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Long‐term efficacy and safety of bosutinib (≥4 years follow‐up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated‐phase [AP, n = 79] chronic myeloid leukemia [CML], blast‐phase [BP, n = 64] CML, acute lymphoblastic leukemia [ALL, n = 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1–88.6), 2.8 (0.03–55.9), 0.97 (0.3–89.2) months. Among AP and BP patients, 57% and 28% newly attained or maintained baseline overall hematologic response (OHR); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 years (most by 12 months). In responders at 1 versus 4 years, Kaplan‐Meier (KM) probabilities of maintaining OHR were 78% versus 49% (AP) and 28% versus 19% (BP); KM probabilities of maintaining MCyR were 65% versus 49% (AP) and 21% versus 21% (BP). Most common AEs (AP, BP) were gastrointestinal (96%; 83%), primarily diarrhea (85%; 64%), which was typically low grade (maximum grade 1/2: 81%; 59%) and transient; no patient discontinued due to diarrhea. Serious AEs occurred in 44 (56%) AP and 37 (58%) BP patients, most commonly pneumonia (n = 9) for AP and pyrexia (n = 6) for BP; 11 and 13 died within 30 days of last dose (2 considered bosutinib‐related [AP] per investigator). Responses were durable in ∼50% AP responders at 4 years (∼25% BP patients responded at year 1, suggesting possible bridge‐to‐transplant role in BP patients); toxicity was manageable.Am. J. Hematol. 90:755–768, 2015. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.

Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor for treatment of chronic myeloid leukemia (CML) following resistance/intolerance to prior therapy. Here, we report the data from the 2-year follow-up of a phase 1/2 open-label study evaluating the efficacy and safety of bosutinib as second-line therapy in 288 patients with chronic phase CML resistant (n = 200) or intolerant (n = 88) to imatinib. The cumulative response rates to bosutinib were as follows: 85% achieved/maintained complete hematologic response, 59% achieved/maintained major cytogenetic response (including 48% with complete cytogenetic response), and 35% achieved major molecular response. Responses were durable, with 2-year estimates of retaining response >70%. Two-year probabilities of progression-free survival and overall survival were 81% and 91%, respectively. The most common toxicities were primarily gastrointestinal adverse events (diarrhea [84%], nausea [45%], vomiting [37%]), which were primarily mild to moderate, typically transient, and first occurred early during treatment. Thrombocytopenia was the most common grade 3/4 hematologic laboratory abnormality (24%). Outcomes were generally similar among imatinib-resistant and imatinib-intolerant patients and did not differ with age. The longer-term results of the present analysis confirm that bosutinib is an effective and tolerable second-line therapy for patients with imatinib-resistant or imatinib-intolerant chronic phase CML. http://ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00261846","term_id":"NCT00261846"}}NCT00261846. Am. J. Hematol. 89:732–742, 2014. © 2014 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.

British journal of haematology : BJH 172(1), 97-110 (2016). doi:10.1111/bjh.13801, Published by Wiley-Blackwell, Oxford [u.a.]

Purpose: Bosutinib, a potent ATP-competitive, quinolinecarbonitrile Src/Abl kinase inhibitor, was tested in this first-in-human phase I trial in patients with advanced solid tumor malignancies. Patients and Methods: This trial was conducted in 2 parts. In part 1 (dose escalation), increasing oral bosutinib doses were administered using a 3 + 3 design. In part 2 (dose expansion), approximately 30 patients each with refractory colorectal, pancreas, or non–small cell lung cancer were treated at the recommended phase II dose (RP2D). Primary efficacy endpoints for part 2 were median progression-free survival (colorectal and non–small cell lung) and median overall survival (pancreas). Results: In part 1, dose-limiting toxicities of grade 3 diarrhea (two patients) and grade 3 rash occurred with bosutinib 600 mg/day and the maximum tolerated dose identified was 500 mg/day. However, the majority of patients treated with 500 mg/day had grade 2 or greater gastrointestinal toxicity, and 400 mg/day was identified as the RP2D. The most common bosutinib-related adverse events were nausea (60% patients), diarrhea (47%), vomiting (40%), fatigue (38%), and anorexia (36%). Bosutinib had a mean half-life of 19 to 20 hours at the RP2D. A partial response (breast) and unconfirmed complete response (pancreas) were observed; 8 of 112 evaluable patients had stable disease for 22 to 101 weeks. However, the primary efficacy endpoints for part 2 were not met. Conclusions: Bosutinib was generally well tolerated in patients with solid tumors, with the main toxicity being gastrointestinal. The RP2D was 400 mg/day orally. Further study of bosutinib is planned in combination regimens. Clin Cancer Res; 18(4); 1092–100. ©2011 AACR.

Author Summary Background. Bosutinib is an oral, selective Src/Abl tyrosine kinase inhibitor with activity in breast cancer (BC). We evaluated bosutinib plus exemestane as second-line therapy in previously treated hormone receptor-positive (HR+) locally advanced or metastatic BC. Methods. This was a phase II study with patients enrolled in a single-arm safety lead-in phase. Patients receiving bosutinib at 400 mg or 300 mg/day (based on toxicity) plus exemestane at 25 mg/day were monitored for adverse events (AEs) and dose-limiting toxicities for 28 days, and initial efficacy was assessed. After the lead-in and dose-determination phase, randomized evaluation of combination therapy versus exemestane was planned. Results. Thirty-nine of 42 patients (93%) experienced treatment-related AEs including diarrhea in 28 (67%) and hepatotoxicity in 11 (26%); overall serious treatment-related AEs were recorded in 4 (10%). No liver toxicity met Hy's law criteria. Dose-limiting toxicities occurred in 5 of 13 patients receiving 400 mg (38%) and 3 of 26 patients receiving 300 mg (12%) of bosutinib; all resolved on treatment discontinuation. One patient (300 mg/day) achieved confirmed partial response; three (400 mg/day, n = 2; 300 mg/day, n = 1) maintained stable disease for >24 weeks; a best response of progressive disease occurred in 15 of 42 patients (36%). Median progression-free survival was 12.3 weeks (80% confidence interval: 11.0–15.6). Conclusion. The risk-benefit profile of bosutinib at 300 mg/day plus exemestane resulted in early study termination before the randomized portion. Alternative bosutinib regimens merit investigation in BC.

Background: This phase 1 study evaluated the maximum tolerated dose (MTD), safety, and efficacy of bosutinib (competitive Src/Abl tyrosine kinase inhibitor) plus capecitabine. Methods: Patients with locally advanced/metastatic breast, pancreatic, or colorectal cancers; cholangiocarcinoma; or glioblastoma received bosutinib plus capecitabine at eight of nine possible dose combinations using an ‘up-down' design to determine the toxicity contour of the combination. Results: Among 32 enrolled patients, none of the 9 patients receiving MTD (bosutinib 300 mg once daily plus capecitabine 1000 mg m−2 twice daily) experienced dose-limiting toxicities (DLTs). Overall, 2 out of 31 (6%) evaluable patients experienced DLTs (grade 3 neurologic pain (n=1); grade 3 pruritus/rash and increased alanine aminotransferase (n=1)). Most common treatment-related adverse events (AEs) were diarrhoea, nausea, vomiting, palmar-plantar erythrodysesthesia (PPE), fatigue; most frequent grade 3/4 AEs: PPE, fatigue, and increased alanine/aspartate aminotransferase. Although diarrhoea was common, 91% of affected patients experienced maximum grade 1/2 events that resolved. Best overall confirmed partial response or stable disease >24 weeks (all tumour types) was observed in 6 and 13% of patients. Conclusions: In this population of patients with advanced solid tumours, bosutinib plus capecitabine demonstrated a safety profile similar to that previously reported for bosutinib or capecitabine monotherapy; limited efficacy was observed.

Purpose Human epidermal growth factor (HER) –mediated signaling is critical in many cancers, including subsets of breast and lung cancer. HER family members signal via the phosphatidylinositide 3-kinase (PI3K) –AKT/protein kinase B–mammalian target of rapamycin (mTOR) cascade; mTOR activation is critical for the expression of multiple contributors to tumor growth and invasion. On the basis of preclinical data suggesting synergy of HER2 inhibition and mTOR inhibition in breast and lung cancer models, we conducted a phase I combination study of neratinib, a small-molecule irreversible pan-HER tyrosine kinase inhibitor, and temsirolimus, an mTOR inhibitor, in patients with advanced solid tumors. Patients and Methods This study enrolled patients to dosing combinations of neratinib and temsirolimus. The primary objective was to estimate the toxicity contour of the combination and establish recommended phase II doses. Results Sixty patients were treated on 12 of 16 possible dosing combinations. Diarrhea was the most common drug-related (93%) and dose-limiting toxicity (DLT), constituting four of 10 DLTs. Dose-limiting grade 3 metabolic abnormalities were also observed. Other frequent drug-related toxicities included nausea, stomatitis (both 53%), and anemia (48%). Two maximum-tolerated dose combinations were identified: 200 mg of neratinib/25 mg of temsirolimus and 160 mg of neratinib/50 mg of temsirolimus. Responses were noted in patients with HER2-amplified breast cancer resistant to trastuzumab, HER2-mutant non–small-cell lung cancer, and tumor types without identified mutations in the HER-PI3K-mTOR pathway. Conclusion The combination of neratinib and temsirolimus was tolerable and demonstrated antitumor activity in multiple tumor types, warranting further evaluation.

Bosutinib is an oral, dual SRC/ABL tyrosine kinase inhibitor (TKI) with clinical activity in Philadelphia chromosome-positive (Ph(+)) leukemia. We assessed the safety and tolerability of bosutinib 500 mg per day in a phase 1/2 study in chronic-phase (CP) chronic myeloid leukemia (CML) or advanced Ph(+) leukemia following resistance/intolerance to imatinib and possibly other TKIs. Patient cohorts included second-line CP CML (n = 286), third-/fourth-line CP CML (n = 118), and advanced leukemia (n = 166). Median bosutinib duration was 11.1 (range, 0.03-83.4) months. Treatment-emergent adverse events (TEAEs) in each cohort were primarily gastrointestinal (diarrhea [86%/83%/74%], nausea [46%/48%/48%], and vomiting [37%/38%/43%]). Diarrhea presented early, with few (8%) patients experiencing grade 3/4 events; dose reduction due to diarrhea occurred in 6% of affected patients. Grade 3/4 myelosuppression TEAEs were reported in 41% of patients; among affected patients, 46% were managed with bosutinib interruption and 32% with dose reduction. Alanine aminotransferase elevation TEAEs occurred in 17% of patients (grade 3/4, 7%); among patients managed with dose interruption, bosutinib rechallenge was successful in 74%. Bosutinib demonstrated acceptable safety with manageable toxicities in Ph(+) leukemia. This trial (NCT00261846) was registered at www.ClinicalTrials.gov (this manuscript is based on a different data snapshot from that in ClinicalTrials.gov).

Background: This phase II study evaluated single-agent bosutinib in pretreated patients with locally advanced or metastatic breast cancer. Patients and methods: Patients received oral bosutinib 400 mg/day. The primary end point was the progression-free survival (PFS) rate at 16 weeks. Secondary end points included objective response rate, clinical benefit rate, 2-year overall survival rate, safety, and changes in levels of bone resorption/formation biomarkers. Results: Seventy-three patients were enrolled and treated. Median time from diagnosis of metastatic disease to initiation of bosutinib treatment was 24.5 months. For the intent-to-treat population, the PFS rate at 16 weeks was 39.6%. Unexpectedly, all responding patients (n = 4) were hormone receptor positive. The clinical benefit rate was 27.4%. The 2-year overall survival rate was 26.4%. The main toxic effects were diarrhea (66%), nausea (55%), and vomiting (47%). Grade 3-4 laboratory aminotransferase elevations occurred in 14 (19%) patients. Myelosuppression was minimal. No consistent changes in the levels of bone resorption/formation biomarkers were seen. Conclusions: Bosutinib showed promising efficacy in prolonging time to progression in chemotherapy-pretreated patients with locally advanced or metastatic breast cancer. Bosutinib was generally well tolerated, with a safety profile different from that of the Src/Abl tyrosine kinase inhibitor dasatinib in a similar patient population., peer-reviewed

Author Summary Background. Endocrine therapy resistance in hormone receptor-positive (HR+) breast cancer (BC) may involve crosstalk between HRs and growth factor signaling pathways. We evaluated bosutinib, a dual Src/Abl tyrosine kinase inhibitor that has previously demonstrated some antitumor activity in BC, plus letrozole as first-line endocrine therapy in locally advanced or metastatic HR+/HER2− BC. Methods. Sixteen postmenopausal women were enrolled in a phase II study evaluating the safety/efficacy of bosutinib plus letrozole. In the single-arm safety/dose-confirming lead-in (part 1), patients received oral bosutinib at 400 mg/day plus letrozole at 2.5 mg/day; adverse events (AEs) and dose-limiting toxicities (DLTs) were monitored, and initial efficacy was assessed. A randomized efficacy/safety phase (part 2) was planned to evaluate the combination versus letrozole monotherapy. Results. Fifteen of 16 subjects experienced treatment-related AEs, most commonly diarrhea (69%). Treatment-related hepatotoxicity AEs (primarily alanine aminotransferase [ALT] or aspartate aminotransferase [AST] elevations) occurred in 6 of 16 patients (38%). Four of 15 evaluable patients (27%) experienced a DLT (grade 3/4 ALT/AST elevations, n = 2; grade 3 rash, n = 1; grade 3 diarrhea or vomiting, n = 1), including 1 Hy's law hepatotoxicity case. All DLTs resolved following treatment discontinuation. One patient achieved confirmed partial response; one had stable disease for >24 weeks. Study termination occurred before part 2. Conclusion. The unfavorable risk-benefit ratio did not warrant further investigation of bosutinib plus letrozole.

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.

Bosutinib (BOS), an oral dual Src/Abl tyrosine kinase inhibitor (TKI), showed clinical activity and manageable toxicity in an open-label, phase 1/2 trial in patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML) following resistance (R)/intolerance (I) to imatinib (IM) only (2nd line; CP2L) or to IM plus dasatinib (D) and/or nilotinib (N) (3rd/4th line; CP3L). In this retrospective analysis, a major cytogenetic response (MCyR) by 3 or by 6 mo (but not by 3 mo) was assessed as a predictor of long-term outcomes in CP2L or CP3L pts receiving BOS. CP-CML pts aged ≥18 y received BOS starting at 500 mg/d. MCyR and complete cytogenetic response (CCyR) rates and maintenance of MCyR were assessed in CP2L pts at 4 y and CP3L pts at 3 y. Pts with MCyR newly attained or maintained from baseline by 3 mo, by >3 to ≤6 mo (but not by 3 mo), or no MCyR by 6 mo were assessed for overall survival (OS) at 2 y (all pts) and cumulative incidence of progression (including lack of efficacy)/death at 4 y (CP2L) or 3 y (CP3L), adjusted for competing risks (see Table). OS rates were limited to 2 y (pts were followed for only 2 y from BOS discontinuation). P values were based on Gray's test for comparison of cumulative incidence distributions and log-rank test for OS distributions (no adjustment for multiple comparisons).Table.MCyR by 3 moMCyR by >3 to ≤6 moNo MCyRby ≤6 moCP2L ptsOSEvaluable pts,* n9628151KM rate at 2 y (95% CI), %98 (91.8–99.5)†96 (77.2–99.5)89 (82.1–92.7)Cumulative incidence of progression (including lack of efficacy)/death,‡ %Evaluable pts,µ n9026100Rate at 4 y (95% CI), %13 (7.9–22.7)†23 (11.4–46.6)40 (31.5–50.9)CP3L ptsOSEvaluable pts,* n281271KM rate at 2 y (95% CI), %89 (68.9–96.2)100 (Not estimable–100)84 (73.1–90.9)Cumulative incidence of progression (including lack of efficacy)/death,‡ %Evaluable pts,µ n241237Rate at 3 y (95% CI), %33 (18.9–58.7)25 (9.4–66.6)51 (37.5–70.3)*Pts known to be alive as of the 6-mo response landmark.†P≤0.0004 vs no MCyR by ≤6 mo (comparison of OS and cumulative incidence distributions, unadjusted [P≤0.0002] and adjusted [P≤0.0004] for pre-existing neutropenia and/or thrombocytopenia and presence of a baseline mutation).‡Adjusted for the competing risk of treatment discontinuation without progression/death.µPts known to be alive with no disease progression as of the 6-mo response landmark. CP2L pts (n=286 [IM-R, n=196; IM-I, n=90]) had a median (range) age of 53 (18–91) y. CP3L pts (n=118 with prior IM failure [D-R, n=38; D-I, n=50; N-R, n=26; N-I or D-R/I + N-R/I, n=4]) had a median (range) age of 56 (20–79) y. Median time from CML diagnosis was 3.7 (0.1–15.1) and 6.6 (0.6–18.3) y for CP2L and CP3L pts, respectively; BOS treatment duration was 24.8 (0.2–83.4) and 8.5 (0.2–78.1) mo; follow-up duration was 47.3 (0.6–90.6) and 33.1 (0.3–84.8) mo. Time from last enrolled pt's first dose to database snapshot was ≥48 mo for CP2L and ≥36 mo for CP3L. Of 264 CP2L pts with a valid baseline assessment, 107/183 (58%) IM-R and 49/81 (60%) IM-I pts attained/maintained a MCyR; 88/183 (48%) and 42/81 (52%) pts had CCyR. The Kaplan-Meier (KM) probability of maintaining MCyR at 4 y was 69% for IM-R and 86% for IM-I pts. Of 110 CP3L pts with valid assessment, overall MCyR and CCyR rates were 40% and 32%; the KM probability of maintaining MCyR at 3 y was 65%. There was no significant difference in OS or cumulative incidence of progression/death distribution between CP2L pts with MCyR by 3 mo vs by >3 to ≤6 mo; however, OS (P=0.0004) and cumulative incidence of progression/death (P=0.0002) distributions were significantly better for CP2L pts with MCyR by 3 mo vs no MCyR by 6 mo (Table). For CP3L pts, there was no significant difference in long-term outcomes between early response groups. In conclusion, in CP-CML pts receiving BOS as 2nd-line therapy following IM failure (CP2L), pts who attained/maintained a MCyR by 3 mo had better OS and a lower progression/death distribution vs pts without MCyR by 6 mo; no significant differences were observed between pts achieving MCyR by 3 mo vs by >3 to ≤6 mo, although pt number was low for late responders. There were no significant differences in outcomes for CP-CML pts receiving BOS as 3rd/4th-line therapy, regardless of when or if MCyR was achieved, although the number of pts with MCyR was low. These results suggest that pts not achieving a MCyR by 6 mo, particularly in the 2nd-line setting, may require alternative therapies if options with better likelihood of response are available. Disclosures: Cortes: Pfizer, Ariad, Teva: Consultancy; Novartis, Bristol Myers Squibb, Pfizer, Ariad, Teva: Research Funding. Hochhaus:Pfizer: Research Funding. Apperley:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Pfizer, Ariad: Honoraria (not direct from company), Honoraria (not direct from company) Other. O'Brien:BMS: Consultancy, Honoraria, Research Funding; Ariad, Novartis, Pfizer: Research Funding. Leip:Pfizer Inc: Employment. Turnbull:Pfizer Inc: Employment. Conlan:Pfizer Inc: Employment. Kantarjian:Pfizer Inc: Research Funding. Brümmendorf:Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties; Ariad: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb, Pfizer: Consultancy, Honoraria.

7099 Background: BOS is an oral dual Src/Abl tyrosine kinase inhibitor (TKI) approved for treatment of Ph+ CML following resistance/intolerance to prior therapy. Prior reports from this phase I/II trial indicated the BOS safety profile was primarily characterized by myelosuppression, gastrointestinal events, and rash. The current analysis compares the incidence of toxicity in Year 1 (Y1) for pts on treatment ≤1 y and within Y1 and Year 2 (Y2) for pts on treatment for >1 y. Methods: BOS 500 mg/d was evaluated in 3 cohorts: chronic phase (CP) CML after imatinib only (CP 2L cohort; n = 286); CP CML after imatinib + dasatinib and/or nilotinib (CP 3L cohort; n = 119); and accelerated/blast phase CML or ALL after prior TKI therapy (ADV cohort; n = 164). Results: The most common treatment-emergent adverse events (TEAEs) in each cohort occurred more frequently within Y1 than Y2 (Table). The incidence for grade 3/4 events followed a similar pattern. AEs were the most common reason for BOS discontinuation in Y1 (CP 2L, 53%; CP 3L, 32%; ADV, 41%). Of the pts whose primary reason for discontinuing BOS was an AE during the first 2 y, most did so during Y1 (CP 2L, n = 51/60 [85%]; CP 3L, n = 22/24 [92%]; ADV, n = 24/25 [96%]); the most common reasons during Y1 were thrombocytopenia (12%; 9%; 4%), increased ALT (6%; 4%; 2%), neutropenia (3%; 6%; 0%), diarrhea (4%; 3%; 0%), and vomiting (3%; 4%; 1%). Serious AEs were more common among pts who discontinued BOS ≤1 y versus on treatment >1 y in the CP 3L and ADV cohorts, but similar in the CP 2L cohort (Table). Conclusions: Discontinuation due to AEs was observed primarily in Y1. For pts on BOS for >1 y, the incidence of common TEAEs decreased substantially after Y1, suggesting BOS tolerability improves after long-term exposure. Clinical trial information: NCT00261846. [Table: see text]

Abstract 3785 Bosutinib (BOS) is an orally active, 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. A total of 119 pts aged ≥18 y with prior imatinib (IM) failure plus dasatinib (DAS) resistance (n = 38), DAS intolerance (n = 50), nilotinib (NIL) resistance (n = 27), NIL intolerance (n = 1), or failure of DAS and NIL (n = 3) received BOS starting at 500 mg/d. Median age was 56 y (range, 20–79 y); 45% of pts were male; median time from CML diagnosis was 6.5 y (range, 0.6–18.3 y). Median BOS duration was 8.6 mo (range, 0.2–60.8 mo); 24% of pts are still on treatment. Dose escalation to BOS 600 mg/d occurred in 19% of pts. Time from last pt's first dose to data cutoff was 25 mo (median follow-up duration of 31.4 mo [range, 0.3–66.0 mo]). A confirmed complete hematologic response (CHR) was attained/maintained by 73% of evaluable pts (Table). The Kaplan-Meier (KM) probability of maintaining a CHR at 2 y was 67%. A major cytogenetic response (MCyR) was attained/maintained by 41%, including 32% with a complete cytogenetic response (CCyR). Among evaluable pts without a baseline CCyR, 36% (n = 37/102) achieved a MCyR, including 28 (28%) with a CCyR. The KM probability of maintaining a MCyR at 2 y was 71%. Of 86 pts with baseline mutation status, 40 (47%) pts had 19 unique Bcr-Abl kinase domain mutations, including 7 (8%) pts with T315I. Responses were seen across mutations (75% CHR, 43% MCyR excluding T315I), including those conferring resistance to other TKIs; responses in pts with T315I were low (29% CHR; 14% MCyR). Nine of 37 pts evaluated at baseline and treatment discontinuation had ≥1 new mutation (V299L, n = 4; L248V, n = 2; T315I, n = 2; F359C, n = 1; G250E, n = 1); 8 of 9 pts had discontinued BOS due to disease progression or lack of efficacy. On-treatment transformation to accelerated phase CML occurred in 5 (4%) pts after 16 to 428 d on study; no pt transformed to blast phase CML. KM-estimated on-treatment progression-free survival (PFS) at 2 y was 75%; KM-estimated overall survival (OS) at 2 y was 84% (Table). There were 23 (19%) deaths on study, with 6 deaths occurring ≤30 d after the last BOS dose. Most deaths were due to disease progression (n = 10 [8%]) or an adverse event (AE; n = 10 [8%]; including 1 treatment-related death due to gastrointestinal bleeding). Three deaths were due to unknown cause ≥509 d after the last BOS dose. Non-hematologic treatment-emergent AEs (TEAEs) seen in ≥20% of pts (all grades; grade 3/4) included diarrhea (82%; 8%), nausea (49%; 1%), vomiting (40%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (24%; 1%), and abdominal pain (20%; 1%). The incidence of individual TEAEs was generally similar across groups regardless of prior TKI exposure. Diarrhea TEAEs were predominantly grade 1/2, first reported early during treatment (median time to first event of 1.5 d [range, 1–210 d]), and transient (median event duration of 2 d [range, 1–524 d]). The incidence of pleural effusion was highest among DAS-intolerant pts (n = 11 [22%], including 3 pts with grade 3 events); for 9 of 11 pts pleural effusion had been indicated as a reason for intolerance to prior DAS. Grade 3/4 laboratory abnormalities reported in ≥10% of pts included thrombocytopenia (25%), neutropenia (19%), lymphopenia (17%), and hypermagnesemia (12%). Dose reductions and interruptions were used to manage AEs in 50% and 66% of pts. A total of 32 (27%) pts discontinued treatment due to an AE, most commonly hematologic events. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity after follow-up of ≥24 mo in CP CML following resistance or intolerance to multiple TKIs, with a majority of pts maintaining response at 2 y and few new transformations, deaths, TEAEs, or discontinuations due to AEs since the prior report ∼1 y earlier (Blood 2012;119:4303–12). n (%) IM + DAS-R IM + DAS-I IM + NIL-R IM + DAS ± NILa Total Evaluableb 37 49 25 4 115 CHR 23 (62) 39 (80) 19 (76) 3 (75) 84 (73) Evaluableb 36 44 26 4 110 MCyR 12 (33) 21 (48) 10 (39) 2 (50) 45 (41) CCyR 7 (19) 19 (43) 7 (27) 2 (50) 35 (32) Treated 38 50 27 4 119 PFS at 2 yc 70% 81% 79% 38% 75% OS at 2 yc 77% 85% 92% 75% 84% R, resistant; I, intolerant. a Includes 3 pts with prior exposure to all 3 TKIs and 1 NIL-I pt. KM rates may be unreliable due to the small number of pts in this cohort. b Received ≥1 dose of BOS and had a valid baseline response assessment. c Based on KM estimates Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Kantarjian:Pfizer: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marin:Novartis: Research Funding; BMS: Research Funding. Dorlhiac-Llacer:Novartis, Bristol Myer Squibb, Pfizer: Research Funding. Bullorsky:Novartis, BMS: Consultancy, Speakers Bureau. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Besson:Pfizer Inc: Employment. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

Abstract 2793 Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated the activity and tolerability of BOS 500 mg/d in Philadelphia chromosome–positive (Ph+) leukemia following prior TKI exposure. The current analysis investigated baseline characteristics as predictors of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR), and 2-year Kaplan- Meier–estimated progression-free survival (PFS) and overall survival (OS). All included patients had chronic phase (CP) chronic myeloid leukemia (CML), had developed resistance/intolerance to prior imatinib, and were also either dasatinib resistant (n = 38), dasatinib intolerant (n = 50), nilotinib resistant (n = 27), nilotinib intolerant (n = 1), or resistant/intolerant to dasatinib and nilotinib (n = 3). Median follow-up was 31.4 mo (range, 0.3–66.0 mo). A summary of results is provided in the Table. Longer time since CML diagnosis versus shorter time (median time 6.61 years) was associated with greater OS (2-y probability, 90% vs 79%; log-rank P= 0.0435); however, no association with MCyR, CCyR, or PFS was observed. A lower percentage of Ph+ cells ( Resistance versus no resistance (ie, only intolerance) to prior TKIs was not significantly associated with response or survival, although a numeric trend toward lower rates of MCyR (39% vs 50%) and CCyR (28% vs 50%), as well as 2-y probabilities of PFS (72% vs 89%) and OS (82% vs 91%) among resistant patients was observed. Prior response of at least a minor cytogenetic response (MiCyR) versus no response to first-line imatinib was associated with a higher rate of MCyR (49% vs 28%; P= 0.0375) and a numeric trend toward a higher rate of CCyR (39% vs 20%) on BOS; no trend for PFS or OS was observed. Prior response of at least MiCyR versus no response to second-line dasatinib/nilotinib was associated with higher rates of MCyR (56% vs 19%; P While baseline demographic characteristics showed a numerical trend toward lower response and/or survival rates with age ≥65 y and female gender, no trends were statistically significant. There was also no predictive effect for presence of a Bcr-Abl kinase domain mutation at baseline or CP status at onset of imatinib therapy. In conclusion, most evaluated baseline characteristics appeared not to be predictive of response and/or survival on BOS in patients with CP CML and resistance/intolerance to multiple prior TKIs, although at least MiCyR to prior dasatinib/nilotinib and lower percentage of Ph+ cells at baseline were found to be consistently predictive of better outcomes on BOS. n/n evaluable (%) Kaplan-Meier estimate, % n MCyRa CCyRa PFS at 2 years OS at 2 years Age ≥65 y 26 7/22 (32) 5/22 (23) 70 80 Disclosures: Cortes: Novartis, Bristo Myer Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding. Gambacorti-Passerini:Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Brümmendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Besson:Pfizer Inc: Employment. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Kantarjian:Pfizer Inc: Research Funding.

3027 Background: NER (HKI-272) is an irreversible pan-ErbB tyrosine kinase inhibitor with antitumor activity in pts with HER2-amplified tumors. TEM inhibits mTOR (TORC1). Hyperactivation of the PI3...