Sara M. Tolaney, MD, MPH
The combination of pembrolizumab (Keytruda) and eribulin (Halaven) demonstrated a 33.3% objective response rate (ORR) for patients with metastatic triple-negative breast cancer (TNBC) who received 0 to 2 prior lines of therapy, according to findings from a phase Ib/II study presented at the 2016 San Antonio Breast Cancer Symposium.
In the open-label study, the ORR with the combination for untreated patients with metastatic TNBC (n = 17) was 41.2% (95% CI, 19.3-62.8). In a cohort of patients pretreated with 1 to 2 therapies (n = 22), the ORR was 27.3% (95% CI, 11.3-46.4). PD-L1 status did not appear to impact results and toxicities were in line with expectations.
"It does seem like triple-negative tumors are more immunogenic, they tend to have higher mutational loads and more lymphocytic infiltration," said lead investigator Sara M. Tolaney, MD, MPH, from the Dana-Farber Cancer Institute. "Our hope is that with newer agents, such as immunotherapeutics, that we can help our patients get more durable responses."
The study enrolled a total of 89 patients with metastatic TNBC who previously received 0 to 2 prior therapies. Eribulin was administered at 1.4 mg/m2
on days 1 and 8 and pembrolizumab was given at a flat dose of 200 mg every 3 weeks. The study focused on the safety and efficacy of the combination, with investigator-assessed ORR as the primary endpoint of the phase II portion of the trial.
"There were no dose-limiting toxicities. So, the regimen was felt to be well tolerated," Tolaney said. "The phase II dose was really the full dose of each agent given together."
The median age of patients was 53 years (range, 32-80). The ECOG performance status was 0 (56.4%) and 1 (43.6%). In the metastatic setting, 43.6% had not received prior chemotherapy and 56.4% had gotten 1 to 2 lines of chemotherapy. Half of patients in the study were PD-L1-positive (43.6%). The primary sites of metastases were the lungs (59%), bone (43.6%), liver (41%), brain (15.4%), skin (12.8%), and other sites (53.8%).
At the July 12, 2016, data cutoff, 39 patients were evaluable for efficacy. The median duration of treatment was 3.9 months with eribulin (95% CI, 1.0-8.3) and 3.7 months with pembrolizumab (95% CI, 0.8-9.0). There was 1 compete response (CR; 2.6%) and 12 partial responses (PR; 30.8%). The stable disease (SD) rate was 28.2% and the durable SD rate (SD for ≥24 weeks) was 7.7%. The clinical benefit rate (CBR; CR + PR + durable SD) was 41%.
The median duration of response was not yet reached, with most of the responders still benefiting from treatment. The longest duration of response at the analysis lasted for >32 weeks. Tolaney hoped to have data on the duration of response by the middle of 2017.
In those with PD-L1-positive disease, the ORR was 29.4% (95% CI, 11.1-51.1). The CBR was 35.3%. In those with PD-L1-negative disease (n = 18), the ORR was 33.3% (95% CI, 14.1-54.6) and the CBR was 44.4%. The 1 CR in the study was seen in a group of 4 patients with unavailable PD-L1 status.
"The response rates were the same between those who were PD-L1-positive and those who were PD-L1-negative. It did not seem that PD-L1-positivity predicted benefit," said Tolaney. "Maybe the combination of chemotherapy with immunotherapy will be more applicable to a broader set of patient and not just those who are PD-L1-positive."
Across all evaluable patients (n = 39), 66.7% of patients experienced a grade 3/4 treatment-emergent adverse event (TEAE). The most common grade 3/4 TEAEs were neutropenia (30.8%) and fatigue (7.7%). The most common TEAEs of all grades were fatigue (74.4%), nausea (51.3%), peripheral neuropathy (43.6%), neutropenia (43.6%), and alopecia (35.9%). TEAEs led to dose reductions for 28.2% of patients and to drug interruptions for 48.7%.
Possible immune-related TEAEs were experienced by 66.7% of patients. Grade 3/4 immune-related TEAEs included rash (5.1%), hyperglycemia (2.6%), pneumonitits (2.6%), and renal failure (2.6%).
Ten patients in the full study population (N = 89) had a TEAE leading to study withdrawal (11.2%). Two of these events were in the phase Ib and the remaining 8 were in phase II. There were 3 fatal AEs in the trial, which were each deemed to be unrelated to the combination (respiratory failure, pleural effusion, and multiple organ dysfunction syndrome).
The phase II portion of the study continues to enroll participants with metastatic TNBC (NCT02513472). Additionally, a second study is planned to assess pembrolizumab with or without eribulin for patients with ER-positive breast cancer.
"There is some preclinical work suggesting that chemotherapy, particularly in ER-positive disease, might make these tumors more sensitive to immunotherapy," said Tolaney. "We are going to conduct a study with or without pembrolizumab for patients with ER-positive disease. This should open in the next 2 or 3 months."
Tolaney S, Savulsky C, Aktan G, et al. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract P5-15-02.
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