Pharmacokinetics and Tolerability of Bosutinib in Asian Versus Non-Asian Patients with Philadelphia Chromosome–Positive Leukemia
Authors: Hsyu Poe-Hirr , Gogat Karin , Duvillie Ladan , Kelly Virginia , Besson Nadine 
Published: October 2019

Abstract
Abstract 4440
Bosutinib (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 study Phase III study Asian (n = 114) Non-Asian (n = 456) Asian (n = 65) Non-Asian (n = 183) Any TEAEa 100 99 97 96     Diarrhea 89 80 83 65     Rash 47 29 51 16     Vomiting 37 40 32 34     Pyrexia 36 25 31 14     Nausea 23 53 28 35     Cough 21 20 14 8     Abdominal pain 20 24 14 14     Increased ALT 17 17 32 33     Increased AST 10 15 28 28     Fatigue 11 26 15 13     Headache 10 23 15 12 Any grade 3/4 TEAE 75 75 77 69 Dose reduction due to AE 49 41 52 34 Dose delay due to AE 64 64 77 64 Treatment discontinuation due to AE 15 24 28 24 Death due to AE within 1 month of last dose 2b 4b 0 1 a Includes TEAEs reported for ≥20% of Asian or non-Asian pts. b One 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.