Phase 3 Trial Finds Adjuvant Neratinib Shows Promise for Early-Stage HER2+ Breast Cancer

Results from the final protocol-defined analysis of the phase 3 ExteNET trial demonstrated that at 8 years of follow-up, fewer deaths and improved cumulative incidence of central nervous system (CNS) recurrences were shown with adjuvant neratinib (Nerlynx) compared with placebo in patients with early-stage HER2-positive breast cancer following trastuzumab (Herceptin)-based therapy.

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

Moreover, patients who received neratinib consistently experienced 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,” lead study author Frankie Ann Holmes, MD, a retired breast medical oncologist, said in a virtual poster presentation during the 2020 San Antonio Breast Cancer Symposium.

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 vs 90.2% in the placebo group (stratified HR, 0.95; 95% CI, 0.075-1.21; 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 (HR)-positive, 76% (n = 1085) were node positive, and 62% (n = 884) received concurrent trastuzumab and chemotherapy.

Additionally, among HR-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 HR-positive subgroups, baseline patient characteristics were similar to the ITT population and those who received placebo.

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

Moreover, patients with HR-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 HR-positive disease who did not achieve a pCR from trastuzumab-based therapy achieved 7.4% (HR, 0.60; 95% CI, 0.33-1.07) and 7.0% (HR, 0.61; 95% CI, 0.32-1.11) absolute benefits, respectively.

Subgroup analyses from the updated 8-year data showed that OS findings were consistent with iDFS findings. OS was numerically improved in HR-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 HR-negative patients (n = 1209), with OS rates of 88.1% and 90.3%, respectively (HR, 1.18; 95% CI, 0.83-1.69).

In the HR-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 HR-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 HR-positive less than 1 year [since trastuzumab-based therapy] population and in the no pCR group,” explained Holmes.

Regarding CNS recurrence, patients with HR-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 HR-positive population who received trastuzumab-based therapy within 1 year prior to randomization, the estimated CNS-DFS [JH8] 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 anti-cancer 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 TKIs in the early-stage setting, particularly with benefit seen in reducing CNS recurrence 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.”

Reference:

Holmes FA, Moy B, Delaloge S, et al. Continued efficacy of neratinib in patients with HER2-positive early-stage breast cancer: final overall survival analysis from the randomized phase 3 ExteNET trial. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11; 2020; Virtual. Poster PD3-03. https://bit.ly/377gMaq