I-SPY2 TRIAL Demonstrates Significant Improvement in pCR wit
SAN FRANCISCO, April 27, 2020 /PRNewswire/ -- I-SPY 2 TRIAL researchers presented results on April 27 at the clinical trial plenary session of the American Association for Cancer Research (AACR) 2020 annual meeting, which showed that adding the immune checkpoint inhibitor durvalumab and the PARP inhibitor olaparib to standard of care pre-operative (neoadjuvant) chemotherapy improved outcomes for women with stage II/III, high-risk, HER2-Negative Breast Cancer. Patients who received durvalumab + olaparib + paclitaxel (DOP) followed by doxorubicin/cyclophosphamide (AC), achieved complete eradication of their cancer from the breast and axillary lymph nodes at the time of surgery (i.e pathologic complete response) at a greater rate than patients treated with chemotherapy alone (37% versus 20%). This degree of response met the threshold for graduation, meaning that there is a greater than 85% predicted probability of success if this combination was tested against standard chemotherapy in a phase 3 trial of 300 neoadjuvant patients.
I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint risk to evaluate novel agents as neoadjuvant therapy for breast cancer. I-SPY 2 evaluates drugs (or combination of drugs) in parallel with the goal of determining which drugs work best in various types of breast cancer. I-SPY 2 patients are given chemotherapy before surgery so that response to treatment can be assessed. The primary endpoint of the study is pathologic complete response (pCR). Patients who participated in this study had tumors ≥ 2.5 cm, were HER2-negative, and if the cancer was hormone receptor positive (HR+) had to be classified as MammaPrint high risk status. Lead investigator of the study arm, Dr. Lajos Pusztai, Professor of Medicine and Director of Breast Cancer Translational Research at Yale Cancer Center, presented the efficacy and biomarker results which showed the predicted probability of pCR for the overall HER2-negative group, (22% vs 37%) and by subtypes, in HER2-negative/ER-positive (14% vs 28%) and triple negative (TNBC) (27% vs 47%) breast cancer subtypes.
The investigators also evaluated proposed potential markers that could identify the subgroup of patients who selectively benefited from the inclusion of immune enhancing agents such as durvalumab and DNA damage response targeting agents such as olaparib. Among the HR+/HER2- cohort, the MammaPrint ultra-high group was the primary beneficiary of the combined therapy (pCR rates 64% with the combination versus 22% with chemotherapy alone). Specific gene expression signatures thought to be associated with response were prospectively identified and the following were found to be associated with higher pCR in the experimental arm among TNBC: low CD3/CD8 ratio; high Macrophage/T cell-MHC class II ratio, and high proliferation. The safety signals were not unexpected. Adverse events were consistent with known side effects of these drugs. Overall 11% of patients in durvalumab + olaparib arm experienced immune-related grade 3 adverse events vs 1.3% in the control arm. According to Dr. Pusztai, chaperone for this arm in the I-SPY 2 TRIAL, "These results provide further evidence for the clinical value of immunotherapy in early stage breast cancer and suggest new avenues for how to exploit these drugs in HR+ breast cancers."
As noted by I-SPY 2 principal investigator, Dr. Laura Esserman of the University of California San Francisco, "There is a consistent signal of improved response from immuno-oncology and DNA damage response targeted agents in the adaptive I-SPY 2 platform trial as well as other trials, which gives us confidence that these types of agents will have a place in improving outcomes for women with highest risk early breast cancer. "
AACR has selected these findings as newsworthy and will be highlight during an AACR webcast with the meeting program chair Dr. Antoni Ribas and AACR President Dr. Elaine Mardis.
About I-SPY and the I-SPY 2 TRIAL
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 U.S. Food and Drug Administration (FDA), leading academic medical centers, pharmaceutical and biotech companies, and patient advocates. It is a collaborative effort among academic investigators from 20 major cancer research centers across the U.S. and Quantum Leap Healthcare Collaborative, the FDA, and the Foundation for the National Institutes of Health (FNIH) Cancer Biomarkers Consortium.
The I-SPY 2 TRIAL's adaptive statistical design was developed by the pioneering principal investigators for the I-SPY trial, Laura J. Esserman, M.D., MBA, and Donald A. Berry, Ph.D., 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 including the Agents working group chair (Doug Yee, M.D. from the University of Minnesota) and the Trial Operations working group chair (Angie DeMichele, M.D. from the University of Pennsylvania). 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 randomized 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. For more information, visit www.ispytrials.org.
About Quantum Leap Healthcare Collaborative™
The I-SPY 2 TRIAL (www.ispytrials.org), is sponsored by Quantum Leap Healthcare Collaborative™, a 501C(3) charitable organization. Quantum Leap is dedicated to integrating high-impact clinical research with patient care to improve and save lives. By bridging the gap between research and clinical care, Quantum Leap works in collaboration with patients, medical researchers at the University of California, other academic centers nationwide, healthcare innovators, and stakeholders--to accelerate learning in medicine, improve the delivery of healthcare, create better outcomes, and increase the quality of life. Our goal is to improve and save lives. For more information, visit www.quantumleaphealth.org.
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