The results from the phase II, I-SPY 2 trial investigating pembrolizumab, anti-PD-1 therapy, 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(HR)-positive/HER2-negative breast cancer show increase in the estimated pathologic complete response (pCR) rate nearly threefold in patients with TNBC (60% vs 20%) and in patients with HR-positive/HER2-negative 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-negative, and HR-positive/HER2-negative). Data were presented by Dr. Rita Nanda of the The University of Chicago, on behalf of study team during an oral session at the ASCO 2017 Annual Meeting in Chicago, US.
The I-SPY 2 trial (NCT01042379), sponsored by QuantumLeap Healthcare Collaborative, is a standing phase II randomised, controlled, multicentre trial for patients 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.
The data presented at ASCO 2017 from the I-SPY 2 trial were based on results observed in patients at high risk of relapse using up-front tumour 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 AC every 3 weeks for four cycles. Sixty-nine patients were adaptively randomised 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% 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-negative breast cancer, an absolute increase in the estimated pCR rate of 30% 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-positive/HER2-negative breast cancer, an absolute increase in the estimated pCR rate of 21% 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 safety profile of pembrolizumab was consistent with that observed in previously reported studies across tumours. In the pembrolizumab arm, grade 3-5 treatment-related adverse events include diarrhoea (n=5), febrile neutropenia (n=5), fatigue (n=4), anaemia (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 pembrolizumab).
The I-SPY (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis) trial is conducted by a consortium that brings together the US Food and Drug Administration (FDA), leading academic medical centres, and patient advocates, as well as pharmaceutical and biotech companies.
The I-SPY 2 trial is a collaborative effort among academic investigators from 20 major cancer research centres across the US and QuantumLeap Healthcare Collaborative, the FDA, and the Foundation for the National Institutes of Health (FNIH) Cancer Biomarkers Consortium. Major supporters include The Safeway Foundation and the Bill Bowes Foundation.
The I-SPY 2 trial’s adaptive statistical design was developed by the pioneering principal investigators for the I-SPY trial, Laura J. Esserman, MD, MBA, and Donald A. Berry, PhD, professor of biostatistics at The University of Texas MD Anderson Cancer Center and founder of Berry Consultants in collaboration with the FDA, industry, and many leading academic collaborators. The trial is a unique collaborative effort where over 50 clinicians are actively engaged in the conduct of the trial.
The I-SPY 2 trial adaptive-trial design is based on Bayesian predictive probability that a biological regimen will be shown to be statistically superior to standard therapy in an equally randomised 300-patient confirmatory trial. Regimens that have a high Bayesian predictive probability of showing superiority in at least one of 10 predefined signatures graduate from the trial. Regimens are dropped for futility if they show a low predictive probability of showing superiority over standard therapy in all 10 signatures. A maximum total of 120 patients can be assigned to each experimental regimen. A regimen can graduate early and at any time after having 60 patients assigned to it.