Response With Neratinib Against Early HER2-Positive, HR-Negative Breast Cancer

Adding neratinib to standard paclitaxel chemotherapy appears to be associated with a better pathological complete response rate than chemotherapy plus trastuzumab.

Despite significant toxicities, adding the investigational tyrosine kinase inhibitor neratinib (PB272, Puma Biotechnology) to standard paclitaxel chemotherapy appears to be associated with a better pathological complete response (pCR) rate than chemotherapy plus trastuzumab among patients with HER2-positive, hormone receptor (HR)-negative early-stage breast cancer, according to findings from an adaptive phase II clinical trial.1

The authors estimated a 79% probability that neratinib will prove effective in confirmatory phase III clinical studies.1 The trial was part of the larger collaborative Investigation of Serial Studies to Predict your Therapeutic Response through Imaging and Molecular Analysis 2 (I-SPY 2) study (NCT01042379) which was designed to assess the safety and efficacy of several investigational antibreast cancer agents plus standard chemotherapy.

“On the basis of our trial results and other clinical data, phase 3 testing of neratinib as neoadjuvant therapy is moving forward in the successor I-SPY 3 program, which is aimed at generating accelerated approval following guidance from the Food and Drug Administration,” reported corresponding coauthor Laura J. Esserman, MD, MBA, of the UC San Francisco Carol Franc Buck Breast Cancer Center, and coauthors.

Neratinib is a pan-HER tyrosine kinase inhibitor that irreversibly binds to, and inhibits, EGFR, HER2, and HER4 receptors.

The authors employed “adaptive randomization” using eight biomarker subtypes to assign patients with stage II or III breast cancer to the study’s control arm (standard paclitaxel chemotherapy, IV 80 mg/m2 followed by 4 cycles of doxorubicin, 60 mg/m2; n=78 evaluable patients), or chemotherapy plus once-daily neratinib (240 mg for 12 weekly cycles; n=115 evaluable patients).

The biomarker subtypes were based on patients’ HER-2 status, hormone receptor status, and MammaPrint™ 70-gene risk status.1

The estimated pCR rate among patients in the neratinib study arm was 56% (95% CI, 37%-73%) versus 33% (95% PI, 11%-54%) among patients assigned to the control group.1

The coauthors calculated a 79% “final predictive probability of success in phase 3 testing” for neratinib.

Dose reductions or treatment interruptions were reported for 64% of patients administered neratinib versus 39% for patients in the control group, and 11% of patients on neratinib versus 1% of controls discontinued treatment early due to treatment-related toxicities.1 Diarrhea was the most common adverse event and grade 3/4 diarrhea was reported for 38% of patients receiving neratinib.1

“The rates of several hematologic and gastrointestinal adverse events were significantly higher in the neratinib group than in the control group, including vomiting of grade 1 or 2 (P = .045), diarrhea of grade 1 or 2, or of grade 3 or 4 (P < .001 for both comparisons), abnormalities of the aspartate aminotransferase level of grade 1 or 2 (P < .001), and abnormalities of the alanine aminotransferase level of grade 1 or 2 (P < .009),” the authors reported.1   

Adaptive clinical trial designs like I-SPY 2 employ biomarker signatures to allow relatively small numbers of patients and to hasten identification of agents that are promising candidates for phase III studies with specific subpopulations of cancer patients. The adaptive randomization study design shows promise for “matching targeted therapies for breast cancer with patients most likely to benefit from them,” noted David Harrington, PhD, and Giovanni Parmigiani, PhD, of Dana-Farber Cancer Institute and the Harvard T.H. Chan School of Public Health, Boston, in a commentary published in the same issue of The New England Journal of Medicine.2

“As more new targets and drugs are discovered, traditional statistical designs, at best cumbersome and inefficient today, will be wholly insufficient for matching patients with effective drugs,” they wrote.2

“Although the results of our trial predict a 79% probability of success of neratinib in a phase 3 trial of neoadjuvant treatment in patients with HER2-positive, hormone receptor-negative cancer, a modified design is required in order to reflect the current standard of dual HER-targeting (regimens containing pertuzumab [Perjeta] and trastuzumab [Herceptin]) that has already received accelerated approval,” the coauthors reported.1 “The updated phase 3 design will test the combination of neratinib, pertuzumab, trastuzumab, and taxane with the combination of pertuzumab, trastuzumab, and taxane, and the combination of neratinib, trastuzumab, and taxane, all followed by doxorubicin and cyclophosphamide.”

I-SPY 3 will allow enrollment of HER2-positive patients with both hormone receptor-negative and -positive cancers, they noted.





1. Park JW, Liu MC, Yee D, et al. Adaptive Randomization of Neratinib in Early Breast Cancer. TheNew England Journal of Medicine, 2016;375:11-22.

2. Harrington D, Parmigiani G. I-SPY 2 - A Glimpse of the Future of Phase 2 Drug Development?TheNew England Journal of Medicine, 2016;375:7-9.