KEYTRUDA’s Recent Success in Triple-Negative Breast Cancer Validates I-SPY 2 Adaptive Platform Approach to Phase II Clinical Trials

August 7, 2019

SAN FRANCISCO, Aug. 7, 2019 /PRNewswire/ -- Quantum Leap Healthcare Collaborative (QLHC) joins Merck in acknowledging the promising data from the KEYNOTE-522 trial. Merck recently announced that the Phase 3 KEYNOTE-522 trial met a primary endpoint, demonstrating statistically significant improved rates of pathological complete response for KEYTRUDA® (pembrolizumab), Merck's anti-PD-1 therapy, in combination with chemotherapy as neoadjuvant therapy for patients with triple negative breast cancer (TNBC). The positive finding serves as validation of the QLHC-sponsored I-SPY 2 trial, an adaptive phase II platform trial designed to rapidly screen agents and find the most effective drug combinations for each specific tumor subtype. In this study, patients start with chemotherapy before surgery so that response to treatment can be assessed.  I-SPY 2's evaluation of pembrolizumab formed the basis for targeting the immunotherapy to the TNBC subtype.

As stated by Dr. Roger M. Perlmutter, president, Merck Research Laboratories, "When I have been asked over the last two years why I was prepared to see Merck initiate a Phase 3 trial in triple negative breast cancer, my response has always rested heavily on data from I-SPY 2. The KEYNOTE-522 pCR results offer promise for triple negative breast cancer patients who need better treatment options."          

The I-SPY 2 trial is considered the archetype of a new approach to clinical trials. Rather than the traditional 'one drug, one disease' model for drug development, it is a 'platform' trial. I-SPY 2 evaluates up to 5 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 is also designed for efficiency and speed, by employing an 'adaptive' statistical model. In this approach, the results of each patient are used to refine how the investigational drugs are assigned to new patients. In this way, I-SPY 2 can achieve similar results in a fraction of the time with fewer patients than traditional trials. The goal is to get the right drug to the right patient at the right time.        

In results presented at the 2017 American Society of Clinical Oncology Annual Meeting, I-SPY 2 investigators reported that pembrolizumab, when added to standard neoadjuvant therapy for early breast cancer, nearly tripled the response (the chance of the tumor going away before surgery) in HER2 negative breast cancer subtypes. It was observed to be particularly effective in the difficult-to-treat 'triple negative' subset of breast cancers, which do not express genes for estrogen or progesterone receptors, nor the HER2 oncogene. I-SPY 2's adaptive model predicted that there was a greater than 99% chance that the treatment regimen including pembrolizumab would be successful in a Phase 3 trial in TNBC.

I-SPY 2 principal investigator, Dr. Laura Esserman of the University of California San Francisco, said the KEYNOTE-522 results validate both I-SPY 2's pioneering approach and the vision of Merck leadership for being one of the trial's early partners.

"The whole I-SPY team is thrilled to see that the KEYNOTE-522 results came out just as we predicted. It is an important advance for TNBC patients and a clear demonstration that the I-SPY model can not only accelerate the development of new cancer treatments, it can target treatment to the patients who will benefit most."

Importantly, the 2017 I-SPY 2 results were obtained after only 11 months and enrolling only 69 patients to the pembrolizumab arm of the study; Traditional Phase 2 trials typically require 100-200 patients and last two years or more.

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, and patient advocates, as well as Merck and other pharmaceutical and biotech companies.

The I-SPY 2 TRIAL 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. 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, 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., University of Minnesota) and the Trial Operations working group chair (Angie DeMichele, M.D., 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.

Based on the confirmatory results of the Merck phase 3 trial, the I SPY 2 team is working on an improved design in an effort to get over 90% of high-risk patients to experience a complete response (disappearance of tumor) with targeted and less toxic combinations before surgery.  This will accelerate the ability to personalize care for women with breast cancer.

About Quantum Leap Healthcare Collaborative

The I-SPY 2 TRIAL (, 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

SOURCE Quantum Leap Healthcare Collaborative

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