Miami Breast Cancer Conference® Abstracts Supplement
In the ExteNET clinical trial, extended adjuvant treatment with neratinib (NER) reduced the absolute risk of recurrence or death by 5.1% at 5 years vs placebo in hormone receptor–positive (HR+)/HER2-positive (HER2+) early breast cancer patients who initiated treatment 1 year or less post trastuzumab. Diarrhea was the main reason for NER discontinuation in the first 3 cycles (c) (1 c = 28 days [d]). DIANER further studied 3 previously reported strategies for managing diarrhea (CONTROL) in patients receiving NER.
DIANER is a European, controlled, randomized, phase 2 study in patients with HER2+/HR+ early breast cancer (stage IB-IIIC) who completed prior neo/adjuvant trastuzumab-based therapy within 1 year. Patients were randomly assigned 1:1:1 to arm A: NER (240 mg/d x 1 year) plus loperamide (LP) (12 mg/d x 14 d → 8 mg/d till end of c 2 → as needed [PRN]); arm B: NER dose escalation (120 mg/d x 7 d → 160 mg/d till d 14 → 240 mg/d x 13 c) plus LP PRN; or arm C: NER (like arm A) plus LP (12 mg/d x 14 d → 8 mg/d x 14 d → PRN) plus colesevelam (3750 mg/d x 28d). Patients were stratified by menopausal status and prior anti-HER2 therapy (trastuzumab vs trastuzumab plus pertuzumab). The primary end point was the rate of early (in the first 3 c) NER discontinuations due to diarrhea. Simon’s optimal 2-stage design was used with a target of 5% (H1) vs 13% (H0). In the first stage, up to 36 patients per arm were to be enrolled. Arms with 4 or more early discontinuations due to diarrhea were planned to be closed, otherwise recruitment would continue up to 105 patients per arm. Secondary end points were the rate of NER discontinuations (any reason); adverse events (AEs) and hospitalizations; duration, severity, and treatments for diarrhea; and NER exposure.
From September 2022 to October2024, 177 patients were randomly assigned (41 arm A, 107 arm B, 29 arm C) at 47 sites. The median age was 51 years (range, 30-80), 50.3% of patients were postmenopausal, and 39.0%, 28.8%, and 15.3% had stage IIA, IIB, and IIIA disease, respectively. Prior pertuzumab and trastuzumab were received by 76.3% and 43.5% of patients, respectively. Arms A and C were closed due to 5 and 4 patients with early discontinuation due to diarrhea, respectively. Early discontinuations due to any reason/diarrhea were 25.6%/17.9% in arm A, 13.3%/8.6% in arm B, and 27.6%/13.8% in arm C. For the first 3 c, the mean (standard deviation)/median (range) duration of NER exposure was 67 d (32)/84 d (4-101) in arm A, 78 d (19)/84 d (12-105) in arm B and 65 d (34)/84 d (1-91) in arm C. Median (range) relative NER dose intensity was 98% (14-107) in arm A, 99% (28-109) in arm B, and 95% (4-105) in arm C. Most common treatment-emergent AEs within the first 3 cycles are shown in Table.
Although none of the 3 strategies for reducing the impact of NER-associated diarrhea assessed in DIANER reduced early treatment discontinuation due to diarrhea to 5% or less, the incidence of early NER discontinuation observed in the study suggests that NER dose escalation is the best strategy for managing diarrhea and other AEs.
