Addition of Pembrolizumab to Trastuzumab in PD-L1–Positive, Trastuzumab-Resistant, HER2-Positive Breast Cancer


Key Points

  • Response was observed in 15% of PD-L1–positive patients.
  • No responses were observed in PD-L1–negative patients.

In the phase II portion of a phase Ib/II trial reported in The Lancet Oncology, Loi et al found evidence of activity of pembrolizumab plus trastuzumab in programmed cell death protein ligand 1 (PD-L1)-positive, trastuzumab-resistant, HER2-positive advanced breast cancer.

Study Details

In the phase Ib portion of the study (n = 6), no dose-limiting toxicities of pembrolizumab plus standard trastuzumab were identified. In the phase II portion, 52 patients, including 40 with PD-L1–positive tumors, received pembrolizumab 200 mg every 3 weeks plus standard trastuzumab. The primary outcome measure was objective response rate in PD-L1–positive patients.


Objective response was observed in 6 (15%) of 40 patients with PD-L1–positive tumors; disease control was observed in 10 patients (25%). Median progression-free survival was 2.7 months, with a 6-month rate of 25% and a 1-year rate of 12%; median overall survival was not reached, with a 1-year rate of 65%.

No responses and no disease control were observed among 12 patients with PD-L1–negative tumors. Median progression-free survival was 2.5 months, with a 6-month rate of 13% and a 1-year rate of 0%; median overall survival was 7.0 months, with a 1-year rate of 12%.

Adverse Events

Among all 58 patients, the most common treatment-related adverse event of any grade was fatigue (21%). Grade ≥ 3 adverse events occurred in 50% of patients and were considered treatment-related in 29%. Serious adverse events occurred in 29 patients (50%), with the most common being dyspnea (5%), pneumonitis (5%), pericardial effusion (3%), and upper respiratory infection (3%). A treatment-related death due to Lambert-Eaton syndrome was observed in a PD-L1–negative patient in phase II evaluation.

The investigators concluded, “Pembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1–positive, trastuzumab-resistant … HER2-positive, [advanced] breast cancer. Further studies in this breast cancer subtype should focus on a PD-L1–positive population and be done in less heavily pretreated patients.”

Sherene Loi, MD, of Peter MacCallum Cancer Centre, University of Melbourne, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Merck and the International Breast Cancer Study Group. The study authors' full disclosures can be found at

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