Presentation Abstract

Abstract Number: CT227
Presentation Title: Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: Efficacy results from the I-SPY 2 TRIAL
Presentation Time: Monday, Apr 07, 2014, 10:30 AM -10:50 AM
Location: Room 29, San Diego Convention Center
Author Block: John W. Park1, Minetta C. Liu2, Douglas Yee3, Angela DeMichele4, Laura van 't Veer1, Nola Hylton1, Fraser Symmans5, Meredith B. Buxton1, A. Jo Chien1, Amy Wallace6, Michelle Melisko1, Richard Schwab7, Judy Boughey2, Debashish Tripathy8, Hank Kaplan9, Rita Nanda10, Stephen Chui11, Kathy S. Albain12, Stacy Moulder5, Anthony Elias13, Julie E. Lang14, Kirsten Edminston15, Donald Northfelt16, David Euhus17, Qamar Khan18, Julia Lyandres1, Sarah E. Davis1, Christina Yau1, Ashish Sanil19, Laura J. Esserman1, Donald A. Berry20. 1UCSF, San Francisco, CA; 2Mayo Clinic, Rochester, MN; 3University of Minnesota, Minneapolis, MN; 4University of Pennsylvania, Philadelphia, PA; 5MD Anderson Cancer Center, Houston, TX; 6University of California San Diego, CA; 7University of California San Diego, San Diego, CA; 8University of Southern California, Los Angeles, CA; 9Swedish Medical Center, Seattle, WA; 10University of Chicago, Chicago, IL; 11Oregon Health & Sciences University, Portland, OR; 12Loyola University, Chicago, IL; 13University of Denver, Denver, CO; 14University of Southern California, CA; 15Inova Fairfax Hospital, Falls Church, VA; 16Mayo Clinic, Scottsdale, AZ; 17UT Southwestern Medical Center, Dallas, TX; 18University of Kansas, Lawrence, KS; 19Berry Consultants, Austin, TX; 20Berry Consultants, TX
Abstract Body: Background: I-SPY 2 is a multicenter, phase II neoadjuvant trial in women with high-risk stage II/III breast cancer using adaptive randomization within biomarker subtypes to evaluate novel agents added to standard chemotherapy. Primary endpoint is pathologic complete response (pCR). Goal is to identify regimens that meet a high Bayesian predictive probability of statistical significance in a neoadjuvant 300-patient phase III trial defined by hormone-receptor (HR), HER2 status, and MammaPrint (MP). Experimental regimens may “graduate” in 1 of 10 signatures, with a maximum of 120 patients. We report efficacy results for neratinib (N).
Methods: Tumors ≥2.5cm by clinical exam & ≥2cm by imaging are eligible for screening. MP low risk/HR+/HER2- tumors are ineligible for randomization. Patients receive chemotherapy (paclitaxel qwk x 12, doxorubicin and cyclophosphamide q2-3 wk x 4, T->AC). HER2- pts were randomized to N+T->AC vs. T->AC and HER2+ pts to N+T->AC vs. trastuzumab+T->AC. Analysis is intent-to-treat with pts who switch to non-protocol therapy regarded as non-pCRs. We provide estimated pCR rates (95% Bayesian probability intervals), probabilities of superiority of neratinib over control, and Bayesian predictive probabilities of success in an equally randomized phase III trial.
Results: Neratinib met the predictive probability criterion in HR-/HER2+, “graduated”, and accrual ceased [115 N patients (65 HER2+), 78 concurrently randomized controls (22 HER2+)]. The table shows results for all 10 signatures. Two patients (1 N and 1 control) withdrew consent and are not included.
Conclusion: I-SPY 2’s standing trial mechanism efficiently evaluates agents in biomarker-defined patient subsets. In a modest number of patients, adaptive randomization successfully identified a biomarker signature (HR-/HER2+) for neratinib’s further development. All HER2+ and MP+ tumors may also benefit from this regimen, consistent with preclinical data. Evaluation in I-SPY 3, a phase III registration trial, is planned.
SignatureEstimated pCR Rate
(95% probability interval)
Predictive Probability of Success in Phase III
NeratinibControl
ALL32% (28-36%)23% (19%-28%)92%44%
HR+23% (18%-28%)17% (11%-22%)81%40%
HR-43% (37%-49%)31% (24%-38%)89%53%
HER2+39% (33%-45%)23% (15%-30%)95%73%
HER2-26% (21%-32%)24% (18%-29%)63%20%
MP+*45% (38%-53%)29% (20%-39%)91%66%
HR-/HER2-36% (29%-43%)30% (23%-38%)72%34%
HR-/HER2+55% (46%-64%)32% (22%-43%)94%78%
HR+/HER2+31% (24%-37%)17% (10%-24%)91%65%
HR+/HER2-14% (8%-19%)16% (10%-21%)39%12%
* MammaPrint 44K Array Low/High score was adjusted to MammaPrint High1 (MP-) or High2 (MP+), using a pre-defined median cut-point of I-SPY 1 participants, who fit the eligibility criteria of I-SPY 2.