1. The addition of neratinib to standard therapy was more likely to result in higher pathological complete response rates compared to standard therapy with trastuzamab in HER-2 positive, hormone receptor negative breast cancer patients.
2. Toxicity associated with neratinib was mainly gastrointestinal related, but was manageable with medication.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Breast cancer is a heterogeneous disease presenting challenges for diagnosis and subsequent management. Using the unique biologic properties of tumours, genetic testing can aid in identifying breast cancer subtypes and, in turn, direct targeted therapies. Neratinib is a tyrosine kinase inhibitor, which has shown promising results against HER-2 positive metastatic breast cancer. This study aimed to rapidly identify these subtypes, and then randomize patients to have neratinib and paclitaxel, versus standard therapy of paclitaxel and trastuzamab. The primary endpoint was pathological complete response (absence of residual cancer in the breast or lymph nodes at the time of surgery). The results showed a favourable pathologic complete response rate in the neratinib group compared to the control group for HER-2 positive, hormone-receptor negative breast cancers. The associated side effects were mainly gastrointestinal related (diarrhea), and was managed adequately with anti-diarrheal medication. The strengths of this study was the randomization of patients, and having data supporting adaptive therapy which allows patients to have a more personalized approach to their care and limits the exposure to therapies that may be ineffective or have increase adverse effects. Further, adaptive approach can streamline future randomized controlled trials. The limitation of this study was the small number of patients involved in the randomization.
In-Depth [randomized controlled trial]: This study was an adaptive randomized controlled trial aimed to match experimental therapies with breast cancer subtypes. The study subdivided early stage patients according to biomarkers status with respect to HER-2, hormone receptors and a 70-gene assay. Patients underwent randomization according to subtype and experimental therapy that would accordingly be best suited. Neratinib was evaluated against 10 biomarkers and control. The primary endpoint was complete pathological response. MRI was used to assess degree of response, and Bayesian predictive probabilities were used to estimate success in subsequent phase 3 study if a success threshold of 85% was reached.
A total of 127 patients were included in the neratnib-paclitaxel group and 78 patients to the neratinib-paclitaxel-trastuzamab group. The estimated complete pathological response rate was 56% (95% Bayesian probability interval (PI) 37-73%) among the neratinib group, versus 33% (95%PI 11-54%) in the control group. The probability of neratinib being superior to control was 95%, and was estimated to have an 79% predicted probability of success in a phase 3 trial involving at least 300 patients.
In terms of toxicity, diarrhea was the most common adverse event, with grade 3 or 4 diarrhea in 38% of the patients in the neratinib group. No deaths occurred as result of adding neratinib.
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