Small Study Shows Immunotherapy Effective in Metastatic Breast Cancer Subset

After a median follow-up of 10 months, the overall response rate in patients with PD-L1-expressing metastatic breast cancer was 33.3 percent.
BY Silas Inman
PUBLISHED December 10, 2015

Treatment with the immunotherapy avelumab demonstrated promising overall response rates (ORR) for patients with PD-L1–positive metastatic breast cancer, particularly for those with triple-negative disease. These phase 1b study findings were presented at the 2015 San Antonio Breast Cancer Symposium, a gathering of over 7,500 oncologists and oncology professionals.

After a median follow-up of 10 months, the ORR in patients with PD-L1-expressing metastatic breast cancer was 33.3 percent. In patients with PD-L1-positive triple-negative breast cancer (TNBC), the ORR was 44.4 percent with avelumab. Across the full study population, which included PD-L1-negative patients, the ORR was 4.8 percent.

“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, 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 four out of nine patients.”

In the phase 1b trial, 168 patients with metastatic breast cancer received avelumab at 10 mg/kg every two weeks. The median duration of treatment was eight weeks (ranging from two to 50). Tumors were HER2-negative/HR-positive (42.9 percent), triple-negative (34.5 percent), HER2-positive (15.5 percent), or unknown (7.1 percent).

Patients had a median age of 55 years (ranging from 31 to 81), and an ECOG performance status of 0 (49.4 percent) or 1 (50.6 percent). A median of three prior therapies had been administered for locally advanced or metastatic disease (ranging from 0 to 10), including a taxane and anthracycline. Median time since diagnosis of metastatic disease was 21.6 months (ranging from 0.7 to 176.8).

In the TNBC group specifically (58 patients), the median age of patients was 52.5 years, with an ECOG performance status of 0 (56.9 percent) and 1 (43.1 percent). Half of patients had received ≤1 prior therapy (50 percent) and 22.4 percent of patients had received at least three 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 (ranging from 5.7 to 17.7). The median duration of response was 28.7 weeks. Overall, five of the eight responses remained ongoing at the time of the analysis. In the full population of the study, the ORR included one CR and seven PRs. An additional 23.2 percent of patients experienced stable disease with avelumab, for a disease control rate of 28 percent.

Of those who responded, five had TNBC (8.6 percent), four of which were PD-L1-positive. Responses were also observed in patients with HER2-negative/HR-positive breast cancer (2.8 percent) and for those with HER2-positive disease (3.8 percent). Tumor shrinkage of at least 30 percent was observed in 9.5 percent of patients in the overall study population, including two patients with progressive disease. When using immune-related response criteria, which adjusted for pseudoprogression, these two patients were considered to have a PR. Overall, 17.2 percent of patients with TNBC had tumor shrinkage of at least 30 percent.

“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 at least 1 percent, at least 5 percent and at least 25 percent. Overall, none of these variables appeared to impact efficacy. However, PD-L1 expression of at least 10 percent 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 percent vs 2.4 percent).

“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 percent of patients, with events of at least grade 3 in 13.7 percent. Potentially immune-related AEs included hypothyroidism (4.8 percent), autoimmune hepatitis (1.8 percent), pneumonitis (1.8 percent) and thrombocytopenia (1.2 percent).

The most common all-grade AEs were fatigue (19 percent), infusion-related reactions (14.3 percent), nausea (13.1 percent), and diarrhea (8.9 percent). Aavelumab-related AEs of at least grade 3 included fatigue (1.8 percent), anemia (1.8 percent), increased GGT (1.8 percent) and autoimmune hepatitis (1.8 percent).

Overall, 4.8 percent of patients discontinued treatment for reasons other than progression. Additionally, there were two treatment-related deaths (1.2 percent), caused by acute liver failure and respiratory distress. At the time of the analysis, nine patients remained on treatment.

“After it became mandatory to pretreat patients with an antihistamine and a antipyretic infusion reactions dropped below 7 percent,” said Dirix. “Avelumab has an acceptable safety profile in patients with metastatic breast cancer.”

Avelumab is a fully human IgG1 antibody that inhibits PD-1/PD-L1 interaction by binding to PD-L1. The agent may also elicit antitumor activity through antibody-dependent cellular cytotoxicity. “This has been shown in preclinical models, and might contribute to its clinical activity,” said Dirix.

Also within the JAVELIN study, which has enrolled over 1,000 patients, avelumab has shown efficacy for patients with lung, gastric, ovarian, and bladder cancers. On November 18, 2015, avelumab also received a breakthrough therapy designation from the FDA for its potential in patients with Merkel cell carcinoma.


Dirix LY, Takacs I, Nikolinakos P, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial. Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract: S1-07.
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