Improved PFS with neratinib vs lapatinib in previously treated HER2+ breast cancer

Roshini Claire Anthony
03 Sep 2019
NALA: Neratinib outdoes lapatinib in improving PFS in HER2+ breast cancer
Dr Yap Yoon Sim

Patients with HER2+ breast cancer with disease progression despite 2 lines of HER2-directed therapy may improve their progression-free survival (PFS) with the addition of neratinib than lapatinib to capecitabine, according to the phase III NALA* trial.

“The NALA study met its primary objective; neratinib plus capecitabine was superior to lapatinib plus capecitabine as third-line or beyond treatment for HER2+ metastatic breast cancer (MBC),” said Dr Yap Yoon Sim from the National Cancer Centre Singapore who presented the findings at the Best of ASCO 2019 annual meeting held in Singapore.

The study population comprised 621 women (79 percent aged <65 years, 59 percent with hormone receptor-positive disease) with HER2+ MBC who had previously received ≥2 lines of HER2-directed regimens for metastatic disease. They were randomized 1:1 to receive oral neratinib (240 mg/day) plus capecitabine (1,500 mg/m2/day on days 1–14 of a 21-day cycle) plus loperamide** or oral lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m2/day on days 1–14 of a 21-day cycle) until disease progression. Endocrine therapy was not permitted during the trial.

Risk of progression or death was 24 percent lower among patients on neratinib plus capecitabine compared with lapatinib plus capecitabine (hazard ratio [HR], 0.76, 95 percent confidence interval [CI], 0.63–0.93; p=0.0059), with PFS rates of 47 percent vs 38 percent at 6 months, 29 percent vs 15 percent at 12 months, and 16 percent vs 7 percent at 18 months. [BASCO 2019, abstract 1002]

Restricted means analysis at 24 months showed that mean PFS was 8.8 and 6.6 months in the neratinib and lapatinib arms, respectively (p=0.0003).

Subgroup analysis showed a trend toward favouring neratinib regardless of age (<65 vs ≥65 years), race, geographic region, or number of prior HER2-directed treatments, with significant risk reductions with neratinib in patients with non-visceral metastasis (HR, 0.44; p=0.007) and hormone receptor-negative disease (HR, 0.42; p<0.001).

Overall survival (OS) did not significantly differ between patients in the neratinib and lapatinib arms (mean 24.0 vs 22.2 months, HR, 0.88, 95 percent CI, 0.72–1.07; p=0.2086), with restricted means analysis showing a 1.7-month difference between arms, favouring the neratinib arm, at 48 months.

The overall cumulative incidence of central nervous system (CNS) metastases was lower in the neratinib than lapatinib arm (22.8 percent vs 29.2 percent; p=0.043). CNS metastases were mainly treated with radiation therapy which was required by fewer patients in the neratinib than lapatinib arm (11 percent vs 15 percent).

This suggests a delay in CNS progression which is consistent with results from previous neratinib studies, said Yap. [JAMA Oncol 2016;2:1557-1564]

In patients with measurable disease (n=256 and 270 in the neratinib and lapatinib groups, respectively), objective response rates were numerically but not significantly higher among neratinib vs lapatinib recipients (33 percent vs 27 percent; p=0.1201). However, neratinib recipients had better clinical benefit rates than lapatinib recipients (45 percent vs 36 percent; p=0.0328) and a longer duration of response (median 8.5 vs 5.6 months, HR, 0.50, 95 percent CI, 0.33–0.74; p=0.0004).

Dose reduction was slightly more frequent in the neratinib than the lapatinib arm (24 percent vs 20 percent, respectively), though dose reduction of capecitabine was more frequent in the lapatinib arm (49 percent vs 39 percent), the latter likely related to the higher dose of capecitabine used in the lapatinib arm, said Yap.

The incidence of grade 3–4 treatment emergent adverse events (TEAEs) was comparable between groups (61 percent vs 60 percent). More lapatinib than neratinib recipients discontinued treatment due to TEAEs (14.5 percent vs 10.9 percent), which was possibly due to high-dose capecitabine-related hand-foot syndrome.

Diarrhoea was the most common AE in both arms, with grade 3 diarrhoea affecting a greater proportion of neratinib than lapatinib recipients (24 percent vs 13 percent). However, treatment discontinuation due to diarrhoea affected a similar proportion of patients in both arms (2.6 percent vs 2.3 percent).

With the significant PFS benefit favouring neratinib and no new safety signals, the trial results suggest that neratinib plus capecitabine is an effective option for treating progressive HER2+ MBC, said Yap.


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