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Pembrolizumab induced durable responses in metastatic triple-negative breast cancer
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The humanized anti–PD-1 antibody pembrolizumab induced durable responses in nearly 20% of heavily treated patients with metastatic, triple-negative breast cancer whose tumors expressed programmed cell death-ligand 1, according to study results presented at the San Antonio Breast Cancer Symposium.
Pembrolizumab (Keytruda, Merck) also appeared well tolerated, results showed.
“There are no approved targeted therapies to treat metastatic triple-negative breast cancer, and the median survival for patients with this disease is approximately 1 year,” said Rita Nanda, MD, assistant professor of medicine and associate director of the Breast Medical Oncology Program at the University of Chicago. “The promising activity of pembrolizumab seen in PD-L1–expressing triple-negative breast cancer is very exciting and certainly worthy of further investigation.”
Pembrolizumab has demonstrated clinical activity in a variety of tumor types. Earlier this year, the FDA approved the agent for treatment of advanced metastatic melanoma.
The current analysis included 32 women with metastatic triple-negative breast cancer who had PD-L1–positive tumors. All patients relapsed after treatment for early-stage disease or progressed on therapy for advanced disease.
Key exclusion criteria included current systemic steroid therapy, history of autoimmune disorders and presence of untreated active brain metastases.
Mean age of the cohort was 51.9 years (range, 29-72). The majority of the cohort was white (78.1%) and had ECOG performance status of 0 or 1 (96.9%). Four women (12.5%) had undergone treatment for brain metastases.
Fifteen patients (42.8%) had undergone at least three prior therapies for metastatic disease, and seven patients (21.9%) had undergone at least five prior therapies in the advanced cancer setting. The majority of patients received prior taxanes, antrhacyclines, and capecitabine- and platinum-based therapy.
All women received 10 mg/kg pembrolizumab via IV infusion every 2 weeks. Response assessments were performed every 8 weeks. Patients were eligible to remain on study as long as they demonstrated benefit and did not experience unacceptable toxicity.
Safety, tolerability and antitumor activity served as primary endpoints.
Median follow-up was 9.9 months (range, 0.4-15.1).
Twenty-seven patients were evaluable for response, and 90% of them had undergone prior neoadjuvant or adjuvant chemotherapy.
Researchers observed one complete response (3.7%) and four partial responses (14.8%), equating to an overall response rate of 18.5%. Four of the five responders had received at least three lines of chemotherapy in the advanced-disease setting. All five had undergone taxane- and capecitabine-based therapies, four had received anthracyclines and three had undergone platinum-based therapies.
“There is no current standard of care for patients who are so heavily pretreated, and in comparison to chemotherapy in this line of therapy, the 18.5% response rate is obviously of interest,” Nanda said.
Seven other patients (25.9%) achieved stable disease and 12 patients (44.4%) progressed during treatment. Three patients (11.1%) discontinued therapy prior to first post-baseline scan due to progressive disease or a treatment-related adverse event and, therefore, did not undergo assessment.
At the time of analysis, three of the five responders remained on therapy, and these patients had been on therapy for ≥48 weeks. The two responders who had discontinued treatment by the time of analysis had received therapy for 40 weeks.
“This speaks to the durability of responses to therapy,” Nanda said.
Mediation time to response was 18 weeks (range, 7-32). Median duration of response had not been reached (range, 15 to >40 weeks).
Median PFS was 1.9 months (95% CI, 1.7-5.4) and the PFS rate at 6 months was 23.3%.
Researchers observed treatment-related adverse events in 18 (56.3%) of patients. The most common were arthralgia (18.8%), fatigue (18.8%), myalgia (15.6%) and nausea (15.6%).
“The vast majority of these toxicities were easily managed … and did not require treatment discontinuation,” Nanda said.
Four patients (12.5%) experienced grade 3 events, one patient (3.1%) experienced a grade 4 event and three patients (9.4%) experienced serious events. One patient died due to disseminated intravascular coagulation.
“The acceptable safety and tolerability profile, coupled with the promising antitumor activity, supports the further development of pembrolizumab in patients with advanced triple-negative breast cancer,” Nanda said.
A phase 2 study in patients with triple-negative breast cancer is scheduled to begin enrollment in the first half of 2015, she said.
For more information:
Nanda R. Abstract #S1-09. Presented at: San Antonio Breast Cancer Symposium; Dec. 9-13, 2014; San Antonio.
Disclosure: The researchers report research funding from Merck Sharpe & Dohme, as well as employment relationships with Merck.
Perspective
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Edith A. Perez, MD
Breast cancer has not typically been felt to be a disease that we should target with immune-modulating therapy. That is one of the reasons that studies were done in other tumor types initially. But I’m very gratified to have the first proof-of-principle study in a group of patients with refractory, advanced metastatic breast cancer that there was a signal that there was some activity to immune-modulating therapy. It would be fantastic to expand this study to determine the true activity of this agent as single-agent treatment, and — most importantly — to see how to combine this agent with other strategies for patients with triple-negative breast cancer. These patients have so few options, to see this glimpse of activity provides me with a lot of enthusiasm.
Perspective
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Jennifer K. Litton, MD
Everyone continues to be quite excited about immunotherapy in breast cancer. This study shows — as we have seen in several studies in other tumor types — that only a small portion of patients may respond, but for those who do, there tends to be some long-term responders and a durability that we don’t often see with other therapies. I don’t think we should really qualify this as a positive or negative trial. It is a phase 1 study. It isn’t a study that will tell us, ‘ Should we move forward with this as standard of care?’ This is a study that says, ‘Should we move on to the phase 2 trial.’ When we see data where you have durable response in triple-negative, highly pretreated patients, I do think this warrants further evaluation. Breast cancer, intrinsically, isn’t like melanoma and some of the other tumors that have higher immune infiltrates. But to put this in context, with regard to harnessing the immune system, we are just scratching the surface in breast cancer.
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