SAN ANTONIO — New results from the ExteNET study of the investigational drug neratinib following adjuvant trastuzumab chemotherapy confirm a benefit of the agent beyond the previously reported 2-year results, researchers reported here at the San Antonio Breast Cancer Symposium (SABCS) 2015.
"The 3-year exploratory analysis is consistent with previously reported results at 2 years and supports that neratinib significantly improves invasive disease-free survival (iDFS)," said principal investigator Arlene Chan, MD, from the Breast Cancer Research Centre–WA, Curtin University, Perth, Western Australia.
"One of the purposes of presenting these results at this meeting was to really demonstrate to the oncology community that with ongoing follow-up — certainly to this point — we are still seeing a consistent benefit of neratinib," she added, explaining that concerns about persistent benefit of therapy have arisen out of follow-up from the HERceptin Adjuvant (HERA) study of patients treated with trastuzumab.
"In the HERA landmark trial, there have been some concerns raised that the early improvement seen was subsequently lost in longer follow-up and that this may also occur with longer follow-up in our dataset."
Despite survival benefits that have been shown with standard adjuvant trastuzumab chemotherapy, these patients with breast cancer still have a 26.3% possibility of relapse at 8.4 years' follow-up, she said.
The ExteNET trial enrolled 2840 patients with HER2-positive breast cancer and prior adjuvant trastuzumab-based chemotherapy (median time since treatment, 4.5 months) who had residual invasive disease or positive lymph nodes.
Patients (median age, 52 years) were randomly assigned to 1 year of neratinib (240 mg/d) — an oral tyrosine kinase inhibitor of HER1, -2, and -4 — or placebo, with the outcome of invasive disease-free survival (iDFS) at 2 and 5 years as well as overall survival.
A primary analysis reported by Medscape Medical News showed a statistically significant benefit of neratinib treatment in terms of higher 2-year iDFS (93.9% vs 91.6%; hazard ratio [HR], 0.67; P = .009), particularly in hormone receptor–positive (HR, 0.51; P = .001) and HER2-positive (HR, 0.51; P = .002) disease.
The newer follow-up, with a different trial sponsor, involves an unplanned exploratory analysis, with unadjusted P values, among 1.778 patients (856 receiving neratinib and 922 receiving placebo) — about 85% of the cohort from the 2-year analysis, Dr Chan cautioned.
In the intention-to-treat analysis, the 3-year iDFS results show "there is again a consistent benefit to those patients receiving neratinib up to 4 years" when compared with placebo (90.5% vs 88.6%; HR, 0.74; P = .023), which is mirrored in the HER2-positive subgroup (90.4% vs 87.9%; HR, 0.70; P = .037), as well as the hormone receptor–positive group (92.3% vs 87.9%; HR, 0.57; P = .003), she said.
Diarrhea is the main adverse event reported in ExteNET. Almost 40% of patients had grade 3 diarrhea within the first 30 days, with notably no prophylactic loperamide given.
"This clearly has an impact on quality of life," said Dr. Chan, "but typically the frequency and severity of this will abate and the incidence can be reduced to a rate of between zero and 17% (with prophylactic loperamide), and I would suggest the rates would be even less with improved patient education and compliance."
"This is good stuff," said Lajos Pusztai, MD, DPhil, Yale Cancer Center, New Haven, Connecticut, when asked by Medscape Medical News to comment on the results.
"Various studies have established that, in general, longer is better with adjuvant therapy. For example, 10 years of tamoxifen is better than 5 years for hormone-receptor positive disease. The problem is that, for HER-positive patients treated with trastuzumab, 1 year of treatment is as good as 2 years," he said, so "an alternative strategy is needed."
Dr Pusztai explained that, to date, neratinib has improved DFS but that the patients best suited for this treatment are "likely higher-risk patients." That's because considerable diarrhea is associated with treatment. Thus, the "tradeoff" between this adverse event and chance of gaining benefit is "more favorable for higher-risk patients because recurrence is more likely."
Dr Chan is a consultant for Pfizer, Amgen, and Eisai and has contracts with Novartis, AbbVie, Aslan, and Spectrum.
San Antonio Breast Cancer Symposium (SABCS) 2015: Abstract S5-02. Presented December 11, 2015.