Efficacy and Safety of Nilotinib In Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients (Pts) with Type 2 Diabetes In the ENESTnd Trial.

Nilotinib is a potent and selective BCR-ABL kinase inhibitor. In the randomized, multicenter phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Philadelphia chromosome-positive CML pts) trial, nilotinib demonstrated superior efficacy, including significantly lower rates of progression on treatment to the accelerated or blastic phases of CML vs imatinib. It was previously reported that nilotinib treatment may lead to transient hyperglycemia in some pts receiving second-line nilotinib (400 mg twice daily [bid]) for resistance or intolerance to imatinib. The objective of this prospective analysis was to determine the effects of frontline nilotinib therapy on glucose metabolism in a subset of pts from ENESTnd with preexisting type 2 diabetes, and to evaluate the efficacy and safety of nilotinib therapy in these pts.

Changes from baseline in glucose metabolism parameters including fasting blood glucose (FBG), insulin, C-peptide, and HbA1c levels at 12 months were assessed in the diabetic subset of pts. Changes in body weight were also assessed.

A total of 836 pts were included in the safety analysis of ENESTnd (279, 277, and 280 pts in the nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively) with a median follow-up of 18 months. In this population, all grade hyperglycemia occurred in 38%, 42%, and 22% of pts in the nilotinib 300 mg bid, 400 mg bid, and imatinib arms, respectively (grade 3/4 in 6%, 4%, and 0%). Importantly, no patient from any treatment arm discontinued study due to hyperglycemia and there were no diabetic serious adverse events (eg, diabetic ketoacidosis, hyperosmolar events, and/or hospitalization due to diabetes). The subset of pts with preexisting type 2 diabetes (n = 57; 23, 18, and 16 pts in the nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively) was analyzed for glucose metabolism parameters and efficacy. Median age was higher (approximately 60 years) in this subset of pts compared to the entire pt population (approximately 47 years). At study entry, 68% (39/57) of pts were on diabetes medications; 18% (7/39) of whom were on insulin. The majority of diabetic pts (74%) did not have a change in diabetes therapy on study. Changes in glucose metabolism parameters were minimal (Table), and no meaningful changes in body weight or HbA1c were noted in any arm. In the subset of pts with preexisting type 2 diabetes, response rates were similar to the overall population, with MMR rates by 12 months of 69.6%, 55.6%, and 25%, and CCyR rates by 12 months of 69.6%, 77.8%, and 68.8% in the nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively. No pt in the diabetic subset has progressed to advanced disease. Overall, 8, 5, and 6 diabetic pts discontinued nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib, respectively. Of these, 3, 5, and 4 pts discontinued due to an adverse event or laboratory abnormality unrelated to diabetes. One diabetic pt in each of the nilotinib arms experienced an ischemic heart disease event (grade 1 or 2). Two diabetic pts died, 1 due to intestinal obstruction and 1 due to suicide, both in the nilotinib 300 mg bid arm.

Hyperglycemia occurring during nilotinib treatment was usually mild, transient, manageable and did not lead to treatment discontinuation in patients with or without preexisting type 2 diabetes. Moreover, the efficacy and safety of nilotinib in this subset of pts was similar to the overall population in ENESTnd. These data suggest that nilotinib is efficacious and well-tolerated in pts with type 2 diabetes.

Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Hughes:Ariad: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding. Marin:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kalaycio:Novartis: Honoraria, Speakers Bureau. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Kayath:Novartis: Employment. Zheng:Novartis: Employment, Equity Ownership. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding.