Immunotherapy Combination Effective Against Chemotherapy-Resistant Breast Cancer

Pembrolizumab plus trastuzumab may overcome drug-resistance among patients with advanced HER2+ breast cancer.

The results of an early clinical trial suggest that the addition of an immunotherapy to a treatment regimen may be able to overcome chemotherapy-resistance in patients with breast cancer.

The combination of pembrolizumab (Keytruda) plus trastuzumab (Herceptin) was well-tolerated and showed clinical benefits in patients with trastuzumab-resistant advanced HER2-positive (HER2+) breast cancer, according to a study presented at the 2017 San Antonio Breast Cancer Symposium.

“We wanted to investigate if immunotherapy approaches can work in patients with advanced HER2-positive breast cancer that is resistant to trastuzumab,” said researcher Sherene Loi, MD, PhD.

Approximately 20% of breast cancers are HER2+ and many patients develop resistance to trastuzumab, a targeted chemotherapy. The authors hypothesized that the addition of an immunotherapy may overcome resistance in these patients.

“We believe that immune evasion is a part of the biological resistance to trastuzumab in patients with this disease,” Dr Loi said. “Prior studies from our group have shown that antitumor immunity is important for improved outcomes in patients with advanced HER2-positive breast cancer.”

Previously, the authors found that patients with trastuzumab-resistant advanced HER2+ disease had poor immune responses, while preclinical studies showed that PD-1 inhibitors improved the efficacy of trastuzumab.

Included in the new phase 1b/2 clinical trial were 58 patients with advanced breast cancer that progressed before treatment with trastuzumab. The authors assessed tumors for HER2 expression, PD-L1 status, and quantity of tumor-infiltrating lymphocytes (TILs), according to the study.

The phase 1b part of the trial was a dose-escalation study of pembrolizumab plus trastuzumab.

The phase 2 part of the clinical trial included 40 patients with PD-L1 positive disease and 12 patients with PD-L1 negative disease. Patients were treated with pembrolizumab 200-mg every 3 weeks plus standard trastuzumab for 2 years.

The authors found that the trial met its primary endpoint with an objective response rate (ORR) of 15% and disease control rate (DCR) of 25% for patients in the PD-L1 positive cohort, according to the study.

In a subgroup analysis of PD-L1 positive patients with 5% or more TILs present in a metastatic tumor, the authors found the ORR was 39% and the DCR was 47%. These results suggest that the number of TILs present may help determine which patients will benefit the most from the combination therapy, according to the study.

These results indicate that patients with chemotherapy-resistant disease who are PD-L1 positive may experience significant benefits from therapy with pembrolizumab plus trastuzumab, according to the authors.

However, there was no treatment response observed among patients with PD-L1 negative disease.

Additionally, 10.8% of PD-L1 positive patients sustained improvements at the time of reporting, according to the authors.

Overall, pembrolizumab plus trastuzumab was well-tolerated. The most common adverse events were fatigue, hyperthyroidism, hypothyroidism, and pneumonitis, according to the study.

“This proof-of-principle study suggests that immune evasion is a mechanism of resistance to trastuzumab and contributes to disease progression in advanced HER2-positive breast cancer,” Dr Loi concluded. “Our results suggest that PD1 inhibition is likely to become part of the treatment armamentarium of HER2-positive disease in the future.”