Pharmacokinetics and Tolerability of Bosutinib in Asian Versus Non-Asian Patients with Philadelphia Chromosome–Positive Leukemia

Abstract

Abstract 4440Bosutinib (BOS) is an orally active, dual Src/Abl competitive inhibitor that has demonstrated clinical activity and a manageable tolerability profile across treatment settings in patients (pts) with Philadelphia chromosome–positive (Ph+) leukemia.The current analysis compared the pharmacokinetics and tolerability of BOS 500 mg/day between Asian and non-Asian pts with Ph+ leukemia. In an open-label phase I/II trial of pts with previously treated Ph+ leukemia, 570 pts with chronic phase (CP), accelerated phase, and blast phase chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia following development of resistance/intolerance to imatinib and possibly dasatinib and/or nilotinib received BOS, including 114 Asian and 456 non-Asian pts. In a phase III trial comparing BOS versus imatinib in pts with newly diagnosed (≤6 months) CP CML, 250 pts received BOS, including 65 Asian and 185 non-Asian pts.Demographic and baseline clinical characteristics were generally similar between Asian and non-Asian pts, although Asian pts were more likely to have an Eastern Cooperative Oncology Group Performance Status of 0 (phase I/II, 88% [Asian] vs 61% [non-Asian]; phase III, 95% vs 67%). The most common reasons for treatment discontinuation in both studies were an AE (phase I/II, 15% [Asian] vs 24% [non-Asian]; phase III, 28% vs 24%) and disease progression (phase I/II, 22% each; phase III, 5% each).Median BOS apparent clearance (CL/F) in the phase I/II trial was 101.2 L/h (range, 28.1–450.9 L/h) in Asian pts and 122.3 L/h (range, 26.6–1,561.9 L/h) in non-Asian pts, and in the phase III trial was 105.2 L/h (range, 20.1–274.3 L/h) in Asian pts and 126.7 L/h (range, 29.3–638.2 L/h) in non-Asian pts.Overall, gastrointestinal events were the most common non-hematologic treatment-emergent adverse events (TEAEs) reported with BOS. Diarrhea, rash, and pyrexia were reported more frequently among Asian versus non-Asian pts in both studies (Table). Regardless of race, diarrhea events were typically low-grade, occurred early (median time to diarrhea, 2–4 days), and were transient (median event duration, 1–3 days). Rash was also typically low-grade and transient (median event duration, 9–27 days). In contrast, nausea was reported more frequently among non-Asian pts. Other TEAEs were similar between Asian and non-Asian pts or showed no consistent pattern between studies (Table).Grade 3/4 laboratory abnormalities were similar between Asian and non-Asian pts for elevated alanine aminotransferase (ALT; phase I/II, 11% vs 8%; phase III, 26% vs 22%) and aspartate aminotransferase (AST; phase I/II, 3% vs 4%; phase III, 12% vs 11%).Among grade 3/4 hematologic laboratory abnormalities, thrombocytopenia was more frequent among Asian versus non-Asian pts in both studies (phase I/II, 41% vs 33%; phase III, 22% vs 11%); anemia was also more common among Asian pts in the phase I/II study (30% vs 16%), but not the phase III study (8% each). Grade 3/4 neutropenia was similar within both studies (phase I/II, 25% vs 24%; phase III, 11% vs 10%).BOS dose modifications due to adverse events (AEs) were similar between Asian and non-Asian pts in the phase I/II trial but more common among Asian pts in the phase III trial (Table). No clear pattern of treatment discontinuations due to AEs was observed. Few deaths due to AEs were reported for either Asian or non-Asian pts during BOS treatment or within 1 month after the last BOS dose.Across studies, BOS CL/F in Asians pts was within the range of CL/F in non-Asian pts, and minor differences in the tolerability profile of BOS were noted. However, BOS 500 mg/day was associated with an overall manageable toxicity profile regardless of race.Event, %Phase I/II studyPhase III studyAsian (n = 114)Non-Asian (n = 456)Asian (n = 65)Non-Asian (n = 183)Any TEAEa100999796Diarrhea89808365Rash47295116Vomiting37403234Pyrexia36253114Nausea23532835Cough2120148Abdominal pain20241414Increased ALT17173233Increased AST10152828Fatigue11261513Headache10231512Any grade 3/4 TEAE75757769Dose reduction due to AE49415234Dose delay due to AE64647764Treatment discontinuation due to AE15242824Death due to AE within 1 month of last dose2b4b01aIncludes TEAEs reported for ≥20% of Asian or non-Asian pts.bOne of 2 (Asian) and 2 of 19 (non-Asian) deaths due to an AE within 1 month of the last BOS dose were considered related to BOS. Disclosures:Hsyu:Pfizer Inc: Employment, Equity Ownership. Gogat:Pfizer Inc: Employment, Equity Ownership. Duvillie:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Besson:Pfizer Inc: Employment.