Neratinib is now approved for use in HER2 positive patients who completed their Trastuzumab-based therapy. This came following the publication of a phase 3 trial with the result indicating the benefit of Neratinib as compared to placebo. In the following blog post I will discuss the result of the ExteNET trial.
all HER2 positive Tumor patients who completed trastuzumab within 2 years must be considered for additional therapy with neratinib.
Background: The addition of Trastuzumab to the standard adjuvant chemotherapy in HER2 positive patients significantly improved overall survival (OS) and became the standard of care (the HERA trial), yet some patients still develop disease recurrence even though they completed the entire Trastuzumab therapy. Neratinib is an oral tyrosine kinase inhibitor of HER1, HER2, and HER4 with proven activity against metastatic HER2-positive metastatic breast cancer.
Study design: this was a multicenter, randomised, double-blind, placebo-controlled, phase 3 trial in multiple countries. The primary objective of the study was to assess the effect of 12 months of Neratinib therapy on disease-free survival (DFS) in women with early-stage HER2-positive breast cancer. Inclusion criteria,
- HER2 positive tumors.
- Sage 1-3 node-positive and node-negative, with ≥T1c.
- Patients were disease free at the time of randomisation.
This was 1:1 randomization with 1420 patients randomised to each arm. There were two major changes to the study protocol pertaining to shortening of the follow-up period and treatment endpoint, please refer to study for details.
In this trial patients treated with Neratinib had fewer recurrences compared to placebo.
Outcome: 2 years after randomisation, patients in the neratinib arm had significantly lower incidence of disease recurrence compared to placebo, HR 0.67, 95% CI 0.50-0.91, p=0.0091. Further subgroup analysis, the greater benefit was seen in the hormone-positive breast cancer patients.
Toxicity: diarrhea was the most common side effects, with grade 3 occurring in 40% of patients, grade 1-2 occurring in 55% of patients, most grade 3 diarrhea occurred in the first month. Dose adjustments were permitted in the management of diarrhea. Both arms of the trial showed a decline in quality of life in the first month, however, after first-month QOL measures adjusted and approached baseline.
Discussion: the investigators in this study admit to the limitations of short follow-up, they also discussed the protocol amendments. However, they raise the point of shorter follow-up positive findings does not mean bad things will happen in longer follow-up. They recommend the consideration of neratinib in HER2 patients with high risk of relapse following completion of the trastuzumab therapy.
Conclusion: Neratinib use in disease-free, HER2 positive patient, following completion of Trastuzumab is welcome addition, I would like to see more confirmation trials both in the adjuvant setting and metastatic setting, I also have some concerns regarding the toxicity, hopefully with more clinical experience clinicians will be able to mitigate common toxicities associated with the drug.