medwireNews: Supplementing capecitabine with neratinib instead of lapatinib is associated with a significant improvement in the progression-free survival (PFS) of previously treated patients with metastatic HER2-positive breast cancer, shows the phase 3 NALA trial.
Noting that neratinib addition also significantly improved other outcomes, albeit not overall survival (OS), the researchers remark that neratinib plus capecitabine “is an appropriate treatment option for patients with HER2-positive [metastatic breast cancer] progressing after ≥ 2 lines of HER2-directed treatment.”
And they add that the results of the study, which “is the first […] to demonstrate superiority of one HER2-directed tyrosine kinase inhibitor over another,” led to the approval by the FDA of the neratinib combination in this setting.
Cristina Saura (Vall d’Hebron University Hospital, Barcelona, Spain) and co-investigators randomly assigned 621 participants to receive either neratinib 240 mg/day alongside twice-daily capecitabine 750 mg/m2 for 14 days of each 21-day cycle or lapatinib 1250 mg/day plus capecitabine on the same schedule but at a dose of 1000 mg/m2. Patients in the neratinib arm received prophylactic antidiarrheal medication during the first treatment cycle.
Over a median follow-up of 29.9 months, the co-primary endpoint of PFS was significantly improved with neratinib versus lapatinib, at a median of 8.8 and 6.6 months, respectively, and a hazard ratio (HR) for progression or death of 0.76.
The study authors point out that the PFS Kaplan–Meier curves were “largely indistinguishable” up to week 24, only separating after this timepoint, suggesting “the proportional hazards assumption was violated, which was confirmed by statistical testing.”
They note, however, that a restricted means analysis confirmed the findings, showing an average PFS difference of 2.2 months in favor of neratinib.
The other primary endpoint of OS was numerically better with neratinib than lapatinib, at 24.0 versus 22.2 months (HR=0.88), but the between-group difference was not statistically significant.
Neratinib addition was associated with a significantly lower cumulative incidence of intervention for central nervous system disease, at a rate of 22.8% compared with 29.2% for lapatinib, and a significantly longer duration of response, with corresponding medians of 8.5 and 5.6 months.
But the objective response rate was only numerically higher in the neratinib than lapatinib group, at 32.8% and 26.7%, respectively.
Saura et al describe the duration of response with neratinib as “promising,” especially when “considering patients’ prior treatment load in the metastatic setting,” and suggest that this “may explain the clear separation of PFS curves beyond 24 weeks.”
The team notes that the “[s]afety data in NALA were consistent with previous studies.”
Serious treatment-emergent adverse events (AEs) were observed in 34.0% of neratinib-treated participants and 29.9% of those given lapatinib. The most common AE of grade 3 or 4 in the neratinib and lapatinib groups was diarrhea, at 24.4% and 12.5%, followed by palmar–plantar erythrodysesthesia, at 9.6% and 11.3%.
Furthermore, health-related quality of life, as assessed by the EORTC QLQ-C30 questionnaire, “was generally maintained, supporting the use of neratinib with appropriate management strategies,” conclude the investigators in the Journal of Clinical Oncology.
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