Prophylactic treatment with the combination of loperamide and budesonide reduced the rate of grade ≥3 diarrhea associated with neratinib to 15% compared with 39.9% observed in the ExteNET trial. The rate of all-grade diarrhea was 65% with the prophylactic regimen versus 95.4% in ExteNET, according to findings from the phase II CONTROL trial.
Carlos H Barcenas, MD, MSc
Prophylactic treatment with the combination of loperamide and budesonide reduced the rate of grade ≥3 diarrhea associated with neratinib to 15% compared with 39.9% observed in the ExteNET trial. The rate of all-grade diarrhea was 65% with the prophylactic regimen versus 95.4% in ExteNET, according to findings from the phase II CONTROL trial presented at the 2016 San Antonio Breast Cancer Symposium.
"Previously, the ExteNET clinical trial had shown a benefit of the drug neratinib in patients with stage 1 to 3 breast cancer. There was a benefit of neratinib given in the adjuvant setting after 1 year of trastuzumab," said Carlos H Barcenas, MD, MSc, assistant professor, The University of Texas MD Anderson Cancer Center. "The problem with this drug is that it gives a lot of diarrhea. This study sought to characterize the diarrhea and control it."
The international open-label CONTROL trial enrolled patients with stage 1 to 3c HER2-positive breast cancer across 4 cohorts focused on diarrhea prophylaxis. All patients had completed trastuzumab-based therapy ≤1 year prior to enrollment. The study included more patients with HR-positive disease and more with stage I tumors compared with those enrolled in ExteNET.
Neratinib was administered at 240 mg once daily for 1 year. Loperamide was given at a variety of doses, with 3 doses of single-agent loperamide examined along with a combination of loperamide and budesonide. In this group, loperamide was given for 2 cycles at 4 mg 3 times per day for days 1 to 14. This was followed by 4 mg twice daily for days 15 to 56. Budesonide was given at 9 mg once daily for 1 cycle. After 2 cycles, loperamide was given as needed at ≤16 mg per day.
In the single-agent loperamide arms (n = 135), 100% of patients had received prior neoadjuvant trastuzumab compared with 87.5% of those in the budesonide arm (n = 40). More patients were treated with pertuzumab before entering the trial in the combination arm (55%) versus the single-agent groups (40%). The median time since last dose of trastuzumab was 4.1 months in the single-agent group and 4.3 months in the budesonide arm.
The median neratinib exposure in the budesonide arm was less compared with the loperamide monotherapy group (1.8 vs 7.5 months), suggesting that additional diarrhea events could still occur. In general, most of the events in the loperamide single-agent arm occurred during the first 2 months of therapy.
"The budesonide data is very early, we only have a couple of months, so of course some of this data may change over time as it matures a little bit more," Barcenas said. "The preliminary results look very promising."
Diarrhea of any grade occurred in 75.5% of patients treated with loperamide alone. These events were grade 1 (24.4%), grade 2 (23.0%), and grade 3 (28.1%) in severity. In the budesonide arm, patients had grade 1 (32.5%), grade 2 (17.5%), and grade 3 (15%) diarrhea. There were no grade 4 or 5 events.
"Fifteen percent with the budesonide is a good number but the idea is to decrease it a bit more," said Barcenas. "Although we think it is inflammatory, it might be multifactorial, so we want to use multiple agents. The next agent that we'll be testing is called colestipol, which is a bile acid sequestrant."
Patients had grade ≥3 diarrhea for a median cumulative duration of 3.0 days in the loperamide monotherapy arm compared with 2.5 days for budesonide. In the ExteNET trial, grade ≥3 diarrhea persisted for 5 days. Patients had a median of 2 episodes of all-grade diarrhea in the single-agent and combination arm compared with 8 episodes without prophylaxis in ExteNET.
There were significantly fewer dose holds, reductions, and discontinuations related to treatment-emergent diarrhea in the prophylaxis arms. For the combination, dose holds were required for 7.5% of patients and dose reductions were needed for 5%. Five percent of patients discontinued therapy and none required hospitalization. In the ExteNET trial, treatment holds were needed for 33.9% of patients and dose reductions were required for 26.4%. Treatment was discontinued for 16.8% of patients and 1.4% required hospitalization.
Prior treatment with pertuzumab led to higher rates of diarrhea. In those in the loperamide single-agent arm, 35.2% of pertuzumab pretreated patients had grade 3 diarrhea compared with 23.5% in those who did not receive the antibody. In the budesonide cohort, the rates were 13.6% and 16.7%, for pertuzumab-treated and not treated patients, respectively.
"The diarrhea is controllable and there are different strategies that we're exploring," Barcenas said. "The study is still open and enrolling."
The rate of constipation was significantly increased with the use of diarrhea prophylaxis. All-grade constipation went from 8.2% in the ExteNET trial to 54.1% with loperamide and 47.5% with loperamide plus budesonide. There were additional increases in fatigue and nausea, which are likely secondary to loperamide, said Barcenas.
"Of course, everything comes with a cost. For loperamide with this combination there was an increase in constipation and nausea and also fatigue," said Barcenas. "It is a balancing act between decreasing diarrhea but also trying not to increase too much the constipation."
Barcenas C, Olek E, Hunt D, et al. Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC): Interim analysis from the multicenter, open-label, phase II control trial. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract P2-11-03.