Reshma L. Mahtani, DO:The NALA trial was an open-label phase 3 study. It enrolled 621 patients with HER2+ metastatic breast cancer, centrally confirmed. Patient characteristics were well balanced at baseline. Nearly 80% of patients in each arm were younger than 65 years, and about 80% of patients in each arm had visceral disease. Almost 70% of patients had at least 2 prior lines of HER2-targeted treatment for metastatic disease, while about 30% had 3 or more. Patients were randomized 1:1 to either neratinib plus capecitabine or lapatinib plus capecitabine, and patients on the neratinib arm also received antidiarrheal prophylaxis with loperamide. The coprimary endpoints were progression-free survival [PFS] and overall survival [OS].
A landmark analysis showed that the progression-free survival curves started to separate after 6 months, with the 6-month PFS rates being 47% versus 38%. A prespecified restricted means analysis for PFS was conducted and was limited to follow-up of 24 months, showing an improvement in PFS of about 2 months with the addition of neratinib compared to lapatinib. It was 8.8 versus 6.6 months. Finally, there was a numerical but not statistically significant benefit in OS documented with neratinib.
Other endpoints including objective response rate, clinical benefit rate, and median duration of response all favored neratinib compared to lapatinib. Most important, there was an increase in time to intervention for symptomatic disease in the central nervous system [CNS]. So this is certainly a clinically meaningful endpoint for patients in the metastatic setting. Although not definitively proven, it may also have implications in the adjuvant setting.
As a reminder, the therapy is also approved. Neratinib is approved in the extended adjuvant setting and for patients who are at extremely high risk for recurrence. For those who have had neoadjuvant treatment and have significant residual disease, we know that the use of T-DM1 [trastuzumab emtansine], as shown in the KATHERINE trial, did not impact the incidence of CNS metastases. So the data really beg the question, “Are there patients in the extended adjuvant setting who are at extremely high risk of relapse, even in the brain, who may benefit?” Again, this could not be demonstrated definitively in the ExteNET trial, but it is something to think about.
In terms of toxicities, it’s important to realize that dose reductions and holds in this study were comparable in the 2 arms. There was a higher rate of grade 3 diarrhea with neratinib24% versus 13%. Treatment discontinuation due to the diarrhea was similar—about 2.5% in each arm. The median cumulative number of days with grade 3 diarrhea was 4 in each arm.
Transcript edited for clarity.
Case: A 59-Year-Old Woman WithHER2+ De Novo Metastatic Breast Cancer
Treatment and Follow-Up