Adding Checkpoint Inhibition in Trastuzumab-Resistant HER2+ Breast Cancer

An early-phase trial found that combining pembrolizumab with trastuzumab was safe and showed promising clinical activity in patients with programmed death ligand 1 (PD-L1)–positive, trastuzumab-resistant, advanced HER2-positive breast cancer.

“Substantial quantities of lymphocytic infiltrate have been observed in primary HER2-positive tumors,” wrote study authors led by Sherene Loi, MD, of the Peter MacCallum Cancer Centre at the University of Melbourne in Australia. “Preclinical studies have suggested that the combination of trastuzumab with drugs targeting immune checkpoints could overcome trastuzumab resistance.”

The researchers conducted a combined phase Ib dose escalation/phase II trial. The phase Ib portion enrolled 6 patients and tested 2-mg/kg and 10-mg/kg doses of pembrolizumab; a protocol amendment stipulated all trials use a 200-mg flat dose of pembrolizumab, and this was used in the 52 patients in the phase II portion of the study. Patients also received 6-mg/kg trastuzumab. All patients had advanced HER2-positive breast cancer and had progressed during previous trastuzumab-based therapy; all phase I patients were PD-L1–positive, as were 40 out of 52 phase II patients. The results of the study were published in Lancet Oncology.

In the phase Ib patients, the median follow-up was 25.7 months, and 1 patient had an objective response (17%).

The median follow-up for the phase II PD-L1–positive patients was 13.6 months. Six of these patients (15%) had a confirmed objective response, and 1 other patient had an unconfirmed partial response. The disease control rate was 25%, and the median progression-free survival (PFS) was 2.7 months. The 6-month PFS rate was 25%, and the 12-month PFS rate was 12%. Of 15 reported deaths in this group, 7 were due to disease progression, 1 was due to a second non-breast malignancy (glioblastoma), and 7 had an undetermined cause of death. The median overall survival (OS) was not reached, and the 6- and 12-month OS rates were 87% and 65%, respectively.

In the PD-L1–negative patients, the therapy did not appear as effective. There were no objective responses, and no patients achieved disease control. The median PFS was 2.5 months, and the 6- and 12-month PFS rates were 13% and 0%, respectively. Nine of the 12 patients died, 5 of which were due to disease progression; 1 was due to Lambert-Eaton syndrome, and 3 had no cause of death determined. The median OS was 7.0 months, and the 6- and 12-month OS rates were 64% and 12%, respectively.

“Our findings set the stage for further studies and show that the combination of trastuzumab plus pembrolizumab is active and has acceptable tolerability as late-line treatment in patients with advanced HER2-positive breast cancer, particularly for those who have PD-L1–positive tumors with tumor-infiltrating lymphocytes present in a recent tumor biopsy,” the authors concluded.

In an accompanying editorial, George E. Peoples, MD, of the University of Texas MD Anderson Cancer Center in Houston, noted that it is difficult to compare the PD-L1–positive and –negative cohorts, because they were not concurrently enrolled. “Furthermore, the PD-L1–negative patients were older, with a lower performance status, and treated later in their disease course,” he wrote.

Among the trial’s more important aspects, Peoples added, is the finding that tumor-infiltrating lymphocyte levels were higher in the patients who responded to therapy than in those who did not. “Ongoing studies of checkpoint inhibitors are assessing not only PD-L1 and tumor-infiltrating lymphocytes, but also tumor mutational burden as a prognostic marker,” he wrote. “Once better understood, these factors, probably in combination, will help improve trial design, select target patient populations, limit toxicities, and improve outcomes in future trials of checkpoint inhibitors alone or in combination therapies.”