CONTROL STUDY

New approaches for managing NERLYNX-induced diarrhea

A structured loperamide prophylactic regimen with or without the addition of colestipol reduces the incidence, severity, and duration of NERLYNX-associated diarrhea compared to that observed in ExteNET.3

Methods3

Overview

  • CONTROL (PUMA-NER-6201) is an international, sequential-cohort, open-label, phase 2 study

  • The study is registered (Clinicaltrials.gov identifier NCT02400476)

Patient population

  • Adults ≥ 18 years of age

  • Histologically confirmed stage 1–3c breast cancer

  • Documented HER2 overexpression or amplification determined locally

  • Completed trastuzumab-based adjuvant therapy, or experienced side effects resulting in early discontinuation, with last trastuzumab dose given > 2 weeks and ≤ 1 year prior to enrollment

Study Treatment

  • Details of dosing schedules are presented in Figure 1

  • All eligible patients received:

    • Oral NERLYNX 240 mg/day for 1 year

    • Oral loperamide prophylaxis for 1 or 2 cycles

    • Loperamide (≤ 16 mg/day) as needed after completion of loperamide prophylaxis

  • Patients in the budesonide and colestipol cohorts also received add-on oral budesonide or colestipol for 1 cycle, respectively

    • Colestipol: 2 g bid for 1 cycle (taken either 4 hours before or 2 hours after NERLYNX)

    • Details and results from the budesonide cohort are not presented herein

  • Details of adverse events management are presented below

Adverse events management

Adverse event Protocol
Treatment-emergent diarrhea
  • NERLYNX dose modifications (ie, dose holds or dose reductions according to a protocol-defined schedule)

  • Dietetic measures and additional pharmacological treatments depending on grade (ie, diphenoxylate plus atropine, octreotide, IV fluids, antibiotics)

Symptomatic constipation
  • Loperamide dose could be held until after the first bowel movement and then resumed at a reduced dose

bid: twice daily; HER2: human epidermal growth factor receptor 2; IV: intravenous

Trial baseline characteristics3

Overview

  • Between February 27, 2015 and November 3, 2017, a total of 321 patients were enrolled, of which 137 were in the loperamide cohort and 120 were in the colestipol cohort

  • Baseline characteristics are presented in Table 1

Table 1: Baseline characteristics

ER: estrogen receptor; PR: progesterone receptor

Dosing schedule3

Figure 1: Treatment schedule by cohort

One cycle = 28 days
bid: twice daily; d: day; tid: 3 times daily

Results3

The addition of colestipol to loperamide prophylaxis resulted in the significant reduction in diarrhea incidence and severity

  • Incidence of Grade ≥ 3 diarrhea, the primary study endpoint (Figure 2):

    • Loperamide with colestipol: 10.8% (95% CI: 5.9, 17.8)

    • Loperamide: 30.7% (95% CI: 23.1, 39.1)

    • ExteNET historical comparator: 39.9% (95% CI: 37.3, 42.5)

Figure 2: Worst grade of treatment-emergent diarrhea (safety population)

Loperamide cohort

(n = 137)

Colestipol cohort

(n = 120)

 Grade 3 diarrhea  Grade 2 diarrhea  Grade 1 diarrhea  No diarrhea

CI: confidence interval

Incidence and duration of diarrhea was reduced in CONTROL vs ExteNET

In both studies, diarrhea generally occurred early and was of short duration (see Table 2).

Table 2: Characteristics of treatment-emergent diarrhea (safety population)

prn: pro re nata (as needed)
*One Grade 4 event reported in ExteNET.

  • The occurrence and severity of diarrhea in CONTROL over the course of NERLYNX treatment was markedly reduced from that observed in ExteNET:

    • ExteNET showed a profile for diarrhea that was chronic and characterized by Grades 2 and 3 diarrhea with the greatest incidence in cycle 1 (month 1), and still observed in months 2–12

    • In CONTROL cohorts, the incidence of Grade 2–3 diarrhea was reduced during cycle 1 (month 1) and was also reduced in months 2–12

    • There appears to be some adaptation to the effects of NERLYNX, as higher-grade diarrhea occurs early during the course of treatment and is less common as treatment continues

Other adverse events

  • Aside from diarrhea, the overall tolerability profile of NERLYNX with loperamide prophylaxis given with or without colestipol was similar to that reported in ExteNET, apart from an increase in constipation

    • Rates of Grade 1/2 constipation in the loperamide and colestipol cohorts were 42.3%/14.6% and 53.3%/9.2%, respectively

    • No Grade 3 or higher constipation has been observed to date

  • The most frequently reported Grade 3/4 events are shown in Table 3

  • Reported Grade 4 events (serious adverse events) were sepsis and urinary tract infection (both unrelated events in the same patient); there were no fatal adverse events reported

Table 3: Most common grade 3 or 4 treatment-emergent adverse events (≥ 1% total incidence in CONTROL)

The addition of colestipol to a structured loperamide prophylaxis regimen markedly reduced the incidence of severe NERLYNX-induced diarrhea from that observed in ExteNET.

View the full study poster to learn about additional details of CONTROL.

Voucher program for a 3-month supply of antidiarrheals is available to eligible patients

In order to best support the patient's experience on NERLYNX, our service program has been expanded to include coverage of products used for antidiarrheal treatment, as based on findings from CONTROL.

This support can be accessed by your patient through a voucher, which can be obtained from your Puma sales representative or from one of the Puma network specialty pharmacies. The voucher can be used at any retail pharmacy to provide your patient a FREE 3-month supply of product(s) that you prescribe for antidiarrheal treatment.

Qualifying guidelines and additional utilization instructions are provided in the voucher.

Select IMPORTANT SAFETY INFORMATION

Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥ 2 diarrhea that occurs after maximal dose reduction.

Please see additional IMPORTANT SAFETY INFORMATION below.

IMPORTANT SAFETY INFORMATION

NERLYNX® (neratinib) tablets, for oral use

INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated for the extended adjuvant treatment of adult patients with early-stage HER2 overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:

ADVERSE REACTIONS: The most common adverse reactions (≥ 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased and urinary tract infection.

To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) and www.NERLYNX.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS:

USE IN SPECIFIC POPULATIONS:

For Full Prescribing Information, please click here.