SAN FRANCISCO, C.A., December 7, 2017– Quantum Leap Healthcare Collaborative, sponsor and manager of the I-SPY TRIALs for Breast Cancer, today announced results from the long-term I-SPY 2 efficacy investigation, which has demonstrated achievement of pathological complete response (pCR) to be a very strong surrogate endpoint for improved event-free survival (EFS) and distant disease-free survival (DDFS) in high-risk breast cancer. Data was presented in an oral presentation at the annual meeting of the San Antonio Breast Cancer Symposium by Douglas Yee, M.D., University of Minnesota, a principal investigator for the I-SPY 2 TRIAL.
The data presented reflect the longer-term outcomes of 12 investigational arms of different drug combinations added to standard neoadjuvant chemotherapy tested in the I-SPY 2 TRIAL where several of these drugs graduated from the trial based on having substantially increased the chance of pCR in at least one pre-specified breast cancer subtype.
The multi-center, adaptively randomized I-SPY 2 platform uses pCR as the primary endpoint to identify investigational drugs that will improve outcomes in women with stage II/III breast cancer at high risk for early recurrence. The trial investigates all breast cancer subtypes, based on hormone receptor (HR), HER2, and 70-gene (MammaPrint) status.
“The results from I-SPY 2 show that achieving pathological complete response is a strong predictor of event-free and distant recurrence-free survival,” said Douglas Yee, M.D., University of Minnesota, a principal investigator for the I-SPY 2 TRIAL. “Our findings suggest that optimizing the strategy to allow each woman to have a pCR should be pursued and I-SPY 2 is the ideal platform trial to test this strategy given that we have multiple investigational drugs that could be matched to the biology of a patient's tumor.”
Investigators evaluated the relationship between pCR and event-free and distant disease-free survival (EFS and DDFS) in 746 patients, with median follow-up of 2.7 years. Of these, 259 patients achieved pCR (35%), while 487 did not. There were 126 EFS events and 109 DDFS events. Over the entire group (including all arms), pCR was highly associated with 3-year EFS (p <0.001). Patients achieving pCR had a 6% recurrence risk (RR) at 3 years; those with non-pCR had 24% RR over this time period. For distant recurrence, the 3-year RR with pCR was 5%, compared to 21% in patients with non-pCR. As expected, pCR rates varied by breast cancer subtype (HR+/HER2-: 18% (49/275), HR+/HER2+: 39% (58/149), HR-/HER+: 68% (52/77), HR-/HER2-: 41% (100/245). The relationship between pCR and EFS was significant and clinically impactful within each subtype.
These initial long-term efficacy results from the I-SPY2 TRIAL demonstrate that achieving pCR is a very strong surrogate endpoint for improved EFS and DDFS in a high-risk population, across all treatment arms, regardless of subtype. I-SPY 2 shows substantially lower estimated EFS hazards for patients achieving pCR versus non-pCR. The I-SPY 2 data support the use of pCR as a primary endpoint for accelerated approval of new drugs if EFS is evaluated in the same population.
“Based on these findings, the I-SPY 2 TRIAL will soon be able to test whether therapy can be de-escalated or escalated for individual patients with the goal of achieving pCR for all patients,” said Dr. Esserman, I-SPY 2 Principal Investigator. “This approach will be a powerful way to accelerate the development of less toxic and more targeted therapies for women with breast cancers that have a high risk for early recurrence.”
The I-SPY TRIAL (Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular analysis) is a unique collaborative effort by a consortium that includes the Food and Drug Administration (FDA), industry, patient advocates, philanthropic sponsors, and clinicians from 16 major U.S. cancer research centers. Under the terms of the collaboration agreement, Quantum Leap Healthcare Collaborative is the trial sponsor and manages all study operations.
The trial’s adaptive statistical design was developed by the pioneering principal investigators for the I-SPY TRIAL, Laura J. Esserman, M.D., M.B.A., professor of surgery and radiology and director of the Carol Franc Buck Breast Care Center at UCSF Helen Diller Family Comprehensive Cancer Center(Dr. Esserman is the overall principal investigator for the I-SPY TRIALS), and Donald A. Berry, Ph.D., professor of biostatistics at The University of Texas MD Anderson Cancer Centerand founder of Berry Consultants in collaboration with the FDA, industry, and many leading academic collaboratorsincluding the Biomarker Working Group chair, Laura van ‘t Veer, Ph.D., and Imaging Working Group chair, Nola Hylton, Ph.D, both from the University California San Francisco.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 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.
Quantum Leap Healthcare Collaborative (Quantum Leap), a non-profit foundation, was established in 2005 as a partnership between medical researchers at University of California at San Francisco and Silicon Valley entrepreneurs. Quantum Leap’s mission is to accelerate transfer of high-impact research in clinical processes and systems technology into widespread adoption so that patients and physicians can benefit from the research as soon as practicable. Quantum Leap provides operational, financial and regulatory oversight to I-SPY. For more information, visit: www.quantumleaphealth.org.
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Jeff Matthews, PhD
University of California San Francisco