Accounting for approximately 15 percent of breast cancer cases, triple negative breast cancer (TNBC) is often considered to be the most deadly form of the disease. TNBC is unresponsive to hormonal therapies and recurrence is common, often leading to metastases in other organs.
New research, presented at the 2017 ASCO Annual Meeting, suggests that pembrolizumab, an immunotherapy drug, is effective in patients with metastatic triple negative breast cancer (mTNBC) (Abstract 1008).
“Triple negative breast cancer with its clear association of tumor infiltrating lymphocytes, survival in early TNBC, and unmet clinical need has attracted the incorporation of immune checkpoint blockade (ICB) therapeutics into clinical trials,” noted Sylvia Adams, MD, Associate Professor of Medical Oncology at NYU Langone's Perlmutter Cancer Center and principal investigator of this study. “Initial phase I studies of ICB were reported in advanced PD-L1-positive TNBC and showed objective responses in 18-19 percent, which were durable in a subset of women with promising longer-term survival.
“The phase II Keynote-086 trial presented at ASCO was based on the phase I data and was designed to study the efficacy and safety of anti-PD-1 immunotherapy in a larger cohort of women with metastatic TNBC, both in the front and later lines of treatment,” she continued.
Abstract 1008 & 1088
Keynote-086, a phase II, multi-cohort, single arm trial, aims to estimate the efficacy of pembrolizumab in mTNBC patients. The trial was conducted at 17 medical centers across four continents.
The immunotherapy drug was investigated in two cohorts of patients. Cohort A included 170 patients with heavily-pretreated mTNBC, regardless of the expression of PD-L1.
The median age of cohort A was 54 years and 82.4 percent of patients were postmenopausal. Additionally, 47.1 percent of the cohort had an ECOG performance status of 1 and 62 percent had PD-L1-positive tumors. Fifty-one percent of patients had elevated LDH, 74 percent had visceral metastases, and 44 percent had received three or more prior lines of therapy, according to study authors.
Women received single agent pembrolizumab intravenously every 3 weeks until disease progression or toxicity, Adams noted. Researchers evaluated tumors via imaging every 9 weeks for the first year, and then every 12 weeks thereafter. Those patients with progressive disease, but remained clinically stable, were allowed to continue pembrolizumab until progressive disease was confirmed on subsequent assessment, according to researchers.
Primary endpoints, included objective response rate (ORR) (RECIST v1.1, central review) in all patients and those with PD-L1-positive tumors, and safety, study authors noted. Secondary endpoints, included duration of response, disease control rate (DCR; CR + PR + SD ≥24 weeks), progression-free survival (PFS), and overall survival (OS).
Cohort B included 52 patients with PD-L1-positive tumors who received pembrolizumab as first-line therapy. While survival data are not yet complete, cohort B's primary aim was to prove the safety of pembrolizumab as well as investigate its efficacy as a first-line treatment. Among the first patients enrolled, all were women, median age was 53, 40 percent had elevated LDH, and 69 percent had visceral metastases (Abstract 1088).
Keynote-086 is the first phase II study of an immunotherapy drug for TNBC to be reported, Adams noted. And, it represents the largest cohort of patients with mTNBC treated with ICB therapeutics to date.
Pembrolizumab was very well-tolerated with few side effects and no new toxicities were identified, Adams reported. Among patients in cohort A, only 12 percent experienced severe side effects and 8 percent experienced them in cohort B. Fatigue and nausea were the most common side effects in both patient populations, according to study data. While seven patients from cohort A discontinued treatment due to side effects, adverse events did not lead to discontinuation by any patients in cohort B.
Adams said efficacy results were quite different in the individual cohorts. “The ORR in cohort A was 4.7 percent and no difference was observed based on PD-L1 expression in tumors (ORR 4.8 and 4.7%, for PD-L1-positive and PD-L1-negative tumors, respectively),” she explained. “The median PFS was 2 months for women in this cohort, and OS was 8.9 months. As seen in prior studies of ICB in mTNBC, responses tended to be durable and survival was greater in these women compared with patients who've progressed.”
At the time of the ASCO meeting, only preliminary results from the first 52 patients in cohort B were available. “The front-line arm of Keynote-086 for patients with PD-L1-positive tumors showed a higher ORR of 23.1 percent (12 of 52 patients) with durability of responses in many patients,” Adams explained. “Data on the full cohort of 84 patients with PD-L1-positive, previously untreated mTNBC from cohort B will be presented at the 2017 San Antonio Breast Cancer Symposium in December.
“Our results suggest that this treatment as a single agent is effective for mTNBC,” Adams emphasized, in a statement. “Interestingly, we found that activity of pembrolizumab was seen in both PD-L1-positive and negative tumors. These data are very encouraging, especially for a disease that is extremely aggressive and has limited treatment options when it metastasizes.”
Implications for Practice
Currently, the standard of care for mTNBC is chemotherapy, which is associated with significant toxicity and a number of side effects. On the other hand, pembrolizumab, which has received FDA approval for use in other cancers, has been proven to have less frequent side effects and greater tolerability, as reported by Adams.
“This research contributes to a larger body of knowledge that could help provide better outcomes to women with few treatment options,” Adams noted. “The data also suggest that immunotherapy administered earlier in the disease course is more beneficial, as response rates are much greater in first compared to second or later lines of therapy.
“Keynote-086 results add to the previously observed trend of better ICB responsiveness with earlier treatment in mTNBC, so patients should be referred early for trial participation,” she told Oncology Times.
While the results of Keynote-086 are promising, more research is needed to fully explore the use of immunotherapy among this patient population.
“Response rates in women with prior treatment were low, indicating that therapeutic benefit is limited to a minority of patients, although for these women, responses can be durable,” Adams observed. “Therefore, predictive biomarkers for patient selection are needed and combination therapies should be investigated in this setting.
“Although only a small subset of women responded to the drug, within that subset pembrolizumab worked extremely well and responses were durable,” she concluded, in a statement. “By causing fewer side effects and promoting longer life expectancy, pembrolizumab could help change the outcome of mTNBC.”
Catlin Nalley is associate editor.
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