Proactive management strategies for potential gastrointestinal adverse reactions with ceritinib in patients with advanced ALK-positive non-small-cell lung cancer

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Approximately 3% to 7% of all patients with non-small cell lung cancer (NSCLC) harbor anaplastic lymphoma kinase (ALK) gene fusions. In 2014, the US Food and Drug Administration granted accelerated approval to ceritinib for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. Ceritinib is known to cause gastrointestinal adverse events, including diarrhea, vomiting, and abdominal pain, in the vast majority of patients treated with the kinase inhibitor. In 1 study, 14% of patients treated with the recommended dose of ceritinib experienced severe cases of gastrointestinal toxicity, and dose modification due to gastrointestinal adverse events occurred in 38%.

Current recommendations for the management of these adverse events are reactive and include symptomatic treatment with antiemetic or antidiarrheal therapy, or treatment interruption and dose reduction in severe cases; however, proactive adverse event treatment may have a place in side effect management. Two regimens have been studied for the prevention of gastrointestinal toxicity.

The first regimen consisted of ondanse­tron 8 mg, with diphenoxylate/atropine 2.5 mg, or loperamide 2 mg, to be taken orally 30 minutes prior to the ceritinib dose. The second regimen comprised dicyclomine 20 mg twice daily (to be taken orally starting with the first ceritinib dose), ondansetron 8 mg (taken orally 30 minutes prior to ceritinib for the first 7 doses), and loperamide 2 mg (taken orally as needed with the onset of diarrhea). If diarrhea was persistent with loperamide, then diphenoxylate/atropine 2.5 mg was used, to be taken every 6 hours as needed.

Using these proactive regimens, 8 of 9 patients were able to continue ceritinib therapy with only 1 of 8 patients requiring a dose reduction for gastrointestinal side effects.

Cancer Management and Research
Cancer Management and Research

Abstract: Anaplastic lymphoma kinase (ALK) gene fusions occur in 3%–7% of non-small-cell lung cancer (NSCLC) cases. Ceritinib, a once-daily, oral ALK inhibitor, has activity against crizotinib-resistant and crizotinib-naïve NSCLC, including brain metastases. Ceritinib (Zykadia™) was granted accelerated approval by the US Food and Drug Administration in 2014 for treating crizotinib-resistant ALK-positive NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/d and ~38% of patients require dose interruption or reduction for GI AEs. This case study details our experience with the use of proactive GI AE management regimens in patients treated with ceritinib (750 mg/d) across two study sites. Proactive Regimens A and B were implemented in patients with metastatic ALK-positive NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to ceritinib dose. Regimen B included dicyclomine (taken with the first ceritinib dose), ondansetron (taken 30 minutes prior to ceritinib dose for the first seven doses), and loperamide (taken as needed with the onset of diarrhea). The proactive medications were tapered off depending on patient tolerability to ceritinib. Nine patient cases are presented. Starting Regimens A or B before the first dose of ceritinib, or as soon as GI symptoms were encountered, prevented the need for dose reduction due to GI toxicity in eight of the nine patients. Using these regimens, 78% of patients were able to remain on 750 mg/d fasting. Two patients received 23 months and 16 months of therapy and remain on ceritinib 750 mg/d and 600 mg/d, respectively. Although not currently recommended or implemented in clinical studies, based on the patients evaluated here, upfront or proactive treatment plans that address AEs early on can allow the majority of patients to remain on the approved 750 mg/d ceritinib dose.

Keywords: case studies, tolerability, antidiarrheal, antiemetic, GI symptoms 
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