Abstract: Bosutinib (BOS) is an oral dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure. Pts (n=118) aged ≥18 y with prior imatinib (IM) failure plus dasatinib (D) resistance (D-R; n=38) or intolerance (D-I; n=50), nilotinib (N) resistance (N-R; n=26), or N-I or D-R/I + N-R/I (n=4) received BOS starting at 500 mg/d. Median (range) age was 56 (20–79) y; time from CML diagnosis was 6.6 (0.6–18.3) y; follow-up duration was 33.1 (0.3–84.8) mo; BOS treatment duration was 8.5 (0.2–78.1) mo. Escalation to BOS 600 mg/d occurred in 21 (18%) pts. For the last enrolled pt, time from first dose was ≥36 mo; 19% are still receiving BOS. Confirmed complete hematologic response (CHR) was newly attained or maintained from baseline by 73% of pts (Table). Major cytogenetic response (MCyR) was attained/maintained by 40% of pts (32% with complete cytogenetic response [CCyR]). Kaplan-Meier probability of maintaining CHR or MCyR at 3 y was 65%.IM + D-R (n=38)IM + D-I (n=50)IM + N-R (n=26)IM + N-I or D-R/I + N-R/Ia (n=4)Total (n=118)Evaluable,b n3849254116Confirmed CHR, n (%)26 (68)37 (76)19 (76)3 (75)85 (73)Probability of maintaining CHR at 3 yc57%74%62%NR65%Evaluable,b n3645254110MCyR, n (%)14 (39)19 (42)9 (36)2 (50)44 (40)CCyR , n (%)8 (22)18 (40)7 (28)2 (50)35 (32)Probability of maintaining MCyR at 3 yc29%87%75%NR65%Treated, n3850264118PD/death at 3 yd26%16%35%NR25%OS at 2 yc80%83%92%NR84%D=dasatinib; I=intolerant; IM=imatinib; N=nilotinib; NR=not reported (small sample size); OS=overall survival; PD=progressive disease; R=resistant.aIncludes 3 pts with prior exposure to all 3 TKIs and 1 N-I pt.bReceived ≥1 BOS dose and had a valid baseline efficacy assessment for the respective endpoint.cBased on KM estimates.dBased on cumulative incidence adjusting for competing risk of treatment discontinuation without PD or death. Of 85 pts with known baseline mutation status, 19 unique BCR-ABL mutations occurred in 39 (46%) pts, including 7 (8%) with T315I. Responses were seen across mutations, but were low in pts with T315I (29% CHR; 14% MCyR). In pts with ≥1 mutation, excluding T315I, 75% had CHR and 40% had MCyR. 38 pts had known baseline and end of treatment mutation status; 8/38 had ≥1 new mutation (V299L, n=4; T315I, n=2; F359C, G250E, L248V, n=1 each); 7/8 discontinued BOS due to disease progression or lack of efficacy. Cumulative incidence of on-treatment transformation to accelerated-phase (AP) CML at 3 y was 4%; 77% discontinued without transformation. No pt transformed to blast-phase (BP); no transformations occurred after 2 y. Cumulative incidence of on-treatment progression (transformation to AP/BP CML, increasing white blood cell count [doubling over ≥1 mo with 2nd count 〉 20×109/L and confirmed ≥1 wk later], or loss of confirmed CHR or unconfirmed MCyR) or death at 3 y was 25%; 55% of pts discontinued without an event. Overall survival (OS) at 2 y was 84% (Table; 3-y OS estimates unreliable; pts followed for OS for only 2 y after BOS discontinuation] ). Overall, 96 (81%) pts discontinued treatment, the most common primary reasons were adverse event (AE; n=29 [25%]), disease progression (n=25 [21%] ), or unsatisfactory efficacy (n=23 [19%]). 26 (22%) deaths occurred on study, 5 within 30 d of last BOS dose. Most deaths were due to disease progression (n=11 [9%] ) or AE (n=11 [9%], including 1 death reported as treatment-related due to lower gastrointestinal bleeding). 4 deaths had unknown cause 33–615 d after the last BOS dose. Non-hematologic treatment-emergent AEs in ≥20% of pts (all grades; grade 3/4) were diarrhea (83%; 9%), nausea (48%; 1%), vomiting (38%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (23%; 2%), and abdominal pain (24%; 1%); common hematologic toxicities included thrombocytopenia (38%; 26%), neutropenia (20%; 15%), and anemia (19%; 7%). Cardiac events occurred in 15% of pts (8% grade 3/4). Grade 3/4 laboratory abnormalities in ≥10% of pts were thrombocytopenia (26%), neutropenia (20%), lymphopenia (16%), and hypermagnesemia (12%). 78 (66%) pts had ≥1 dose delay; 59 (50%) had ≥1 dose reduction. 31 (26%) pts discontinued BOS due to AE, most commonly thrombocytopenia (7%). BOS continues to demonstrate durable efficacy and manageable toxicity after ≥36 mo follow-up in CP-CML pts following resistance or intolerance to multiple TKIs. Disclosures: Cortes: Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Bristol Myer Squibb: Research Funding; Teva: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Pfizer Inc: Research Funding. Lipton:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squib: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kim:Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Conlan:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Turnbull:Pfizer Inc: Employment. Brümmendorf:Ariad: Consultancy; Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria. Gambacorti-Passerini:Bristol Myer Squibb: Consultancy; Pfizer Inc: Consultancy, Research Funding; Novartis: Consultancy.

Abstract: Objectives: Bosutinib (BOS), an oral dual Src/Abl tyrosine kinase inhibitor for adult patients with Philadelphia chromosome−positive chronic myeloid leukemia (Ph+ CML), has a recommended starting dose of 500 mg/d. This analysis evaluates efficacy and safety following BOS dose reduction due to intolerance in patients with Ph+ CML. Methods: Data from 2 studies were analyzed: a phase 1/2 study (NCT00261846) that included patients with chronic phase (CP) CML following resistance/intolerance to imatinib (IM; CP2L) or to IM plus dasatinib and/or nilotinib (CP3L), and those with accelerated/blast phase CML or acute lymphoblastic leukemia after at least IM (advanced [ADV]); and a phase 3 study (NCT00574873) in CP CML patients treated with BOS or IM as first-line therapy (CP1L). Results: Of 570 CP2L/CP3L/ADV patients receiving BOS (median treatment duration 11 months [range: 0.03−96]), 257 (45%) experienced ≥1 dose reduction (236 patients to 400 mg/d and 95 to 300 mg/d). Median time to dose reduction to 400 and 300 mg/d was 54.5 (range: 4-1875) and 146 days (8-2166), respectively; median duration of dose reduction was 3.6 (0.03-87.7) and 4.2 months (0.03-60.5), respectively. In CP1L, 248 patients received BOS (median treatment duration: 55.4 months [0.03−76] ), of whom 111 (45%) experienced ≥1 dose reduction (103 to 400 mg/d and 56 to 300 mg/d). Median time to dose reduction to 400 and 300 mg/d was 64.0 (2-1714) and 139 days (20-1778), respectively; median duration of dose reduction was 2.6 (0.03-66.1) and 8.9 months (0.03-71.2), respectively. Patients achieved anew or maintained a previously achieved complete cytogenetic response following BOS dose reduction to 400 mg/d (achieved: 29% [CP2L/CP3L/ADV], 40% [CP1L] ; maintained: 13% [CP2L/CP3L/ADV], 26% [CP1L] ) and to 300 mg/d (achieved: 14% [CP2L/CP3L/ADV], 18% [CP1L] ; maintained: 24% [CP2L/CP3L/ADV], 45% [CP1L] ; Table 1). Treatment-emergent adverse events (TEAEs) were generally similar in incidence, type, and severity before vs after BOS dose reduction. However, incidences of certain gastrointestinal TEAEs were lower and of similar severity following BOS dose reduction to 400 mg/d (diarrhea: 84% vs 50% [CP2L/CP3L/ADV], 70% vs 41% [CP1L] ; nausea: 45% vs 23% [CP2L/CP3L/ADV], 34% vs 21% [CP1L] ; vomiting: 33% vs 21% [CP2L/CP3L/ADV], 28% vs 22% [CP1L] ) or to 300 mg/d (diarrhea: 85% vs 31% [CP2L/CP3L/ADV], 75% vs 38% [CP1L] ; nausea: 43% vs 14% [CP2L/CP3L/ADV], 43% vs 21% [CP1L] ; vomiting: 34% vs 11% [CP2L/CP3L/ADV], 34% vs 18% [CP1L] ). Conclusions: CP2L/CP3L/ADV and CP1L CML patients who required BOS dose reduction due to AEs were still able to achieve or maintain cytogenetic responses and appeared to experience fewer gastrointestinal AEs. Disclosures Kota: Incyte: Membership on an entity's Board of Directors or advisory committees; Ariad Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Brümmendorf:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Lipton:Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Kantarjian:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. An:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Crescenzo:Pfizer Inc: Employment. Woloj:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Equity Ownership. Khoury:Pfizer Inc: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees.

Abstract: The dual Src/Abl tyrosine kinase inhibitor (TKI) bosutinib (BOS) is indicated for adults with Ph+ CML resistant/intolerant to prior therapy. This long-term update of an ongoing open-label, phase 1/2 study evaluated 2nd-line BOS in CP CML pts aged ≥18 y following imatinib resistance (IM-R) or intolerance (IM-I). This analysis included IM-R (n=195) or IM-I (n=89) CP CML pts receiving BOS starting at 500 mg/d. Median (range) age was 53 (18–91) y; time from CML diagnosis was 3.7 (0.1–15.1) y; treatment duration was 25.6 (0.2-94.9) mo; and follow-up duration was 45.1 (0.6–94.9) mo. BOS dose was escalated to 600 mg/d in 13% of pts. For the last enrolled pt, time from first BOS dose was ≥60 mo (41% of pts still receiving BOS at 5 y). Major cytogenetic responses (MCyR, including complete cytogenetic response [CCyR]) newly attained (54% of pts) or maintained from baseline (6%) are summarized (Table). In 224 pts assessed at baseline, 42 unique BCR-ABL mutations occurred in 78 (35%) pts, including 12 with 〉 1 mutation; common mutations were T315I and F359V (n=9 each), M351T (n=8), G250E and M244V (n=6 each). MCyR rate was similar in pts without mutations (58%) and with 1 single mutation (61%); 45% of pts with 〉 1 mutation and 22% of pts with T315I had MCyR. During therapy, of 92 pts evaluable for mutations, 20 acquired a new BCR-ABL mutation (T315I, n=9; V299L, n=4; E255V, E450A, E450G, G250E, K378E, L273M, and M244V, n=1 each [all in different pts]; 11 of these 20 pts had baseline mutations); 19 of these 20 pts discontinued due to either progressive disease (PD; n=12), lack of efficacy (n=6), or death (n=1). Cumulative incidence of on-treatment PD (ie, transformation to accelerated-/blast-phase [AP/BP] CML, increasing white blood cell count, loss of confirmed complete hematologic response or unconfirmed MCyR) or death* at 5 y was 19% (Table); 40% of pts discontinued BOS prior to 5 y without an event. Kaplan-Meier (KM)–estimated overall survival (OS) at 2 y was 91% (Table; per protocol, pts were followed for OS for only 2 y after BOS discontinuation). Cumulative incidence of on-treatment transformation to AP/BP CML* at 5 y was 4%; 55% of pts discontinued BOS prior to 5 y without transformation. In 12 pts with transformations, 6 were to AP and 6 were to BP. There was limited follow-up of patients after treatment discontinuation. Overall, 168 (59%) pts discontinued BOS within 5 y, commonly due to adverse event (AE; n=64 [23%]) or disease progression (n=47 [17%] ) as primary reason for discontinuation. Forty-four (16%) deaths occurred on study, 10 within 30 d of last BOS dose. Most deaths were due to disease progression (n=26; IM-R: 23 pts; IM-I: 3 pts) or AE unrelated to BOS (n=16; IM-R: 14 pts; IM-I: 2 pts); 2 were due to unknown causes. No deaths were reported as BOS-related. The most frequent (≥30%) hematologic treatment-emergent AE (TEAE; all grade/grade 3/4) was thrombocytopenia (42%/26%); common non-hematologic TEAEs were diarrhea (86%/10%), nausea (47%/1%), vomiting (37%/4%), and rash (36%/9%). Cardiac events (MedDRA system organ classification of cardiac disorders) occurred in 17% of pts (8% grade 3/4). Toxicities were managed by ≥1 dose delay in 73% of pts (IM-R: 67%; IM-I: 85%) and by ≥1 dose reduction in 50% of pts (IM-R: 46%; IM-I: 58%). AEs led to BOS discontinuation in 68 (24%) pts (IM-R: n=32 [16%]; IM-I: n=36 [40%] ); the most common reason was thrombocytopenia, in 16 (6%) pts (IM-R: n=6 [3%]; IM-I: n=10 [11%] ). Overall incidence of newly occurring TEAEs for pts on treatment during specific years was 100% (n=283/284) in year 1 (y1), 74% (n=139/189) in y2, 68% (n=100/148) in y3, 52% (n=68/130) in y4, and 57% (n=70/124) in y5. Discontinuations due to AEs were most common in y1 (18% [n=50/284]); 8, 3, 3, and 1 pts discontinued due to AEs in y2, y3, y4, and y5. After ≥60 mo of follow-up, BOS shows efficacy and manageable toxicity in CP CML pts following IM-R or IM-I. Table IM-R (n=195) IM-I (n=89) Total (n=284) Evaluable,a n 182 80 262 MCyR, n (%) 107 (59) 49 (61) 156 (60) CCyR , n (%) 88 (48) 42 (53) 130 (50) Probability of maintaining MCyR at 5 yb 67% 80% 71% Probability of maintaining CCyR at 5 yb 72% 68% 71% Treated, n 195 89 284 PD/death at 5 yc 23% 10% 19% OS at 2 yb 88% 98% 91% aReceived ≥1 BOS dose and had a valid baseline efficacy assessment for the respective endpoint; responses newly attained or maintained from baseline. bBased on KM estimates. cBased on cumulative incidence, *adjusting for competing risk of treatment discontinuation without event. Disclosures Brümmendorf: Patent on the use of imatinib and hypusination inhibitors: Patent on the use of imatinib and hypusination inhibitors Patents & Royalties; Pfizer Inc: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Cortes:Ariad: Consultancy, Research Funding; Pfizer Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Kantarjian:Pfizer Inc: Research Funding. Kim:Pfizer Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ILYANG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schafhausen:Pfizer Inc: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Zeremski:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer Inc: Consultancy, Research Funding. Lipton:Ariad: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract: Bosutinib (BOS) is an oral dual Src/Abl tyrosine kinase inhibitor (TKI). This long-term update of an ongoing open-label, phase 1/2 study evaluated the efficacy and safety of BOS as 3rd-line therapy in CP CML pts after prior TKI failure. Pts (n=119) were aged ≥18 y with prior imatinib (IM) failure plus dasatinib (D) resistance (D-R; n=38) or intolerance (D-I; n=50), nilotinib (N) resistance (N-R; n=26), or N-I or D-R/I + N-R/I (n=5) and received BOS starting at 500 mg/d. Median (range) age was 56 (20-79) y; time from CML diagnosis was 6.6 (0.6–18.3) y; follow-up duration was 31.1 (0.3–89.1) mo; and BOS treatment duration was 8.6 (0.2–87.7) mo. Escalation to BOS 600 mg/d occurred in 22 (19%) pts. For the last enrolled pt, time from first dose was ≥48 mo (24% still receiving BOS at 4 y). Major cytogenetic response (MCyR) was newly attained or maintained from baseline by 33% and 7% of pts, respectively (32% attained/maintained complete cytogenetic response [CCyR]) (Table). Kaplan-Meier probability of maintaining MCyR or CCyR at 4 y was 69% and 54%, respectively. At baseline, 95 pts had known mutation status. Twenty unique BCR-ABL mutations occurred in 39 (41%) pts, including 11 with 〉 1 mutation; common mutations were F317L (n=8), T315I (n=7), G250E, and Y253H (n=6 each). MCyR rate was similar in pts without mutations (37%) and pts with 1 mutation (38%); 27% of pts with 〉 1 mutation and 14% of pts with T315I had MCyR. Of 57 pts assessed for mutations at end of treatment, 13 had new mutations (V299L, n=6; T315I, n=3; G250E, n=2 [1 pt also had a new V299L mutation]; F359C, L248V, and L273M, n=1 each; 10 pts had prior mutation); 11/13 pts with new mutations discontinued BOS due to progressive disease (PD) or lack of efficacy. Cumulative incidence of on-treatment PD (ie, transformation to accelerated-/blast-phase [AP/BP] CML, increasing white blood cell count, loss of confirmed complete hematologic response or unconfirmed MCyR) or death* at 4 y was 24%; 52% of pts discontinued before 4 y without an event. Overall survival (OS) at 2 y was 84% (Table; pts followed for OS for only 2 y after BOS discontinuation] ). Cumulative incidence of on-treatment transformation* at 4 y was 4%; 71% discontinued before 4 y without transformation. No pt transformed to BP. There was limited follow-up of patients after treatment discontinuation. Overall, 90 (76%) pts discontinued treatment within 4 y, most commonly due to adverse event (AE; n=28 [24%]) as primary reason for treatment discontinuation. Twenty-six (22%) deaths occurred on study, 5 within 30 d of last BOS dose. Most deaths were due to disease progression (n=12) or AE (n=11; 1 related to BOS); 3 had unknown cause. Non-hematologic treatment-emergent AEs (TEAEs) commonly included (all grades; grade 3/4) diarrhea (83%; 9%), nausea (48%; 1%), and vomiting (38%; 1%); hematologic toxicities included thrombocytopenia (39%; 26%), neutropenia (21%; 16%), and anemia (20%; 7%). Cardiac events (MedDRA system organ classification of cardiac disorders) occurred in 18% of pts (8% grade 3/4). Overall incidence of newly occurring TEAEs for pts on treatment during specific years was 99% in year 1 (y1; n=118/119), 74% in y2 (n=37/50), 64% in y3 (n=25/39), and 72% in y4 (n=23/32). The most common TEAEs were diarrhea in y1 (n=98), pleural effusion in y2 (n=6), abdominal pain in y3 (n=5), and pleural effusion in y4 (n=5). TEAEs were managed primarily by dose delays (66%) and dose reductions (50%). Discontinuations due to AEs were most common in y1 (19% [n=23/119]); 2, 2, and 3 pts discontinued due to AEs in y2, y3, and y4, respectively. The most common reason for discontinuation due to AE was thrombocytopenia (6%). After ≥48 mo follow-up, third-line BOS therapy shows efficacy and manageable toxicity in CP CML pts. Table 1IM + D-R (n=38)IM + D-I (n=50)IM + N-R (n=26)IM + N-I orD-R/I+ N-R/I (n=5)Total (n=119)Evaluable,a n3645265112MCyR, n (%)14 (39)19 (42)10 (39)2 (40)45 (40)CCyR , n (%)8 (22)18 (40)8 (31)2 (40)36 (32)Probability of maintaining MCyR at 4 yb43%87%78%NR69%Probability of maintaining CCyR at 4 yb17%66%63%NR54%Treated, n3850265119PD/death at 4 yc24%16%35%NR24%OS at 2 yb80%83%92%NR84% NR=not reported (small sample size). aReceived ≥1 BOS dose and had a valid baseline efficacy assessment for the respective endpoint. bBased on KM estimates. cBased on cumulative incidence, *adjusting for competing risk of treatment discontinuation without event. Disclosures Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Kantarjian:Pfizer Inc: Research Funding. Lipton:Ariad: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kim:Pfizer Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ILYANG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schafhausen:Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria. Matczak:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Noonan:Pfizer Inc: Employment. Brümmendorf:Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc: Consultancy, Honoraria; Patent on the use of imatinib and hypusination inhibitors: Patent on the use of imatinib and hypusination inhibitors Patents & Royalties. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer Inc: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Abstract: Bosutinib (BOS) is an oral dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) aged ≥18 y with chronic-phase (CP) chronic myeloid leukemia (CML) following imatinib resistance (IM-R) or intolerance (IM-I). IM-R (n=196) or IM-I (n=90) CP-CML pts received BOS as 2nd-line TKI therapy starting at 500 mg/d. Median (range) age was 53 (18–91) y; time from CML diagnosis was 3.7 (0.1–15.1) y. Treatment duration was 24.8 (0.2-83.4) mo and follow-up duration 47.3 (0.6–90.6) mo. BOS dose was escalated to 600 mg/d in 13% of pts. For the last enrolled pt, time from first BOS dose was ≥48 mo; 40% of pts are still receiving BOS. Confirmed complete hematologic responses (CHR) and major cytogenetic responses (MCyR, including complete cytogenetic response [CCyR]) newly attained or maintained from baseline are summarized (Table).TableIM-R (n=196)IM-I (n=90)Total (n=286)Evaluable,a n19590285Confirmed CHR, n (%)168 (86)76 (84)244 (86)Probability of maintaining CHR at 4 yb64%79%68%Evaluable,a n18381264MCyR, n (%)107 (58)49 (60)156 (59)CCyR , n (%)88 (48)42 (52)130 (49)Probability of maintaining MCyR at 4 yb69%86%75%Treated, n19690286 PD/death at 4 yc22%10%19% OS at 2 yb88%98%91%I=intolerant; PD=progressive disease; R=resistant.aReceived ≥1 BOS dose and had a valid baseline efficacy assessment for the respective endpoint.bBased on KM estimates.cBased on cumulative incidence adjusting for competing risk of treatment discontinuation without PD or death. Of 210 pts with known mutation status at baseline, 79 (38%) had ≥1 BCR-ABL kinase domain mutation (n=42 unique), most commonly T315I (n=9), M351T (n=9), F359V (n=8), G250E (n=6), M244V (n=6), and L248V (n=5). Among pts with T315I, CHR and MCyR rates were low (22% each). Of 67 pts evaluated for mutations before and during therapy, 18 had ≥1 new BCR-ABL mutation (T315I, n=8; V299L, n=3; and E255V, E450A, E450G, G250E, K378E, L273M, and M244V, n=1 each); 17 of these 18 pts discontinued due to disease progression (n=12), lack of efficacy (n=4), or death (n=1). The cumulative incidence of on-treatment progression (transformation to accelerated phase [AP] or blast phase [BP] CML, increasing white blood cell count [doubling over ≥1 mo with second count 〉 20×109/L and confirmed ≥1 wk later], or loss of confirmed CHR or unconfirmed MCyR) or death at 4 y was 22% for IM-R and 10% for IM-I pts; 40% of pts discontinued BOS without an event. Kaplan-Meier (KM)–estimated overall survival (OS) at 2 y was 88% for IM-R and 98% for IM-I pts (4-y OS not reliable; pts were followed for OS for only 2 y after BOS discontinuation). The cumulative incidence of on-treatment transformation to AP/BP CML at 4 y was 4%; 57% of pts discontinued treatment without transformation. No new transformations occurred after 2 y. Overall, 173 (60%) pts discontinued BOS, most common primary reasons were adverse event (AE; n=64 [22%] ) and disease progression (n=51 [18%]). Forty (14%) deaths occurred on study, 7 within 30 d of last BOS dose. Most deaths were due to disease progression (n=24 [8%; 22 and 2 in IM-R and IM-I pts, respectively] ) or AE unrelated to BOS (n=13 [5%; 11 and 2]). 3 deaths occurring ≥99 d after last BOS dose were due to unknown causes; no deaths were assessed as BOS-related. The most frequent hematologic treatment-emergent AEs (TEAEs; all grades/grade 3/4) were thrombocytopenia (42%/26%) and anemia (27%/11%); the most frequent non-hematologic TEAEs were diarrhea (86%/10%), nausea (46%/1%), vomiting (37%/4%), rash (36%/9%), abdominal pain (26%/2%), fatigue (26%/1%), pyrexia (26%/1%), increased alanine aminotransferase (ALT; 22%/9%), cough (22%/0), and upper abdominal pain (20%/ 〈 1%). Cardiac events occurred in 16% of pts (7% grade 3/4). Grade 3/4 on-treatment hematologic and non-hematologic laboratory abnormalities in ≥10% of pts included thrombocytopenia (25%), neutropenia (17%), lymphopenia (15%), anemia (14%), alanine transaminase elevation (11%), and hypermagnesemia (11%). Toxicities were managed by ≥1 BOS dose reduction in 44% of IM-R and 58% of IM-I pts and by ≥1 dose delay in 66% of IM-R and 83% of IM-I pts. AEs led to BOS discontinuation in 32 (16%) IM-R and 35 (39%) IM-I pts; the most common reason was thrombocytopenia (3% of IM-R and 12% of IM-I pts). In conclusion, BOS demonstrates durable efficacy and manageable toxicity in CP-CML pts following IM-R or IM-I after ≥48 mo of follow-up, highlighting the therapeutic potential of BOS in these pts. Disclosures: Brümmendorf: Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties; Ariad: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myer Squibb: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Ariad: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Bristol Myer Squibb: Research Funding. Kantarjian:Pfizer Inc: Research Funding. Kim:BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Conlan:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Turnbull:Pfizer Inc: Employment. Gambacorti-Passerini:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer Inc: Consultancy, Research Funding. Lipton:Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract: Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinibintolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events ( 〉 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.

Abstract: Bosutinib (BOS), a Src/Abl tyrosine kinase inhibitor (TKI), is approved for adults with Philadelphia chromosome-positive (Ph+) CML that is resistant/intolerant to prior therapy. In this retrospective analysis, baseline and on-treatment characteristics of chronic phase (CP) CML pts receiving second-line BOS following imatinib resistance (IM-R) or intolerance (IM-I) in an ongoing open-label, phase 1/2 study and a long-term extension study were examined to identify potential predictors of duration of major cytogenetic response (MCyR), overall survival (OS), and progression-free survival (PFS), using a backward-elimination multivariate Cox regression model. A total of 284 (IM-R, n=195; IM-I, n=89) pts who received BOS starting at 500 mg/d were included in this analysis. Median (range) age was 53 (18‒91) y; time from CML diagnosis was 3.7 (0.1‒15.1) y; treatment duration was 25.6 (0.2‒106.7) mo; follow-up duration was 53.7 (0.5‒106.8) mo. For the last enrolled patient, time from first BOS dose was ≥6 y. After ≥6 y of follow-up, median MCyR duration and OS were not yet reached. Kaplan-Meier estimated probability of maintaining MCyR at 6 y was 71%, OS rate was 83%, and cumulative incidence of on-treatment disease progression or death was 21%. Several factors were identified as predictive of MCyR duration, OS or PFS, including baseline Ph+ ratio ≥95% vs ≤35% and MCyR by week 12, which were significant predictors of all 3. Other significant predictors of decreased OS included: age ≥65, BOS-sensitive mutations vs no mutations and higher peripheral blood (PB) blasts at baseline (all P ≤0.031; Table). Other significant predictors of decreased PFS included: higher PB blasts and no dose reduction to 400 mg/d due to AEs (all P ≤0.025; Table). Prior IM response or resistance did not predict long-term outcomes, nor did any treatment-emergent adverse events examined except for abnormal liver function test (LFT), which was predictive of increased OS. In conclusion, pts with CP CML resistant/intolerant to IM treated with BOS were identified as having an increased risk of poorer outcomes if they had the following characteristics: baseline Ph+ ratio ≥95% vs ≤35%, higher PB blasts at baseline or no MCyR by week 12. Having a better understanding of factors that may be predictive of long-term patient outcomes with TKI therapies may aid healthcare providers in the future selection of optimal treatment regimens for pts with Ph+ CML. Disclosures Cortes: ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Brümmendorf:Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Patent: Patents & Royalties: Patent on the use of imatinib and hypusination inhibitors. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ILYANG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schafhausen:ARIAD: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Nadanaciva:Pfizer Inc: Employment. Bardy-Bouxin:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Other: Stock Ownership. Leip:Pfizer Inc: Employment. Lipton:Ariad: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gambacorti-Passerini:Pfizer: Consultancy, Research Funding; BMS: Consultancy.