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AACR 2014: I-SPY 2 Trial Identifies Subset of Breast Cancer Patients Most Likely to Benefit From Neratinib

AACR: American Association for Cancer Research

I-SPY 2 Trial Identifies Subset of Breast Cancer Patients Most Likely to Benefit From Neratinib

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SAN DIEGO — The I-SPY 2 trial identified a neo-adjuvant regimen containing the investigational drug
neratinib and standard chemotherapy to be beneficial for hormone recepto (HR)-negative,
HER2-positive primary (non-metastatic) breast cancer patients, according to d presented here at the
AACR Annual Meeting 2014, April 5-9.

“The I-SPY 2 trial is a randomized phase II clinical trial for women with newly diagnosed sta 2
breast cancer,” said John W. Park, M.D., professor of medicine at the UCSF Helen Diller Family
Comprehensive Cancer Center in San Francisco. “The trial tests whether adding investigational drugs
to standard chemotherapy in the neoadjuvant setting is better than standa chemotherapy alone, and
the goal is to match investigational regimens with patient subsets on the basis of molecular
characteristics [referred to as biomarker signatures] that benefit from th regimen.

“We were pleased that the algorithm used for the predictions functioned so well and that it
actually stopped assigning neratinib to patient subgroups which were not benefiting from the drug
while at the same time increasing its assignment to patient subgroups which were benefiti from the
drug,” added Park.

A Bayesian algorithm used in this trial identified that the neratinib-containing regimen had
accrued sufficiently to “graduate” based on its prediction that this regimen would be highly likely
to succeed in a phase III trial in this same subset of patients.

The trial is conducted using adaptive randomization: A patient with a particular subtype of bre
cancer who enters the trial is preferentially assigned to treatment regimens that are performing
better in patients with the same subtype of breast cancer.

Patients who have stage 2 breast cancer with a tumor size of at least 2.5 cm, and are considere to
be at high risk for early breast cancer recurrence when evaluated by a test called MammaPri are
eligible for this trial. The primary endpoint of this study is pathological complete response (pCR)
in breast and lymph nodes at the time of surgery.

The algorithm randomly assigned 115 patients to the arm of the trial that contained neratinib, a
pan-HER inhibitor. The rates of pCR on the neratinib arm were compared with those of 78 patients
who were concurrently randomized to the control arm containing standard

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chemotherapy. These comparisons were made for 10 biomarker signatures prospectively defin by
categories of HR, HER2, and MammaPrint.

The investigators concluded that the probability that the neratinib-containing regimen has a higher
rate of pCR than control therapy in HR-negative, HER2-positive breast cancer (one of t 10 biomarker
signatures) is 95 percent and its predictive probability of success in a future, randomized,
300-patient phase III trial is 79 percent. The algorithm also predicted this drug combination is
likely to be beneficial for all HER2-positive breast cancer patients (a second of the 10 biomarker
signatures), with the probability of superiority over standard therapy and the probability of
success in a phase III trial being 95 percent and 73 percent, respectively.

The I-SPY 2 trial’s adaptive statistical design was developed by the overall principal
investigators for the I-SPY trial, Laura J. Esserman, M.D., MBA, professor of surgery and radiology
and director of the Carol Frank Buck Breast Care Center at UCSF Helen Diller Fami Comprehensive
Cancer Center, and Donald A. Berry, Ph.D., professor of biostatistics at The University of Texas MD
Anderson Cancer Center and founder of Berry Consultants.

“Traditional phase III clinical trials are large because they include patients who do not benefit
from the experimental therapy, and they persist in randomizing such patients in the trial to the
very end,” said Berry. “Clinical trial designs have to change to keep pace with the amazing
advances being made in biology. I-SPY 2 may not be the final answer, but so far it has been
successful in expanding the boundaries of clinical trials, making them more patient-friendly while
preserving their scientific integrity,” said Esserman.

I-SPY 2 is sponsored by QuantumLeap Healthcare Collaborative, a 501(3)C charitable foundation,
dedicated to accelerating health care solutions. QuantumLeap shares a unique partnership with the
Foundation for the National Institutes of Health Biomarkers Consortium, which sponsored the trial
until 2013, and continues to manage the intellectual property that emerges from it.

Follow the AACR Annual Meeting 2014 on Twitter: #AACR14

About the American Association for Cancer Research
Founded in 1907, the American Association for Cancer Research (AACR) is the world’s oldes
and largest professional organization dedicated to advancing cancer research and its mission to
prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translation and
clinical researchers; population scientists; other health care professionals; and cancer advocates
residing in more than 90 countries. The AACR marshals the full spectrum of experti of the cancer
community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by
annually convening more than 20 conferences and educational workshops, the largest of which is the
AACR Annual Meeting with more than 18,000 attendee In addition, the AACR publishes eight
peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their
caregivers. The AACR funds meritorious research directly well as in cooperation with numerous
cancer organizations. As the Scientific Partner of Stand

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To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of
team science and individual grants in cancer research that have the potential for near-term patient
benefit. The AACR actively communicates with legislators and policymaker about the value of cancer
research and related biomedical science in saving lives from cancer. For more information about the
AACR, visit www.AACR.org. Follow the AACR Twitter:
@AACR. Follow the AACR on Facebook: http://www.facebook.com/aacr.org.