SABCS 2017: Combination of Pembrolizumab and Trastuzumab Shows Early Promise for Patients With Trastuzumab-Resistant Breast Cancer
A combination of pembrolizumab (Keytruda) and trastuzumab (Herceptin) tested in patients with trastuzumab-resistant advanced HER2-positive breast cancer was well tolerated and had clinical benefit in patients whose tumors were positive for a biomarker for pembrolizumab, according to data presented from the phase Ib/II PANACEA trial by Loi et al at the 2017 San Antonio Breast Cancer Symposium (Abstract GS2-06).
“We wanted to investigate if immunotherapy approaches can work in patients with advanced HER2-positive breast cancer that is resistant to trastuzumab,” said Sherene Loi, MD, PhD, Associate Professor at Peter MacCallum Cancer Centre in Melbourne, Australia, working with the International Breast Cancer Study Group (IBCSG).
It is estimated that approximately 20% of invasive breast cancers are HER2-positive, and some of these patients develop resistance to trastuzumab. Dr. Loi and colleagues hypothesized that immunotherapy may help to overcome trastuzumab resistance in this subset of breast cancers.
“We believe that immune evasion is a part of the biological resistance to trastuzumab in patients with this disease,” commented Dr. Loi. “Prior studies from our group have shown that antitumor immunity is important for improved outcomes in patients with advanced HER2-positive breast cancer.”
Dr. Loi and colleagues previously demonstrated that patients with trastuzumab-resistant advanced HER2-positive breast cancer had evidence of poor immune responses, and preclinical studies revealed that anti–programmed cell death protein 1 (PD-1) immunotherapy improved the therapeutic activity of trastuzumab.
PANACEA Details
In this phase Ib/II clinical trial, Dr. Loi and colleagues enrolled 58 patients with advanced breast cancer that had progressed on prior trastuzumab-based therapies. Tumors were assessed centrally for HER2 positivity and programmed cell death ligand 1 (PD-L1) status, and for quantity of tumor-infiltrating lymphocytes (TILs).
The phase Ib portion of the trial was a dose-escalation study of pembrolizumab, an anti-PD-1 therapy that targets the T-cell checkpoint protein PD-1, in conjunction with the standard dose of trastuzumab. No dose-limiting toxicities were observed.
In phase II, the investigators enrolled 40 patients and 12 patients to the PD-L1–positive and PD-L1–negative cohorts, respectively. Patients received 200mg of pembrolizumab every 3 weeks in combination with the standard dose of trastuzumab for 24 months or until disease progression.
Findings
In the PD-L1–positive intent-to-treat population, the trial met its primary endpoint with an objective response rate of 15% and disease control rate of 25%. In a subgroup of PD-L1–positive patients with 5% or more TILs present in the metastatic lesion, the objective response rate was 39% and the disease control rate was 47%, suggesting that quantification of TILs may help identify patients who will most benefit from this treatment. No responses were observed in the PD-L1–negative cohort.
Five (10.8%) patients in the PD-L1–positive cohort continued to have no disease progression at the time of reporting, Dr. Loi noted. Pembrolizumab with trastuzumab was well tolerated, with grade 1 to 2 fatigue as the most commonly reported adverse event (21%). The most common immune-related adverse events reported were hyper- and hypo-thyroidism (grade 1–2 at 6.7%) and pneumonitis (grade 3–4 at 3.4%).
“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,” noted Dr. Loi. “Our results suggest that PD-1 inhibition is likely to become part of the treatment armamentarium of HER2-positive disease in the future.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
