Luc Y. Dirix, MD
Treatment with the PD-L1 inhibitor avelumab demonstrated promising overall response rates (ORR) for patients with PD-L1–positive metastatic breast cancer, particularly for those with triple-negative disease, according to findings from a phase Ib study presented at the 2015 San Antonio Breast Cancer Symposium.
After a median follow-up of 10 months, the ORR in patients with PD-L1-expressing metastatic breast cancer was 33.3%. In patients with PD-L1-positive triple-negative breast cancer (TNBC), the ORR was 44.4% with avelumab. Across the full study population, which included PD-L1-negative patients, the ORR was 4.8% (95% CI, 2.1-9.2).
“In an unselected cohort, there is a modest overall response rate; however, there are signs of more activity in subgroups, like triple-negative breast cancer,” said lead investigator Luc Y. Dirix, MD, Department of Medical Oncology, Sint-Augustinus Hospital, Oosterveldlaan, Wilrijk, Belgium. “In patients with triple-negative disease with PD-L1 in immune cells this led to a response in 4 out of 9 patients.”
In the phase Ib trial, 168 patients with metastatic breast cancer received avelumab at 10 mg/kg every 2 weeks. The median duration of treatment was 8 weeks (range, 2-50). Tumors were HER2-negative/HR-positive (42.9%), triple-negative (34.5%), HER2-positive (15.5%), or unknown (7.1%).
Patients had a median age of 55 years (range, 31-81), and an ECOG performance status of 0 (49.4%) or 1 (50.6%). A median of 3 prior therapies had been administered for locally advanced or metastatic disease (range, 0-10), including a taxane and anthracycline. Median time since diagnosis of metastatic disease was 21.6 months (range, 0.7-176.8).
In the TNBC group specifically (n = 58), the median age of patients was 52.5 years, with an ECOG status of 0 (56.9%) and 1 (43.1%). Half of patients had received ≤1 prior therapy (50%) and 22.4% of patients had received ≥3 prior regimens.
The study enrolled patients regardless of PD-L1 status. Tumor samples were collected 90 days prior to entering the trial and efficacy by PD-L1 status was assessed as a secondary endpoint. PD-L1 status was assessed by immunohistochemistry on tumor cells and immune cells.
The median time to response was 11.4 weeks (range, 5.7-17.7). The median duration of response was 28.7 weeks. Overall, 5 of the 8 responses remained ongoing at the time of the analysis. In the full population of the study, the ORR included 1 CR and 7 PRs. An additional 23.2% of patients experienced stable disease with avelumab, for a disease control rate of 28%.
Of those who responded, 5 had TNBC (8.6%), 4 of which were PD-L1-positive. Responses were also observed in patients with HER2-negative/HR-positive breast cancer (2.8%) and for those with HER2-positive disease (3.8%).
Tumor shrinkage of ≥30% was observed in 9.5% of patients in the overall study population, including 2 patients with progressive disease. When using immune-related response criteria, which adjusted for pseudoprogression, these 2 patients were considered to have a PR. Overall, 17.2% of patients with TNBC had tumor shrinkage of ≥30%.
“There were two patients who were progressive during the first evaluation period who actually had a substantial decrease in tumor size, meaning, we think, that they actually benefited from avelumab,” said Dirix.
A PD-L1 analysis assessed PD-L1 expression on tumors cells using a cut-off of ≥1%, ≥5%, and ≥25%. Overall, none of these variables appeared to impact efficacy. However, PD-L1 expression of ≥10% on immune cells was associated with a response to avelumab. When compared with patients with PD-L1-negative immune cells across full study, the different was statistically significant (33.3% vs 2.4%; P
“PD-L1 expression by immune cells within the tumor was associated with response to avelumab,” said Dirix. “Among patients with triple-negative breast cancer, PD-L1 expression by immune cells within the tumor was also associated with response to avelumab.”
All-grade treatment-related adverse events (AEs) were seen in 68.5% of patients, with grade ≥3 events in 13.7%. Potentially immune-related AEs included hypothyroidism (4.8%), autoimmune hepatitis (1.8%), pneumonitis (1.8%), and thrombocytopenia (1.2%).
The most common all-grade AEs were fatigue (19%), infusion-related reactions (14.3%), nausea (13.1%), and diarrhea (8.9%). Grade ≥3 avelumab-related AEs included fatigue (1.8%), anemia (1.8%), increased GGT (1.8%), and autoimmune hepatitis (1.8%).
Overall, 4.8% of patients discontinued treatment for reasons other than progression. Additionally, there were 2 treatment-related deaths (1.2%), caused by acute liver failure and respiratory distress. At the time of the analysis, 9 patients remained on treatment.