Severe diarrhea is a side effect experienced by more than one-third of women with HER2-positive early-stage breast cancer receiving secondary treatment with Nerlynx (neratinib). But preventive treatment with loperamide (brand name Imodium A-D, among others) and other anti-diarrheal medications reduces the severity and duration of this complication, improving treatment tolerability, according to findings from a Phase 2 clinical trial.
Results from the CONTROL trial (NCT02400476) were shared earlier this month in Chicago, Illinois, at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, in a poster titled “Effect of prophylaxis on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer: Phase II CONTROL trial.”
Puma Biotechnology‘s Nerlynx is an oral medicine that works by blocking the action of several proteins that promote cell growth, including epidermal growth factor receptors (EGFRs) and human epidermal growth factor receptor 2 (HER2).
In a prior Phase 3 trial, called ExteNET trial (NCT00878709), Nerlynx was tested as an extended adjuvant (secondary) treatment for early-stage, HER2-positive breast cancer patients who had received prior Herceptin (trastuzumab) as part of their adjuvant treatment and had not experienced recurrence or metastatic disease.
An adjuvant treatment is one given after the primary treatment — usually surgery — to lower the risk of the cancer returning.
However, nearly all patients in the trial (95.4%) experienced diarrhea as a side effect of the treatment, and 39.8% had severe diarrhea. This adverse effect lasted five days on average and was the reason for stopping Nerlynx in 16.8% of the patients.
Intending to determine whether preventive treatment with anti-diarrhea medicines could reduce the incidence and severity of diarrhea in Nerlynx-treated patients, researchers conducted an additional clinical trial, the CONTROL Phase 2 trial.
CONTROL had five patient groups, one received loperamide alone (137 patients), the second received loperamide and budesonide, an anti-inflammatory corticosteroid believed to reduce diarrhea (64 patients), and the third received loperamide plus colestipol, a bile acid sequestrant that also is expected to reduce diarrhea (136 patients).
In a fourth group, patients received mandatory colestipol plus loperamide as needed (104 patients), and the fifth group received Nerlynx in increasing doses — 120 mg a day on week 1, followed by 160 mg a day on week 2, and 240 mg a day thereafter until the end of treatment — plus loperamide when needed (60 patients).
Treatment was given within the first two cycles of Nerlynx therapy.
The poster presented at the ASCO meeting showed that all preventive regimens reduced the proportion of patients experiencing severe diarrhea, but they weren’t equally effective at reducing incidence of diarrhea of any grade, or at cutting the proportion of patients discontinuing treatment due to diarrhea.
Among those treated with loperamide only in group 1, the incidence of diarrhea of any grade was 79.6%, severe diarrhea affected 30.7% of patients (lasting a median of three days), and 20.4% of patients discontinued treatment due to diarrhea.
For those treated with loperamide plus budenoside in group 2, the incidence of diarrhea of any grade was 85.9%, severe diarrhea affected 28.1% of patients (lasting a median of 2.5 days), and 10.9% of patients discontinued treatment due to diarrhea.
In group 3, patients treated with loperamide and colestipol, the incidence of diarrhea of any grade was 83.1%, severe diarrhea affected 20.6% of patients (lasting a median of 3.5 days), and 4.4% of patients discontinued treatment due to diarrhea.
Among those in group 4, treated with mandatory colestipol and loperamide as needed, the incidence of diarrhea of any grade was 95.2%, severe diarrhea affected 31.7% of patients (lasting a median of three days), and 6.7% of patients discontinued treatment due to diarrhea.
Finally, in the group receiving escalating doses of Nerlynx without mandatory anti-diarrheal medicines (only loperamide as needed), the incidence of diarrhea of any grade was 95%, severe diarrhea affected 11.7% of patients (lasting a median of two days), and 3.3% of patients discontinued treatment due to diarrhea.
Hospitalization due to diarrhea was required only in the group treated with preventive loperamide alone (1.5% of cases).
“We are pleased to see the reductions in the incidence of severe neratinib-related diarrhea in the CONTROL trial when using the antidiarrheal regimens and the dose escalation. The reduction in the discontinuations due to diarrhea are encouraging and appear to represent a marked improvement in tolerability over what was seen in the ExteNET trial,” Alan H. Auerbach said in a press release. Auerback is CEO and president of Puma Biotechnology.
“Along with the continued reduction in the incidence and severity of grade 3 diarrhea with neratinib, diarrhea appears to be early onset, acute, self-limiting and manageable. Not only does the addition of budesonide or colestipol to loperamide prophylaxis appear to greatly improve the tolerability of neratinib, the dose escalation regimen appears as another promising option since there is no mandatory prophylaxis,” said Carlos H. Barcenas, MD. Barcenas is an assistant professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center.
“We look forward to the completion of the dose escalation [group],” he said.
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