Neratinib Leads to Fewer Deaths, CNS Benefit, Potential OS Improvement in Early-Stage HER2+ Breast Cancer

At 8 years of follow-up, fewer deaths and a reduced cumulative incidence of central nervous system (CNS) recurrences were reported with adjuvant neratinib (Nerlynx) compared with placebo in patients with early-stage HER2-positive breast cancer after trastuzumab (Herceptin)–based therapy, according to the results of the final protocol-defined analysis of the phase 3 ExteNET trial (NCT00878709) that were presented in a virtual poster during the 2020 San Antonio Breast Cancer Symposium.

In the intention-to-treat (ITT) population (n = 2840), 8.9% (n = 127) of patients who received neratinib (n = 1420) died prior to the analysis cutoff date compared with 9.6% (n = 137) of patients who received placebo (n = 1420).

Notably, patients who received neratinib had consistently fewer CNS events compared with placebo. The cumulative incidence of CNS recurrences in the ITT population was 1.3% (95% CI, 0.8%-2.1%) with neratinib versus 1.8% (95% CI, 1.2%-2.7%) with placebo.

At 5 years, the Kaplan-Meier estimated rate of CNS disease-free survival (DFS) in the ITT population was 97.5% (95% CI, 96.4%-98.3%) with neratinib (n = 29 events) versus 96.4% (95% CI, 95.2%-97.4%) with placebo (n = 42 events; HR, 0.73; 95% CI, 0.45-1.17).

“Neratinib is the first HER2-directed agent to show a trend toward improved CNS outcomes in early-stage HER2-positive breast cancer, with consistently fewer CNS events observed in the neratinib arm in all groups reported,” said lead study author Frankie Ann Holmes, MD, a retired breast medical oncologist, in a poster presentation of the data.

However, no statistically significant improvement in overall survival (OS) was observed between arms. The estimated 8-year OS rate was 90.1% in the neratinib group versus 90.2% in the placebo group (stratified HR, 0.95; 95% CI, 0.75-1.21; P = .6916).

The multicenter, double-blind, placebo-controlled ExteNET trial randomized patients to receive 240 mg of daily neratinib or placebo for 1 year.

The trial enrolled patients with stage I to IIIC HER2-positive primary breast cancer who received locoregional treatment and completed trastuzumab-based adjuvant therapy, with or without neoadjuvant therapy, within 2 years of randomization.

In February 2010, per amendment 3 protocol, recruitment was restricted to higher-risk patients with stage II to IIIC disease who completed trastuzumab-based therapy within 1 year of randomization; patients who completed neoadjuvant therapy and did not achieve a pathologic complete response (pCR) also qualified.

Within the ITT population, 57% (n = 816) of patients who received neratinib were hormone receptor–positive, 76% (n = 1085) were node positive, and 62% (n = 884) received concurrent trastuzumab and chemotherapy.

Additionally, among hormone receptor–positive patients who received prior trastuzumab within 1 year of randomization (n = 1334), 81% (n = 540) were node positive, and 61% (n = 411) received concurrent trastuzumab and chemotherapy. Furthermore, 89% (n = 116) of HR-positive patients who did not achieve a pCR (n = 295) were node positive, and 69% (n = 90) had concurrent trastuzumab and chemotherapy.

Across hormone receptor–positive subgroups, baseline patient characteristics were similar to those of the ITT population and those who received placebo.

Prior findings from the ExteNET study demonstrated a 2.5% absolute benefit in 5-year invasive DFS with neratinib (IDFS; HR, 0.73; 95% CI, 0.57-0.92) and a 1.7% absolute benefit in 5-year distant DFS (DDFS; HR, 0.78; 95% CI, 0.60-1.01) in the ITT population.

Moreover, patients with hormone receptor–positive disease who received trastuzumab-based therapy within 1 year of randomization had a 5.1% absolute benefit in 5-year IDFS (HR, 0.58; 95% CI, 0.41-0.82) and a 4.7% absolute benefit in 5-year DDFS (HR, 0.57; 95% CI, 0.39-0.83). Patients with hormone receptor–positive disease who did not achieve a pCR from trastuzumab-based therapy achieved absolute benefits of 7.4% (HR, 0.60; 95% CI, 0.33-1.07) and 7.0% (HR, 0.61; 95% CI, 0.32-1.11), respectively.

Subgroup analyses from the updated 8-year data showed that OS findings were consistent with IDFS findings. OS was numerically improved in hormone receptor–positive patients who received neratinib (91.6%) compared with those who received placebo (90.1%; HR, 0.80; 95% CI, 0.58-1.12). However, neratinib versus placebo did not appear to improve OS among hormone receptor–negative patients (n = 1209), with OS rates of 88.1% and 90.3%, respectively (hazard ratio, 1.18; 95% CI, 0.83-1.69).

In the hormone receptor–positive patients who received trastuzumab within 1 year prior to randomization, 7.9% (n = 53) of patients who received neratinib died compared with 10.2% (n = 68) of patients who received placebo. The estimated OS rates were 91.5% and 89.4%, respectively (HR, 0.79; 95% CI, 0.55-1.13).

Patients with hormone receptor–positive disease who had residual disease (no pCR) reported a 91.3% 8-year OS rate with neratinib versus 82.2% with placebo, which translated to an absolute benefit of 9.1% (HR, 0.47; 95% CI, 0.23-0.92). Patients who achieved a pCR reported 8-year OS rates of 93.3% and 73.7%, respectively, reflecting an absolute benefit of 19.6% (HR, 0.40; 95% CI, 0.06-1.88).

“Although the powered OS analysis in the ITT population did not achieve statistical significance, descriptive analyses suggest that there is a trend that neratinib may improve OS in the hormone receptor–positive less than 1 year [since trastuzumab-based therapy] population and in the no-pCR group,” explained Holmes.

Regarding CNS recurrence, patients with hormone receptor–positive disease who received trastuzumab within 1 year of randomization, as well as patients who received neoadjuvant therapy, irrespective of pCR status, had a lower number of CNS events.

In the hormone receptor–positive population who received trastuzumab-based therapy within 1 year prior to randomization, the estimated CNS-DFS rates were 98.4% (95% CI, 96.8%-99.1%) with neratinib (n = 9 events) and 95.7% (95% CI, 93.6%-97.2%) with placebo (HR, 0.41; 95% CI, 0.18-0.85).

Further stratification showed that the estimated CNS-DFS rate for patients who did not receive prior neoadjuvant therapy (n = 980) was 98.2% (95% CI, 96.3%-99.2%) with neratinib (n = 7 events) and 97.5% (95% CI, 95.3%-98.6%) with placebo (n = 10 events; HR, 0.70; 95% CI, 0.25-1.82). Among patients who did receive prior neoadjuvant therapy (n = 354), estimated CNS-DFS rates were 98.7% (95% CI, 94.8%-99.7%) and 91.2% (95% CI, 85.1%-94.8%), respectively (neratinib, n = 2 events; placebo, n = 13 events; HR, 0.18; 95% CI, 0.03-0.63).

Finally, the estimated CNS-DFS rate among patients who did not achieve a pCR was 98.4% (95% CI, 93.6%-99.6%) with neratinib (n = 2 events) and 92.0% (95% CI, 85.6-95.7%) with placebo (n = 10 events; HR, 0.24; 95% CI, 0.04-0.92). Among patients who did achieve a pCR, the CNS-DFS rate was 100% (95% CI, 100%-100%) with neratinib (n = 0 events) and 81.9% (95% CI, 53.1%-93.9%) with placebo (n = 3 events; HR, 0; 95% CI, not estimable-1.08).

Additionally, the uptake of anticancer medications, including endocrine therapy, HER2-directed therapy, and chemotherapy, among other agents, by patients in the ITT population during follow-up was balanced between groups (neratinib, 25.2%; placebo, 28.2%).

“We think this analysis offers hope for a strategy of tyrosine kinase inhibitors in the early-stage setting, particularly with benefit seen in reducing CNS recur-rence for highest-risk patients,” said Tiffany A. Traina, MD, vice chair of oncology care and section head of the Triple-Negative Breast Cancer Clinical Research Program at Memorial Sloan Kettering Cancer Center, in a virtual discussion of the updated ExteNET data. “[However], we may never know how extended-adjuvant neratinib performs following either pertuzumab [Perjeta] or T-DM1 [ado-trastuzumab emtansine; Kadcyla]–based regimens.”

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