immunotherapy, cancer

Pembrolizumab May Overcome Trastuzumab Resistance in HER2-Positive Advanced Breast Cancer

Human epidermal growth factor receptor 2 (HER2)–positive breast cancer is generally associated with high levels of tumor infiltrating lymphocytes (TILs), and tumors with high levels of TILs have better outcomes on HER2-targeted therapy and chemotherapy. While resistance to trastuzumab is associated with poor immune responses, preclinical data indicate that trastuzumab resistance can be overcome by adding immune checkpoint blockades to anti-HER2 therapy.

At the 2017 San Antonio Breast Cancer Symposium (SABCS), Sherene Loi, MD, PhD (Peter MacCallum Cancer Center, Melbourne, Australia), presented results from the phase Ib/II PANACEA study, which evaluated the combination of pembrolizumab and trastuzumab in 58 patients with HER2-positive metastatic breast cancer who had progressed on a prior trastuzumab-based therapy. In the phase Ib dose escalation portion of the trial, no dose-limiting toxicities were observed and a final dose of 200 mg pembrolizumab every three weeks in combination with standard dose trastuzumab was selected for further investigation.

The phase II portion of the study examined the safety and efficacy of the pembrolizumab plus trastuzumab combination in patients who were either PD-L1-positive (n = 40) or PD-L1–negative (n = 12). In the PD-L1–positive cohort, the immunotherapy combination resulted in an objective response rate (ORR) of 15.2% and a disease control rate (DCR) of 24%. Median duration of disease control was 11.1 months. In a subgroup of PD-L1–positive patients with 5% or more tumor-infiltrating lymphocytes (TILs) in the metastatic lesion, ORR was 39% and DCR was 47%. Patients who were PD-L1–negative did not respond to treatment.

The pembrolizumab/trastuzumab combination was well-tolerated, with mostly grade 1/2 adverse events (AEs). The most common AE was fatigue (21%). The most common immune-related AEs of any grade were thyroid dysfunction (6.9%) and pneumonitis (any grade, 6.9%, grade ≥3, 3.4%).

In her conclusions, Dr Loi highlighted metastatic HER2+ breast cancer in heavily pretreated patients is poorly immunogenic. Therefore, future directions of immunotherapy in metastatic HER2+ breast cancer should focus on combinations with effective anti-HER2 therapy, particularly in patients with low TIL metastases.

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