Sherene Loi, MD, PhD

The combination of pembrolizumab (Keytruda) plus trastuzumab (Herceptin) may turn out to be a good treatment option for patients with trastuzumab-resistant advanced HER2-positive breast cancer, according to the results of an early study presented at the 2017 San Antonio Breast Cancer Symposium (SABCS).¹ The phase Ib/II PANACEA trial offers the first data on immunotherapy in HER2-positive breast cancer. If larger randomized studies confirm the benefits of this combination, it will be studied earlier in the course of therapy.

In a phase Ib/II trial, the combination met its primary endpoint, with an objective response rate of 15% and a disease control rate of 25% at 6 months or more among 58 patients with HER2-positive, advanced breast cancer that had become resistant to trastuzumab. In a subgroup of 40 patients with programmed cell death ligand 1 (PD-L1)–positive disease and 5% or more tumor-infiltrating lymphocytes in the metastatic lesion, the objective response rate was 39%, and the disease control rate was 47%. This finding suggests that quantifying tumor-infiltrating lymphocytes may select patients who will derive the most benefit from this combination. No responses were observed in the 18 patients who had PD-L1–negative disease.

“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,” said lead author Sherene Loi, MD, PhD, Associate Professor at Peter MacCallum Cancer Centre in Melbourne, Australia, on behalf of the International Breast Cancer Study Group (IBCSG).

Previous studies have suggested that HER2-positive breast cancer has high levels of T-cell infiltration, and tumor-infiltrating lymphocytes are associated with improved prognosis and response to trastuzumab and chemotherapy, she explained. Trastuzumab has been shown to have immune-mediated mechanisms of action, and preclinical studies suggest checkpoint inhibitor combinations may be able to overcome immune-mediated mechanisms of trastuzumab resistance.

To investigate this potential treatment, Dr. Loi and colleagues enrolled 58 patients with centrally confirmed HER2-positive breast cancer and divided them into two cohorts: PD-L1–positive and PD-L1–negative tumors.

Study Details

Phase Ib of PANACEA was a dose-escalation study of the combination of pembrolizumab plus trastuzumab in 18 PD-L1–positive patients. No dose-limiting toxicities were observed, so the investigators moved on to phase II, studying 58 patients treated with pembrolizumab at 200 mg intravenously plus standard trastuzumab given every 3 weeks (40 patients had PD-L1–positive disease and 18 had PD-L1–negative disease). Patients were treated until disease progression, toxicity, patient withdrawal, investigator decision, or for a maximum of 2 years.

At the end of the study, 3 patients (5%) were still on treatment. Treatment discontinuations were due to progressive disease in 46 patients (84%), death from progressive disease in 1 patient (2%), adverse events in 6 patients (10%), withdrawal of consent in 1 patient (2%), and patient deterioration in 1
patient (2%).

At baseline, the median age was 50 years, 56.9% had estrogen receptor–negative disease and 43.1% had estrogen receptor–positive disease, 100% had become resistant to trastuzumab, and 12% had additional anti-HER2 therapy.

Key Findings

At a median follow-up of 13.6 months, low-grade fatigue was the most commonly reported adverse event (12 patients [21%]). No cardiac events were observed. Eleven patients (19%) developed an immune-related adverse event; six patients (10/3%) developed a grade 3 or higher immune-related event. The most common immune-related adverse events were thyroiditis (four patients [6.9%]) and pneumonitis (all grades, four patients [6.9%], and grade 3 or higher in two patients [3.4%]).

“For those patients who had an objective response or stable disease, responses were persistent without chemotherapy,” Dr. Loi said.

In the PD-L1–positive patients, the median duration of disease control was 11.1 months. In estrogen receptor–negative patients, the median duration of response was 3.5 months; in estrogen receptor–positive patients, the median duration of response was 10 months. Three patients (10.3%) continued to be in response at the time of the SABCS.

“There is the tantalizing suggestion of a tail in the curve for progression-free and overall survival in the PD-L1–positive patients,” Dr. Loi said. “This requires further study.”

Estimated progression-free survival was 13% at 12 months in the PD-L1–positive cohort vs 0% in PD-L1–negative patients. Estimated overall survival at 12 months was 65% for PD-L1–positive patients and 12% for PD-L1–negative patients.

Higher tumor-infiltrating lymphocyte levels in metastatic lesions were associated with improved responses. “Tumor-infiltrating lymphocytes > 5% predict for an improved objective response rate, and they were noted in 41% of patients. Among these patients, the objective response rate was 39%,” she said. “The tumor-infiltrating lymphocyte level of 5% has high sensitivity and reproducibility.”

Although metastatic HER2-positive disease in heavily pretreated patients is poorly immunogenic, as seen by the low levels of tumor-infiltrating lymphocytes in metastatic lesions, response rates in this study are higher than with checkpoint inhibitor therapy in triple-negative breast cancer, she continued.

“Future directions should focus on combinations of immunotherapy with effective anti-HER2 therapy, particularly in patients with low tumor-infiltrating lymphocytes,” she concluded. “The key is to target HER2 ‘potently’ along with the checkpoint inhibitor.” ■

DISCLOSURE: Dr. Loi reported no conflicts of interest.

REFERENCE

1. Loi S, Giobbe-Hurder A, Gombos A, et al: Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzu-mab-resistant HER2-positive metastatic breast cancer: Results from the -PANACEA (IBCSG 45-13//KEYNOTE-014) study. 2017 San Antonio Breast Cancer Symposium. Abstract GS2-06. Presented December 6, 2017.