Pembrolizumab overcomes trastuzumab resistance in advanced breast cancer
The phase IB/II PANACEA study recently showed that the addition of pembrolizumab to trastuzumab in patients with trastuzumab-resistant advanced HER2-positive breast cancer resulted in disease control with a tolerable safety profile.
The study, presented at the 2017 San Antonio Breast Cancer Symposium held in Texas, US, included six programmed death ligand 1 (PD-L1)–positive patients in the phase Ib cohort and 40 PD-L1–positive patients in the phase II cohort. The patients achieved an objective response rate (ORR) based on an intent-to-treat analysis of 15.2 percent after a median follow-up of 13.6 months. [SABCS 2017, abstract GS2-06]
The rate of disease control (ie, complete response, partial response, or stable disease) for ≥6 months was 24 percent, with a median duration of disease control of 11 months. None of the 12 PD-L1–negative patients responded to treatment.
At the time of reporting, 10.8 percent of patients were still receiving treatment and had not experienced disease progression.
"We wanted to investigate if immunotherapy approaches can work in patients with advanced HER2-positive breast cancer that is resistant to trastuzumab. This study suggests that immune evasion is a mechanism of resistance to trastuzumab and contributes to disease progression in advanced HER2-positive breast cancer," explained investigator Dr Sherene Loi of The Peter MacCallum Cancer Centre, Melbourne, Australia.
The median quantity of stromal tumour-infiltrating lymphocyte (TILs) among patients enrolled in the study was 1 percent (mean, 4.8 percent; range 0–60 percent). Median TILs of patients in the PD-L1–positive cohort was 2 percent (mean, 8.1 percent; range, 0–40 percent) and 0 percent (mean, 1.2 percent; range, 0–5 percent) in the PD-L1–negative cohort.
“We noticed higher TIL levels in the PD-L1–positive cohort and among patients who achieved an objective response and disease control. Higher TIL levels could be associated with an increased chance of response,” Loi commented.
Patients who tested with ≥5 percent stromal TILs achieved higher ORR (39 percent vs 5 percent) and disease control rate (47 percent vs 5 percent) vs those who did not meet the 5 percent cut-off.
The most common adverse event (AE) in the study was fatigue (21 percent), followed by diarrhoea and arthralgia (both 14 percent).
Immune-related AEs of any grade were observed in 19 percent of patients, with 10 percent experiencing grade ≥3 AEs.
“Based on the findings of this study, PD1 inhibition is likely to become part of the treatment armamentarium of HER2-positive disease in the future,” Loi commented.
The enrolled patients with a median age of 51 years (range 28–72), 69 percent of whom had visceral metastases, were treated with a dose-escalation regimen of two pembrolizumab doses (2 mg/kg and 10 mg/kg) every 3 weeks (phase IB cohort).
Those enrolled in the phase II cohort received pembrolizumab 200 mg every 3 weeks. Both groups were treated for 24 months until disease progression, toxicity, patient withdrawal, or investigator decision.