On June 4, 2021 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that results at the virtual 2021 ASCO (Free ASCO Whitepaper) Annual Meeting comparing the diarrhea mitigation strategies investigated in the Phase II CONTROL trial with the neratinib treatment arm of the ExteNET trial where diarrhea prophylaxis was not required (Press release, Puma Biotechnology, JUN 4, 2021, View Source [SID1234583592]). The presentation, entitled "Dose escalation for mitigating diarrhea: Ranked tolerability assessment of antidiarrheal regimens in patients receiving neratinib for early-stage breast cancer," is included in the Breast Cancer—Local/Regional/Adjuvant Poster Session (#536).

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The CONTROL trial is an international, open-label, Phase II study investigating the use of antidiarrheal prophylaxis or dose escalation to improve the tolerability of neratinib-associated diarrhea. The primary endpoint of the trial is the incidence of grade 3 diarrhea. Patients ≥18 years of age with stage I–IIIc HER2-positive breast cancer received neratinib (240 mg/day orally for 1 year) together with one of the regimens investigated: loperamide alone, in combination with budesonide or colestipol, or neratinib dose escalation (DE): 120 mg/day on days 1–7, 160 mg/day on days 8–14, then 240 mg/day thereafter + loperamide PRN.

In the analysis presented at ASCO (Free ASCO Whitepaper) 2021, five CONTROL cohorts that had completed follow up were evaluated for 13 endpoints related to tolerability. The DE cohort ranked the best among the CONTROL cohorts and was then compared with the neratinib arm of the ExteNET trial, which included patients ≥18 years of age with stage I–III HER2-positive breast cancer receiving neratinib 240 mg/day or matching placebo for one year, without mandated anti-diarrheal treatment. ExteNET was a multicenter, randomized, double-blind, Phase III trial (NCT00878709) of 2,840 HER2-positive early stage breast cancer patients who received neratinib after neoadjuvant and/or adjuvant therapy with chemotherapy and a trastuzumab-based regimen.

Comparison of the CONTROL DE cohort with the ExteNET neratinib arm demonstrated that grade 3 diarrhea was substantially lower in CONTROL DE compared to ExteNET (13.3% vs. 39.9%). Neratinib DE also resulted in fewer total days of grade 3 diarrhea compared to ExteNET (2.5 days vs 5 days). Dose escalation also led to fewer discontinuations due to diarrhea in the first three months of treatment compared to ExteNET (3.3% vs 14.5%). Additionally, the average duration of treatment with neratinib was much longer in the DE cohort versus ExteNET. Overall, the findings of this analysis suggest that escalating the dose of neratinib in the first 2 weeks of treatment may help patients stay on neratinib longer, allowing them the opportunity to complete the recommended 1-year of treatment.

"Dose escalation of neratinib with loperamide PRN is an effective way of minimizing the extent of grade 3 diarrhea. This strategy showed improvements in overall tolerability as compared to ExteNET and resulted in more patients being able to remain on therapy," said Gavin M. Marx, MBBS, Sydney Adventist Hospital.

"These results confirm that dose escalation of neratinib lowered the incidence and duration of grade 3 diarrhea as well as discontinuations due to diarrhea, said Adam M. Brufsky, MD, PhD, University of Pittsburgh School of Medicine. "Using dose escalation, the average duration of neratinib was longer (compared to ExteNET)."

Alan H. Auerbach, Chief Executive Officer and President of Puma, added, "We are committed to research that seeks to understand how to improve the tolerability of neratinib. The CONTROL trial evaluated multiple diarrhea mitigation strategies and dose escalation of neratinib resulted in the best tolerability, allowing more patients to stay on treatment for the recommended duration."

About HER2-Positive Breast Cancer

Up to 20% of patients with breast cancer tumors over-express the HER2 protein (HER2-positive disease) and in the ExteNET study, 57% of patients were found to have tumors that were hormone-receptor positive. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Although research has shown that trastuzumab can reduce the risk of early stage HER2-positive breast cancer recurring, up to 25% of patients treated with trastuzumab experience recurrence within 10 years, the majority of which are metastatic recurrences.