Early Signals of Response With PD-L1 Inhibitor Avelumab in Metastatic Breast Cancer

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Luc Y. Dirix, MD

The immunotherapy agent avelumab yielded encouraging overall response rates (ORR) for patients with PD-L1—positive metastatic breast cancer and had an acceptable safety profile, according to findings reported at the San Antonio Breast Cancer Symposium (SABCS).

Avelumab was especially effective in patients with triple-negative breast cancer (TNBC), the phase 1b study found. After 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 = .001).

“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.

“After it became mandatory to pretreat patients with an antihistamine and a antipyretic infusion reactions dropped below 7%,” 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 1000 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.