Phase II I-SPY 2 TRIAL investigated pembrolizumab in combination with standard therapy [paclitaxel followed by doxorubicin and cyclophosphamide (AC)] as a neoadjuvant treatment for patients with locally advanced triple negative breast cancer (TNBC) or hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. The results showed the addition of pembrolizumab increased the estimated pathologic complete response (pCR) rate nearly threefold in patients with TNBC (60% vs. 20%) and in patients with HR+/HER2- breast cancer (34% vs. 13%) compared to standard therapy.
Overall, based on Bayesian predictive probability of success in a confirmatory phase III trial, pembrolizumab has graduated from the I-SPY 2 TRIAL for all signatures in which it was tested (TNBC, all HER2-, and HR+/HER2-). Data was presented by Rita Nanda, MD, Assistant Professor of Medicine and Associate Director of Breast Medical Oncology at The University of Chicago, at the 2017 ASCO Annual Meeting (Abstract 506).
“[Pembrolizumab] in combination with standard therapy tripled the rate of pathologic complete responses in HER2- patients in the I-SPY 2 Trial,” noted Laura J. Esserman, MD, MBA, Professor of Surgery and Radiology and Director of the Carol Franc Buck Breast Care Center at UCSF Helen Diller Family Comprehensive Cancer Center, and the overall principal investigator for the I-SPY TRIALS. “The regimen indicates a new and important treatment pathway and gives us well-grounded hope for new options for patients with these aggressive breast cancers—and that's potentially very good news.”
The I-SPY 2 TRIAL (NCT01042379) is a standing, phase II, randomized, controlled, multi-center trial for women with newly diagnosed, locally advanced breast cancer (stage II/III), and is designed to screen promising new treatments and identify which therapies are most effective in specific patient subgroups based on molecular characteristics (biomarker signatures). The trial is an adaptive study design assessing the combination of biologically targeted investigational drugs with standard chemotherapy in the neoadjuvant setting, compared to standard chemotherapy alone. The primary endpoint is to determine whether the combination of certain therapies increases the probability of pCR in the breast and the lymph nodes at the time of surgery.
I-SPY 2 Results
The data presented at ASCO from the I-SPY 2 TRIAL were based on results observed in patients at high risk of relapse using up-front tumor profiling (including HR status, HER2 status, and the MammaPrint 70-gene signature test). Patients were treated with weekly standard chemotherapy (paclitaxel) for 12 weeks, with or without pembrolizumab, followed by doxorubicin and cyclophosphamide (AC) every 3 weeks for four cycles. Sixty-nine patients were adaptively randomized to receive pembrolizumab in the trial from December 2015 until it graduated in November 2016. In total, 46 patients have undergone surgery; the other 23 have on-therapy MRI assessments.
In patients with TNBC, an absolute increase in the estimated pCR rate of 40 percent was observed in the pembrolizumab arm (based on the estimated pCR rate of 60% with pembrolizumab plus standard therapy compared to 20% with standard therapy alone). In patients with HER2- breast cancer, an absolute increase in the estimated pCR rate of 30 percent was observed in the pembrolizumab arm (based on the estimated pCR rate of 46% with pembrolizumab plus standard therapy compared to 16% with standard therapy alone). In patients with HR+/HER2- breast cancer, an absolute increase in the estimated pCR rate of 21 percent was observed in the pembrolizumab arm (based on the estimated pCR rate of 34% with pembrolizumab plus standard therapy compared to 13% with standard therapy alone). The Bayesian model estimated pCR rates appropriately adjust to characteristics of the I-SPY 2 population, including MammaPrint status.
The safety profile of pembrolizumab was consistent with that observed in previously reported studies across tumors. In the pembrolizumab arm, grade 3-5 treatment-related adverse events include diarrhea (n=5), febrile neutropenia (n=5), fatigue (n=4), anemia (n=3), nausea (n=3), neutropenia without fever (n=1), peripheral motor neuropathy (n=1), peripheral sensory neuropathy (n=1), and vomiting (n=1). Immune-mediated adverse events of grade 3-5 include adrenal insufficiency (n=5), hepatitis (n=2), colitis (n=1), and hypothyroidism (n=1). Five of six patients presented with adrenal insufficiency after completion of AC (21-24 weeks after starting pembrolizumab), and one presented during pembrolizumab treatment (5 weeks after starting the drug).
“Not all breast cancers are the same—and there has continued to be a significant gap in the treatment options available for patients with certain subtypes, particularly TNBC,” explained Nanda. “The results observed in this trial are not only encouraging, but demonstrate the potential for treatment combinations that can make a difference in patient outcomes.”