Neratinib Improve OS and CNS-Related Outcomes in Early-Stage HER2+ Breast Cancer

Treatment with the irreversible pan-HER inhibitor neratinib (Nerlynx) demonstrated a modest overall survival (OS) benefit in patients with HER2-positive breast cancer compared with placebo, according to the long-term OS and central nervous system (CNS) results from the phase 3 ExteNET trial presented in a poster during the ESMO Breast Cancer Virtual Meeting 2021.

Previously in the ExteNET trial (NCT00878709), the final efficacy results published in Clinical Breast Cancer showed that neratinib lead to significant improvement in invasive disease-free survival (iDFS) in patients with HER2-positive, HR-positive disease who received therapy for ≤1 year. At 5 years, the iDFS absolute benefit the intention-to-treat (ITT) population of 2840 patients was 2.5% compared with the placebo arm (hazard ratio, 0.73; 95% CI, 0.57-0.92). The study also showed improvements in CNS events and OS leading to a subgroup analysis of these populations.

Prior studies including the phase 3 KATHERINE study (NCT01772472), the phase 3 APHINITY study (NCT01358877), and the phase 3 ALTTO study (NCT00490139) also demonstrated the ability of neratinib to prevent CNS recurrence, but available therapies for this purpose remain an unmet medical need.

For the final protocol-defined analysis of OS and CNS outcomes from ExteNET the subgroups of patients from the HR-positive/≤1-year group who fit the European Medicine Agency indication for neratinib as well as those with a higher risk of relapse, including the HR-positive/≤1 year no pathological complete response (pCR) group were evaluated. For the assessment, OS was defined as the time from randomization to the date of death of any cause. The CNS-related end points included the cumulative incidence of CNS recurrence and CNS-DFS.

Baseline characteristics were well-balanced between the subgroups assessed and were found to be similar to the ITT population.

At a median follow-up of 8.1 years (range, 0.0-9.9 years), during which time treatment was completed by 54.3% of the study population, neratinib achieved an estimated OS rate of 90.1% in the ITT population compared with 90.2% in the placebo arm (stratified hazard ratio, 0.95; 95% CI, 0.75-1.21; P =.6916). In the subgroup of patients with HR-positive disease, the 8-year OS rates were 91.6% with neratinib compared with 90.1% in the placebo group (hazard ratio, 0.80; 95% CI, 0.58-1.2).

An improvement in OS was not observed with neratinib n the subgroup of 1209 patients with HR-negative tumors. The 8-year OS rate observed was 88.1% with neratinib compared with 90.3% with placebo (hazard ratio, 1.18; 95% CI, 0.83-1.69).

The estimated 8-year OS rates were modestly higher in the subgroup of patients with centrally confirmed HER2-positive tumors than those observed in the ITT population. Specifically, neratinib led to an 8-year OS rate of 91.2% in this subgroup compared with 90.8% with placebo (hazard ratio, 0.86; 95% CI, 0.63-1.18; P =.3585).

In HR-positive/≤1 year population, the estimated 8-year OS rate was 91.5% versus 89.4% with placebo (hazard ratio, 0.79; 95% C, 0.55-1.13). This result corresponded to a 2.1% absolute benefit with neratinib.

Eight-year OS rates were also estimated in the analysis based on pCR status. Among 295 patients with no pCR, the 8-year OS rates observed were 91.3% with the neratinib treatment versus 82.2% with placebo (hazard ratio, 0.47; 95% CI, 0.23-0.92), achieved an absolute benefit of 9.1%. Among the 38 patients with a pCR, the 8-year OS rate observed with neratinib was 93.3% compared with 73.7% in the placebo arm for an absolute benefit of 19.6% (hazard ratio, 0.40; 95% CI, 0.06-1.88).

Looking at the incidence of CNS recurrence at 5 years, the rate of CNS recurrence was 1.3% (95% CI, 0.8%-2.1%) in the neratinib arm compared with 1.8% (95% CI, 1.2%-2.7%) in the placebo arm. The HR-positive/≤1-year population has 0.7% (95% CI, 0.2%-1.7%) cumulative incidence of CNS recurrence on treatment with neratinib compared with 2.1% (95% CI, 1.1%-3.5%) with placebo, and those without prior neoadjuvant therapy in this subgroup had a lower incidence of CNS recurrence than those who did. In addition, those with a CR had a lower incidence of CNS recurrences compared with those who did not.

CNS-DFS was assessed in a Kaplan-Meier analysis the results favored the neratinib arm in all populations. First, in the ITT group, the CNS-DFS was estimated as 97.5% (95% CI, 95.2%-97.4%) with neratinib compared with 96.4% (95% CI, 95.2%-97.4%) with placebo (hazard ratio, 0.73; 95% CI, 0.45-1.17). In the HR-positive/≤1 population, the CNS-DFS was estimated as 98.4% (95% CI, 96.8%-99.1%) in the neratinib arm compared with 95.7% (95% CI, 93.6%-97.2%) in the placebo arm (hazard ratio, 0.41; 95% CI, 0.18-0.85).

Notably, CNS-DFS was better in patients who received prior neoadjuvant therapy compared with those who did not, as well as those who had a pCR.

Neratinib is the first HER2-directed therapy to show a trend towards an improvement in CNS-related outcomes for patients with early-stage HER2-positive breast cancer. The benefit of neratinib in these patients was also consistent across multiple subgroup populations.

_Reference:

_{Chan A, Moy B, Mansi J, et al. Long-term efficacy of neratinib in HER2-positive early-stage breast cancer: overall survival and central nervous system outcomes from the phase 3 ExteNET trial. Presented at: ESMO Breast Cancer Virtual Meeting 2021; May 5-9, 2021; virtual Abstract 45P.}