San Francisco, CA—April 18, 2016 — QuantumLeap Healthcare Collaborative announced Results from the I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2) indicating that a neoadjuvant (presurgery) therapy combination of the antibody-drug conjugate trastuzumab emtansine (T-DM1; Kadcyla) and pertuzumab (Perjeta) was more beneficial than paclitaxel plus trastuzumab for women with HER2-positive invasive breast cancer. Research was presented today at the AACR Annual Meeting 2016, April 16-20.

In this portion of the I-SPY2 TRIAL, the investigators tested if T-DM1 plus pertuzumab could bring a substantially greater proportion of patients to the primary endpoint of pathological complete response [pCR] compared with paclitaxel plus trastuzumab. They also examined whether this combination could meet that goal without the need for patients to receive paclitaxel. pCR is an outcome in which, following neoadjuvant therapy, no residual invasive cancer is detected in the breast tissue and lymph nodes removed during surgery.

“The combination of T-DM1 and pertuzumab graduated from I-SPY 2 in all biomarker signatures tested,” said lead author, Angela DeMichele, MD, MSCE, Professor of Medicine and Epidemiology at the Perelman School of Medicine at the University of Pennsylvania, meaning that it substantially improved pCR for all subgroups of HER2-positive breast cancers compared with those in the control group, and would be likely to succeed in a confirmatory 300-patient, neoadjuvant, phase III, randomized trial testing this combination against paclitaxel plus trastuzumab. “This could, in turn, result in fewer women developing recurrent, metastatic breast cancer without the short and long-term toxicity of taxane therapy.”

Traditional trials have simply added new drugs to the existing regimens, but paclitaxel has some serious side effects, including neuropathy (numbness in the fingers and toes, that can progress to pain and, in some cases, become permanent), lowering of blood counts (with a risk of infection or bleeding), and hair loss, DeMichele explained. “Being able to offer patients a more effective and less toxic regimen would be extremely beneficial to patients’ overall prognosis, and quality of life.”

“The process of bringing one cancer drug to market currently takes up to 15 years and costs well over $2.5 billion, while involving 1,000 to 6,000 patient-volunteers. Despite this high cost, 60 to70 percent of drugs fail or do not complete phase III trials,” said Laura Esserman, MD, MBA, Professor of Surgery and Radiology at the University of California, San Francisco and senior author on the report. “The I-SPY approach to clinical trials is designed to reduce the cost, time, and number of patients required, in order to identify active drugs and the tumor types most likely to respond and get such drugs to market sooner, as well as to identify inactive drugs that should not be further developed.”

“The I-SPY2 TRIAL is a ‘standing platform trial,’ in which drugs can be evaluated on an ongoing basis, without designing a new trial for each new drug. This trial platform allows drugs to enter and leave the trial quickly and seamlessly. We use adaptive randomization to learn faster about better performing drugs and also to treat trial participants more effectively, depending on their tumors’ molecular characteristics,” says Donald Berry, Professor of Biostatistics at the University of Texas M.D. Anderson Cancer Center and co-PI of I-SPY 2.

Prior studies have shown that a combination of T-DM1 and pertuzumab was safe and effective against advanced, metastatic HER2-positive breast cancer, DeMichele said. In this trial, the investigators tested whether this combination would also be effective if given earlier in the course of treatment, before surgery.

In this trial, using a statistical approach called the Bayesian probability of superiority versus control, patients whose HER2-positive invasive breast cancers were 2.5 cm or bigger were adaptively randomly assigned to 12 weekly cycles of paclitaxel plus trastuzumab (control) or T-DM1 plus pertuzumab (test). Following this, all patients received four cycles of the chemotherapies doxorubicin and cyclophosphamide, and surgery.

Patients’ tumors were determined to have one of three biomarker signatures: HER2-positive, HER2-positive and hormone receptor (HR)-positive, and HER2-positive and HR-negative.

At the time of assessment, there were 52 patients in the test arm and 31 patients in the control arm. The trial’s unique statistical method confirmed that, based on pCR data, there is a 90% - 94% chance that T-DM1 + pertuzumab combination will deliver positive results in a 300-patient phase III trial in women with HER2-positive breast cancers with any of the three biomarker signatures aforementioned.

“These data provide a possible new treatment option for patients with newly diagnosed breast cancer that can not only effectively shrink the tumor in the breast but potentially reduce the chance of the cancer coming back later, in another part of the body, which is an incurable situation,” DeMichele said. “This also shows that by replacing older, nontargeted therapies with more effective, less-toxic new therapies, we have the potential to both improve outcomes and decrease side effects,” she added.

“While these results are promising, a phase III confirmatory study is necessary. In addition, since pertuzumab received accelerated approval in the neoadjuvant setting, many patients now receive a taxane with both trastuzumab and pertuzumab (“THP”). The THP regimen was also tested in I-SPY2, and is also superior to standard paclitaxel and trastuzumab (results being presented at Poster Session on Tuesday April 19). Though we found both T-DM1 plus pertuzumab and the THP regimen to be superior to paclitaxel plus trastuzumab, our trial was not designed to compare THP to T-DM1 plus pertuzumab directly,” DeMichele said. “However, the toxicity seen in the TDM-1 plus pertuzumab arm was clearly less than with either paclitaxel plus trastuzumab or THP.”

The I-SPY 2 Trial is sponsored by QuantumLeap Healthcare Collaborative, a 501(c)3 charitable foundation, dedicated to accelerating health care solutions. Over the course of the trial, important philanthropic support has been provided by: The Safeway Foundation, Bill Bowes Foundation, a number of private individuals, family foundations and the pharmaceutical industry. Additional funding for the trial has been provided by pharmaceutical trial participants, including: Amgen, Genentech, Merck, Medivation, Plexxikon and Synta.

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About QuantumLeap Healthcare Collaborative
QuantumLeap Healthcare Collaborative, a non-profit foundation, was established in 2005 as a collaboration between medical researchers at University of California at San Francisco, and Silicon Valley entrepreneurs. QuantumLeap’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. QuantumLeap provides operational, financial and regulatory oversight to I-SPY 2 and is also the sponsor of its companion phase 3 confirmatory trial, I-SPY 3.
For more information, visit: http://www.quantumleaphealth.org.

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