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

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 TEAE[a][1] | 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 | 2[b][2] | 4[b][2] | | 1 | * [↵][3]a Includes TEAEs reported for ≥20% of Asian or non-Asian pts. * [↵][4]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. [1]: #fn-1 [2]: #fn-2 [3]: #xref-fn-1-1 [4]: #xref-fn-2-1