Antidiarrheal Prophylaxis Remains a Key Focus in TKI Treatment for Patients with HER2+ Breast Cancer

Loperamide prophylaxis showed promising results in curbing rates of grade 3 diarrhea for patients with HER2-positive breast cancer who received adjuvant pyrotinib (Irene) plus nab-paclitaxel (Abraxane); however, better antidiarrheal prophylaxis are still needed in this setting, according to a poster presentation from the 2022 San Antonio Breast Cancer Symposium.¹

In a cohort of patients receiving loperamide 3 times daily on days 1 through 7 and twice daily for days 8 through 21 with the initiation of adjuvant therapy (cohort A; n = 60), the incidence of any grade diarrhea was 92%. The rate of grade 3 or worse diarrhea was 33%, and none of these cases were categorized as severe by investigators. The median number of grade 3 or worse diarrhea episodes was 1 (IQR, 1-2), and the median time to first grade 3 diarrhea event was 6.5 days (IQR, 1.0-8.3). One patient had to reduce the dosage and 1 patient had to discontinue pyrotinib because of diarrhea.

Among patients who received loperamide 3 times daily on days 1 through 7 and twice daily for days 8 through 42 (cohort B; n = 60), the incidence of any grade diarrhea was 97%. As with the first cohort, the rate of grade 3 or worse diarrhea was also 33%, and none of these cases were categorized as severe by investigators. Similarly, the median number of grade 3 or worse diarrhea episodes was 1 (IQR, 1-1), the median time to first grade 3 diarrhea event was 6 days (IQR, 4.0-10.0), and although 1 patient needed to discontinue treatment because of diarrhea (2%), no dose reductions were reported in response to this adverse effect.

“The effects of both loperamide regimens on antidiarrheal prophylaxis are consistent with that of loperamide prophylaxis in the CONTROL trial (NCT02400476) but with extremely fewer constipation events,” wrote Changjun Wang, MD, associate professor in the Department of Breast Surgery at Peking Union Medical College Hospital, in Beijing, China, and co-investigators, in the poster.

The CONTROL trial was a study assessing antidiarrheal strategies, including dose escalation, in patients with early HER2-positive breast cancer receiving neratinib (Nerlynx), a different pan-HER tyrosine kinase inhibitor (TKI), which was approved in the adjuvant study for this patient population. The study showed that preemptive prophylaxis with loperamide and dose escalation the reduced the rate, severity, and duration of grade 3 diarrhea. However, higher rates of grade 1 or 2 constipation did emerge in this trial.²

Pan-HER TKIs are commonly associated with diarrhea, as the study authors explained in the poster; however, there is no consensus on therapeutic or prophylactic strategy of pyrotinib-related diarrhea.

The ongoing, multicenter single-arm, phase 2 PHAEDRA trial (NCT04659499) is set to evaluate adjuvant pyrotinib plus nab-paclitaxel for patients with low-risk HER2-positive breast cancer. This study included patients with N0/N1mi, HER2-positive invasive breast cancer and primary tumor that were 3 cm or less. These patients received nab-paclitaxel 260 mg/m2 once every 3 weeks for 12 weeks and pyrotinib 400 mg once daily for 1 year within 90 days after surgery.

The study presented at the 2022 San Antonio Breast Cancer Symposium showed results from a sub-study of PHEADRA, in which the effect of different prophylactic strategies with loperamide were assessed between 2 cohorts. Patients were randomly assigned to either cohort; the primary end point was the incidence of grade 3 or worse diarrhea and secondary end points include the incidence and severity of diarrhea during the first 2 cycles of adjuvant therapy, the incidence and severity of constipation, as well as the onset time, frequency, and duration of grade 3 diarrhea, as well as the incidence of dose reduction, discontinuation, and hospitalization because of diarrhea, and patients quality of life, as assessed via the Functional Assessment of Cancer Therapy-Breast (FACT-B).

Patients were enrolled between January 2021 and May 20202, and 120 patients were included in the sub-study. In cohort A, the median patients age was 50 years (range, 27-72), 70% of patients had estrogen receptor (ER)-positive and/or progesterone receptors (PgR)-positive disease (n = 42), and 30% had ER-negative and PgR-negative disease (n = 18). Thirty-one patients (52%) had an ECOG performance status of 0 and 29 (48%) had an ECOG performance status of 1. In cohort B, 52 years was the median patient age (range, 29-68); 70% (n = 42) had ER-positive and/or PgR-positive disease, 43% (n = 26) had ER-negative and PgR-negative disease, and 62% (n = 37) and 38% (n =23) of patients had an ECOG performance status of 0 and 1, respectively.

Overall, 3 patients (5%) in each cohort experienced constipation, which were rated as grade 1 or 2. Additionally, 1 patient (2%) in cohort A, and 2 patients in cohort B (3%) needed to reduce their loperamide use because of constipation. No patients discontinued loperamide because of constipation.

Of note, the 2 cohorts demonstrated similar FACT-B total scores during the first 3 months. At months 6 and 9, cohort B demonstrated higher FACT-B total scores.

The poster concluded by noting that long-course and short-course loperamide prophylaxis showed numerically consistent incidence of grade 3 or worse diarrhea, and long-course administration appears to result in a better long-term quality of life.

“Proactive diarrhea management can promote the full-dose and full-course treatment with pyrotinib,” study authors wrote. “It is still necessary to develop more effective antidiarrheal prophylaxis regimens for pan-HER tyrosine kinase inhibitors.”

References

1. Wang C, Zhou Y, Lin Y, et al. Antidiarrheal prophylaxis with loperamide for patients with lymph node-negative (N0) or micrometastatic (N1mi) HER2-positive breast cancer who received adjuvant pyrotinib plus nab-paclitaxel: a randomized sub-study of PHAEDRA. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. P1-12-03.
2. Barcenas CH, Hurvitz SA, Di Palma JA, et al. Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial. Ann Oncol. 2020;31(9):1223-1230. doi:10.1016/j.annonc.2020.05.012