five or more previous therapies.
‘Durability of Responses’
At the time of this analysis three of the five responders had been on therapy for at least 48 weeks. Four patients came off study due to disease progression, and two of those had been on treatment for 40 weeks—“This speaks to the durability of responses to therapy,” Nanda said in a news conference highlighting newsworthy presentations at the meeting.
She said median duration of response has not been reached, and median time to response was 18 weeks. Median progression-free survival was just under two months, and the progression-free survival rate at six months was 23 percent.
Among patients who had post-treatment imaging, 30 percent showed a reduction in tumor burden.
Treatment-related adverse events occurred in 56 percent of participants, mainly low-grade arthralgias, fatigue, and nausea. One patient died, of disseminated intravascular coagulation attributed to the treatment.
Nanda concluded by saying that pembrolizumab showed an acceptable safety and tolerability profile in heavily pretreated PDL-1-positive triple negative breast cancer patients, and that a Phase II trial in women with triple-negative breast cancer is planned to begin enrollment in the first half of 2015.
The moderator of the news conference, Jennifer Litton, MD, Director of the Breast Medical Oncology Education Program and Associate Professor in the Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center, said excitement continues regarding immunotherapy in breast cancer: “From what we've seen in other tumor types, only a small proportion may respond, but for those who do respond there tends to be some long-term responders in durability that we don't see in other cancers.”
‘Roughed Up a Bit’
At the news conference, Nanda was roughed up a bit by some members of the press who wanted to know if an 18.5 percent response rate really was positive, considering the response rates to PD-1 inhibitors seen in other diseases such as Hodgkin lymphoma and melanoma, and whether one death on this study was acceptable.
Nanda replied that in a Phase I trial with heavily pretreated patients, 18.5 percent was “worth noticing” and the drug warranted further research.
And one death out of 27 heavily treated patients with advanced triple-negative disease, while regrettable and tragic for the patient, was not excessive, she said. “Given the experience with PD-1 inhibitors in other malignancies, this death appears to be an outlier.”
Litton elaborated, pointing out that this was a Phase I trial and should not have to be qualified as positive or negative.
“This is the study that says we should move on to the Phase II trial,” Litton said. “With the single-agent response we see, the durability of response and the tolerability, this drug does warrant further evaluation.”
Edith A. Perez, MD, Deputy Director at Large for the Mayo Clinic Cancer Center and Professor at Mayo Clinic College of Medicine, Jacksonville, Florida, on the panel at the news conference as presenter of another study (page 13), also weighed in: “Breast cancer has not typically been felt to be a disease we should target with immune-modulating therapy, and that's one of the reasons studies were done in other tumor types initially,” she said. “But I am gratified that we have the first proof-of-principle study showing that in a group of patients with refractory, metastatic breast cancer there was a signal of activity to immune-modulating therapy.
“It would be fantastic to expand this study to figure out whether staining for PD-1 is relevant [in breast cancer], to determine the true activity of pembrolizumab as a single agent, and most importantly, how to combine this agent with other strategies for patients with triple negative breast cancer,” Perez continued. “These patients have so few options, that to see this glimpse of activity provides me with a lot of enthusiasm.”