Abstract P3-14-01: Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2+ early-stage breast cancer: The CONTROL trial

Abstract

Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor. Results from the randomized, placebo-controlled, Phase III ExteNET study demonstrated that neratinib significantly improves 24-month iDFS in patients (pts) with trastuzumab-treated early-stage HER2+ breast cancer (HR 0.67; 95% CI 0.50–0.91; p=0.009) [Chan et al. Lancet Oncol 2016]. In ExteNET, loperamide prophylaxis was not mandated, and diarrhea was the most commonly observed toxicity (grade 3, 39.8%). To reduce neratinib-associated diarrhea, high-dose loperamide prophylaxis given with the first 1–2 cycles of neratinib has been incorporated into all neratinib clinical trials; available data suggest that loperamide prophylaxis reduces the incidence and median cumulative duration of higher-grade neratinib-related diarrhea. CONTROL is an international, open-label, sequential cohort, phase II study investigating the effects of prophylaxis with loperamide ± the long-acting corticosteroid budesonide or bile acid sequestrant colestipol on neratinib-associated diarrhea. We present updated data from this study. Methods: Pts with stage 1–3c HER2+ breast cancer who completed trastuzumab-based adjuvant therapy within 1 year were eligible. All pts received oral neratinib 240 mg once daily for 1 year + oral loperamide prophylaxis for 1 or 2 cycles (1 cycle = 28 days) ± budesonide or colestipol for the first cycle (see table). Adverse events were graded according to NCI-CTCAE (v4.0). Primary endpoint: incidence of grade ≥3 diarrhea. Results: StudyCONTROLExteNET5Cohort or study armLoperamideBudesonideColestipolNeratinibAntidiarrheal prophylaxisLoperamide1,2Budesonide + loperamide2,3Colestipol + loperamide2,4Loperamide prnN (at data cut-off)137664391408Diarrhea, % Any grade78.179.753.895.4Grade 124.125.025.622.9Grade 223.429.720.532.5Grade 330.725.07.739.8Grade 40000.1Median cumulative duration of diarrhea, days Any grade12.013.011.059.0Grade ≥24.03.02.010.0Grade ≥373.02.04.05.0Median episodes of diarrhea per patient, n Any grade2.04.03.08.0Grade ≥22.02.01.03.0Grade ≥371.01.02.02.0Neratinib discontinuation (due to diarrhea), %20.49.4016.8Hospitalization, %1.5001.4Median duration of neratinib treatment, mo811.06.32.111.61. Oral loperamide 4 mg, then 2 mg q4h d1-3, then 2 mg q6-8h d4-56 (original); 2. Oral loperamide 4 mg, then 4 mg tid d1-14, then 4 mg bid d15-56 (modified); 3. Oral budesonide 9 mg qd d1-28; 4. Oral colestipol 2 g qd d1-28; 5. Chan et al. Lancet Oncol 2016; 6. Original,1 n=28; modified,2 n=109; 7. Grade 4 events: CONTROL, n=0; ExteNET, n=1; 8. Treatment ongoing in all CONTROL cohorts. CONTROL data cut-off: Apr 2017. Conclusions: A structured loperamide prophylactic regimen for 1 or 2 cycles reduces the incidence, severity and duration of neratinib-associated diarrhea compared with events observed in the ExteNET trial. Adding budesonide or colestipol appears to further diminish the duration and number of episodes of diarrhea and improves neratinib tolerability. Final analysis of the CONTROL study will be performed when all pts have completed 12 months of neratinib therapy. Updated data will be available at the meeting. Clinicaltrials.gov: NCT02400476. Citation Format: Hurvitz S, Chan A, Iannotti N, Ibrahim E, Chien J, Chan N, Kellum A, Hansen V, Marx G, Kendall SD, Wilkinson M, Castrellon A, Ruiz R, Fang P, Hunt D, Moran S, Olek E, Barcenas CH, Rugo HS. Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2+ early-stage breast cancer: The CONTROL trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-01.

Preclinical Characteristics of the Irreversible Pan-HER Kinase Inhibitor Neratinib Compared with Lapatinib: Implications for the Treatment of HER2-Positive and HER2-Mutated Breast Cancer

“…The results of the trial also showed that treatment with neratinib plus capecitabine statistically significantly improved time to intervention for symptomatic brain metastases, a secondary endpoint of the study, versus lapatinib plus capecitabine. Prophylactic treatment for diarrhea has improved the major clinical side effect of neratinib [141], allowing further investigation of neratinib in additional clinical settings for patients with HER2-positive or HER2- mutated tumors. Given its unique potent, irreversible, pan-HER kinase inhibitor properties, neratinib has potential to synergize with a variety of molecular targeted therapies, such as trastuzumab, T-DM1, anti-estrogens, Src inhibitors, CDK4/6 inhibitors, HSP90 inhibitors, and HDAC inhibitors, in the treatment-naive or treatment-refractory settings.…”

Update Breast Cancer 2018 (Part 2) – Advanced Breast Cancer, Quality of Life and Prevention

“…The rate of grade III diarrhea reported in the approval study was 39.8%, which led to termination of the therapy by 16.8% of patients. The CONTROL study compared an intensified loperamide regimen (12 mg/day, d1–14, followed by 6 – 8 mg/day, d15–56) with combinations of loperamide and the steroid budesonide or the cholesterol-lowering drug colestipol 28 . Grade III diarrhea occurred in 30.7, 25.0 and 7.7% of patients, and therapy termination rates were 20.4, 9.4 and 0%, respectively.…”

“…In der Zulassungsstudie zeigte sich eine Diarrhörate Grad 3 von 39,8%, die zu einem Abbruch bei 16,8% der Patientinnen führte. In der CONTROL-Studie wurde ein intensiviertes Loperamid-Schema (12 mg/d, d1–14, gefolgt von 6 – 8 mg/d, d15–56) mit den Kombinationen von Loperamid und dem Steroid Budenosid oder dem Cholesterinsenker Colestipol verglichen 28 . Es zeigten sich Grad-3-Diarrhöen in 30,7, 25,0 und 7,7% mit Abbruchraten von 20,4, 9,4 und 0%.…”

Advances in HER2-Positive Breast Cancer: Novel Therapies and Adverse Event Management

“…Patients reported a transient reduction in health-related quality of life during the first month of therapy, followed by steady recovery toward baseline. The follow-up CONTROL trial (Hurvitz et al, 2017) showed the incidence of diarrhea to be further reduced as compared to the ExteNET trial with the use of prophylactic loperamide alone or in combination with budesonide, or colestipol.…”