In an 8-year follow up analysis of patients on the ExteNET trial, researchers saw that overall survival was not significantly different to rates on placebo.
Neratinib (Nerlynx) did not show a significant overall survival (OS) Improvement compared with placebo for patients with early-stage HER2 positive breast cancer in the extended adjuvant setting, however, invasive free survival (IFS) remained significant, according to data from the final OS analysis of the ExteNET trial (NCT00878709).1
The final analysis of the international, randomized, double-blind, placebo-controlled, phase 3 trial was published in the European Journal of Cancer and showed that at a median follow up of 8.1 years (IQR, 7.0-8.8) 8.9% (n = 127) of the patients in the neratinib group and 9.6% (n = 137) of patients in the placebo group died at the time of analysis. The 8-year OS rates between the neratinib group vs placebo group was 90.1% (95% CI, 88.3%-91.6%) vs 90.2% (95% CI, 88.4%-91.7%), respectively and the slight difference was not statistically significant (HR 0.95; 95% CI, 0.75–1.21, P = .6914).
Across predefined subgroups in the intention-to-treat (ITT) population, these OS similarities were still seen. In patients that were hormone-receptor positive (n = 1631) the 8-year OS rate was 91.6% in the neratinib group compared with 90.1% in the placebo group with a HR of 0.80 (95% CI, 0.58-1.11), while in the hormone-receptor negative group (n = 1209) the OS rate for patients on the study drug was 88.1% compared with 90.3% in the placebo group (HR, 1.18; 95% CI, 0.83–1.69).
For patients that were node-negative (n = 1209) OS was still similar but were slightly higher in the placebo group than in the neratinib group at 90.3% vs 88.1%, respectively (HR, 1.18; 95% CI, 0.83–1.69). For patients with positive nodes these similarities were seen, but patients with 4 or more positive nodes (n = 841) the 8-year OS rate was also slightly higher for those on placebo than with the study drug at 85.9% vs 83.8%, respectively (HR, 1.17; 95% CI, 0.82–1.69).
A subgroup analysis was also performed on patients that were confirmed to be HER2-positive finding that, again, the 8-year OS rate did not show a significant difference between the 2 groups. In these patients who were hormone-receptor positive (n = 951) the 8-year OS rate was 93.2% in the neratinib group and 90.4% in the placebo group (HR, 0.65; 95% CI, 0.41–1.03), whereas in the hormone-receptor negative group (n = 845) the OS rate was slightly higher in the placebo group vs the neratinib group at 91.2% vs 89.0%, respectively (HR, 1.13; 95% CI, 0.73–1.76).
At the time of 5-year follow up for patients on this trial, researchers had initially found that 1-year with the irreversible pan-HER tyrosine kinase inhibitor (TKI) after treatment with chemotherapy and trastuzumab (Herceptin) reduced the amount of disease relapse in these patients.2 Looking at 2840 women with early HER2-positive breast cancer, patients in the neratinib group (n = 1420) had 116 invasive disease-free survival (DFS) events compared with 163 invasive DFS events in the placebo group (HR, 0.73; 95% CI, 0.57–0.92, P = .0083). Thus, the DFS rate favored patients in the neratinib group vs the placebo group at 90.2% (95% CI, 88.3%-91.8%) vs 87.7% (95% CI, 85.7%-89.4%), respectively. Subgroup DFS findings were also consistent with the initial findings.
Safety findings showed that the treatment remained tolerable. At the 2-year follow up the most common grade 3/4 adverse events (AEs) for patients on neratinib were diarrhea (40, vomiting, and nausea. Patients the needed a dose reduction of neratinib due to treatment emergent AEs (TEAEs) was at 31% and 28% of patients discontinued treatment due to TEAEs. Researchers also observed serious TEAEs in 7% of patients in the neratinib including diarrhea (n =22), vomiting (n = 12), and dehydration (n = 9).
In the ITT population of the 8-year follow up, the number of documented deaths which occurred was 264 with 184 of those deaths due to disease progression.1 Among the patients who died because of disease progression, 6.0% (n = 85) were on neratinib compared with 7.0% (n = 99) on placebo. Eighty deaths were due to other causes, which included cardiovascular events and secondary cancer, with 3.0% (n = 42) of patients on neratinib and 2.7% (n = 38) of patients on placebo dying due to these other causes.
“This final analysis of the intention-to-treat population of the ExteNET trial did not demonstrate an overall survival benefit with extended adjuvant neratinib therapy versus placebo after a median follow-up of 8 years for women with early-stage HER2-positive breast cancer,” concluded researchers on the 8-year follow up analysis,” wrote the study authors.
1. Holmes FA, Moy B, Delaloge S, et al; ExteNET Study Group. Overall survival with neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): A randomised, double-blind, placebo-controlled, phase 3 trial. Eur J Cancer. 2023;184:48-59. doi: 10.1016/j.ejca.2023.02.002
2. Martin M, Holmes FA, Ejlertsen B, et al; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1688-1700. doi:10.1016/S1470-2045(17)30717-9