Search

TPS8074 Background: Elranatamab (PF-06863135) is a humanized bispecific antibody that targets both B cell maturation antigen (BCMA)-expressing multiple myeloma (MM) cells and CD3-expressing T cells, with binding resulting in T cell-mediated cytotoxicity. Elranatamab has demonstrated antitumor activity and delayed tumor progression in preclinical studies, as well as promising efficacy and manageable safety in the ongoing phase 1 MagnetisMM-1 study in patients (pts) with relapsed/refractory MM (Bahlis et al, J Clin Oncol 2021). Methods: MagnetisMM-5 is an open-label, multicenter, randomized phase 3 study designed to evaluate the efficacy and safety of subcutaneous (SC) elranatamab monotherapy and SC elranatamab + SC daratumumab in pts with relapsed/refractory MM who have received prior therapy, including lenalidomide and a proteasome inhibitor (PI). The study consists of 2 parts. In part 1, a minimum of 20 pts will be enrolled to assess the safety of an elranatamab priming regimen and identify the recommended combination dose for SC elranatamab + SC daratumumab for part 2. The primary endpoint of part 1 is dose-limiting toxicities encompassing the elranatamab monotherapy priming duration (14 d) and the first cycle of SC elranatamab + SC daratumumab dosing (28 d). In part 2, ̃450 pts will be stratified by prior lines of therapy (1 vs 2–3 vs ≥4) and prior treatment with anti-CD38 therapy (yes vs no) and enrolled in a 1:1:1 ratio to receive SC elranatamab or SC elranatamab + SC daratumumab or SC daratumumab + oral pomalidomide + oral dexamethasone. The primary endpoint of part 2 is progression-free survival (PFS), according to International Myeloma Working Group (IMWG) response criteria and blinded independent review. Secondary endpoints include PFS and PFS on next-line treatment by investigator per IMWG, overall survival, objective response rate, duration of response, complete response (CR) rate, duration of CR, time to response, overall and sustained minimal residual disease negativity rates, safety, quality of life, immunogenicity, and PK. Key inclusion criteria are age ≥18 y, MM diagnosis with measurable disease according to IMWG criteria, ECOG performance status 0–2, and clinical laboratory values within specified ranges. For part 2, pts should have received ≥1 prior line of anti-myeloma therapy, including treatment with lenalidomide and a PI. Key exclusion criteria include smoldering MM, plasma cell leukemia, amyloidosis, POEMS syndrome, stem cell transplant within 12 wk of enrollment, primary refractory MM, active, uncontrolled bacterial, fungal, or viral infections, previous treatment with BCMA-targeted therapy, anti-CD38 therapy within 6 mo of the first dose of study treatment, and previous pomalidomide therapy. MagnestisMM-5 will include sites in 28 countries. Clinical trial information: NCT05020236.

8006 Background: Elranatamab (PF-06863135) is a humanized bispecific antibody that targets both BCMA-expressing MM cells and CD3-expressing T cells. MagnetisMM-3 (NCT04649359) is an open-label, multicenter, non-randomized, phase 2 study to evaluate the safety and efficacy of elranatamab monotherapy in pts with R/R MM. Initial safety results are presented. Methods: MagnetisMM-3 enrolled pts who are refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Pts were assigned to 1 of 2 independent, parallel cohorts: those naïve to BCMA-directed therapies (Cohort A) and those with previous exposure to BCMA-directed antibody-drug conjugates or CAR-T cells (Cohort B). Pts received subcutaneous elranatamab 76 mg QW on a 28-d cycle with a 2-step-up priming dose regimen administered during the first week. Dose modifications were permitted for toxicity. Treatment-emergent adverse events (TEAEs) were graded by CTCAE (v5.0), and cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) by ASTCT criteria. Results: As of the data cutoff on Dec 31, 2021, 60 pts in Cohort A had received ≥1 dose of elranatamab; the last pt’s first dose was ̃2 months prior to the cutoff. Median age was 69.0 y (range, 44−89), 48.3% were male, 63.3% were white, 18.3% were Asian and 11.7% were Black/African American. At baseline, 60.0% of pts had an ECOG performance status 1−2 and pts had received a median of 5 (range, 2−12) prior therapies. Median duration of elranatamab treatment was 9.57 wks (range, 0.1−46.1); median relative dose intensity was 87.4% (range, 23.1−101.4). TEAEs were reported in 100% (Grade [G] 3/4, 75.0%) of pts. Most common (≥30%) hematologic TEAEs were neutropenia (36.7% [G3/4, 35.0%]), anemia (36.7% [G3/4, 30.0%]) and thrombocytopenia (30.0% [G3/4, 21.7%]). Among pts who received the 2-step-up priming regimen (n = 56), CRS and ICANS, respectively, were reported in 58.9% (G3/4, 0%) and 3.6% (G3/4: 0%); of those pts, 57.6% (n = 19/33) and 100% (n = 2/2) received tocilizumab and/or steroids. Most common (≥30%) non-hematologic TEAE, other than CRS/ICANS, was fatigue (31.7% [G3/4, 3.3%]). Infections were reported in 46.7% (G3/4: 18.3%) of pts; most frequently reported were upper respiratory tract infections (11.7% [G3/4: 0%]). Discontinuations due to adverse events were reported in 5.0% of pts. No pts permanently discontinued treatment due to CRS or ICANS. There were 10 deaths; causes were MM progression (n = 8), septic shock (n = 1) and unknown (n = 1). Data will be updated at the time of presentation to include ̃90 pts. Conclusions: Preliminary results of MagnetisMM-3 in pts with R/R MM and no prior BCMA-targeted treatment suggest that 76 mg QW elranatamab with a 2-step-up priming regimen is well tolerated, with no G ≥3 CRS or ICANS observed. Clinical trial information: NCT04649359.

7049 Background: Efficacy and safety of BOS vs imatinib (IMA) in patients (pts) with newly diagnosed chronic phase CML was assessed in the phase 3 BFORE trial. Here we characterize the safety profile of BOS after 5 yrs follow-up, with a focus on GI, liver, effusion and renal treatment-emergent adverse events (TEAEs). Methods: Pts who received ≥1 dose of BOS (n=268) or IMA (n=265) 400 mg/d in BFORE were included. Adverse events (AEs) of special interest were analyzed by selecting prespecified MedDRA terms to generate TEAE clusters. Final database lock: June 12, 2020. Results: Median duration of treatment (Tx) was 55 mo for pts receiving BOS or IMA; respective median (range) dose intensity was 393.6 (39–583) vs 400.0 (189–765) mg/d. Any grade TEAEs occurred in 98.9% and 98.9% of BOS- vs IMA-treated pts. Most common newly occurring TEAEs (any grade) after 12 mos were increased lipase (9.0%) with BOS, and diarrhea (8.3%) with IMA. In BOS- vs IMA-treated pts, 25.4% vs 14.3% had AEs leading to permanent Tx discontinuation; the majority discontinued in yr 1 (14.2% vs 10.6%). Most frequent AEs leading to discontinuation were increased ALT (overall, 4.9%; yr 1, 4.5%) with BOS vs thrombocytopenia (overall, 1.5%; yr 1, 1.5%) with IMA. GI, liver, effusion and renal TEAEs, respectively, occurred in 79.9%, 44.0%, 6.0% and 10.4% (maximum grade 3/4 [G3/4]: 9.0%, 26.9%, 1.1% and 2.2%) of BOS- vs 61.5%, 15.5%, 2.3% and 9.8% (G3/4: 1.1%, 4.2%, 0.4% and 0.8%) IMA-treated pts. One grade 5 renal TEAE occurred in the BOS arm and was not considered related to Tx. Cumulative rates per Tx yr are shown in the Table. Most common GI TEAEs were diarrhea (BOS vs IMA: 75.0% vs 40.4% [G3/4: 9.0% vs 1.1%]) with BOS, and nausea (37.3% vs 42.3% [G3/4: 0% vs 0%]) with IMA. In both arms, the most common liver, effusion and renal TEAEs, respectively, were increased ALT and/or AST (34.0% vs 8.3% [G3/4: 22.0% vs 2.3%]), pleural effusion (5.2% vs 1.9% [G3/4: 0.7% vs 0.4%]) and increased blood creatinine (6.7% vs 8.3% [G3/4: 0.4% vs 0.4%]). GI, liver, effusion and renal TEAEs infrequently led to Tx discontinuation (1.9%, 7.8%, 0.7% and 0.7% vs 1.1%, 0.8%, 0% and 0.4%). Conclusions: The safety profiles of BOS and IMA in BFORE were distinct, with no new safety signals identified after 5 yrs follow-up. Onset of TEAEs occurred primarily during yr 1 (eg, GI and liver), with an increased incidence of some TEAEs (eg, effusion and renal) in later yrs. Discontinuations due to AEs generally occurred early into Tx, with few due to GI, liver, effusion and renal AEs. These safety results support the use of first-line BOS as a standard of care in pts with CP CML. Clinical trial information: NCT02130557. [Table: see text]

e19055 Background: Bosutinib (BOS) is approved for pts with Philadelphia chromosome-positive CML resistant/intolerant to prior therapy and newly diagnosed pts in chronic phase. Methods: The BYOND trial (NCT02228382) evaluated the efficacy and safety of BOS in 163 pts with CML resistant/intolerant to prior tyrosine kinase inhibitors (TKIs; Gambacorti-Passerini et al, Blood, 2021). We report a sub-analysis of 48 pts treated with 2 (3L) and 3 (4L) prior TKIs, categorized by resistance/intolerance to the last received TKI. This sub-analysis is based on the final Nov 23, 2020 database lock. Results: There were 18 and 30 pts resistant or intolerant to the last TKI who entered the study without complete cytogenetic response (CCyR) or major molecular response (MMR), respectively. Median (range) treatment duration was 10.6 mo (1.6–48.5) vs 28.3 mo (0.2–48.6) and median (range) dose intensity was 447.1 mg/d (131.3–520.4) vs 288.8 mg/d (79.7–500.0) for resistant vs intolerant pts. Prior TKIs included imatinib (88.9% vs 100.0%), dasatinib (88.9% vs 83.3%), and nilotinib (66.7% vs 63.3%) for resistant vs intolerant pts. Overall, 61.1% vs 66.7% of resistant vs intolerant pts discontinued BOS, mostly commonly due to adverse events (AEs) in 27.8% vs 16.7% pts; 16.7% vs 6.7% discontinued BOS due to insufficient clinical response. Rates of CCyR/MMR are shown in the table. Among responders (resistant vs intolerant pts), median (range) time to CCyR was 5.1 mo (2.8–8.8) vs 3.0 mo (2.7–6.1); median (range) time to MMR was 5.8 mo (2.8–9.4) vs 3.2 mo (2.8–9.3). In resistant vs intolerant pts, any grade treatment-emergent AEs (TEAEs) were reported by 100.0% vs 96.7% pts; grade 3/4 TEAEs were reported by 72.2% vs 83.3% pts. Grade 3/4 TEAEs > 10% in resistant pts were thrombocytopenia (22.2%) and neutropenia (11.1%), and in intolerant pts were increased alanine aminotransferase (26.7%), diarrhea (23.3%), pleural effusion (13.3%), and rash (13.3%). Conclusions: This sub-analysis of resistant/intolerant pts without baseline CCyR or MMR shows BOS was active in heavily pretreated pts with resistance/intolerance to the last TKI. Despite a difference between resistant/intolerant pts, efficacy outcomes, though lower than the overall BYOND population, are encouraging, and safety was generally consistent with previous reports. Clinical trial information: NCT02228382. [Table: see text]

7039 Background: Bosutinib (BOS) is approved for patients (pts) with Philadelphia chromosome-positive chronic myeloid leukemia (CML), at a starting dose of 400 mg QD in newly diagnosed pts in chronic phase (CP). This analysis evaluated the impact dose reduction has on the outcomes of BOS and imatinib (IMA) in pts with CP CML. Methods: In the open-label BFORE trial, 536 pts with newly diagnosed CP CML were randomized to receive 400 mg QD BOS (N = 268) or IMA (N = 268; 3 untreated). Dose could be reduced to 300 mg QD for toxicity. Following sponsor approval, dose reduction to BOS 200 mg QD was permitted for 4 wks maximum; after this time, dose escalation or treatment discontinuation was required. Maintenance of response after dose reduction was defined as having a response > 6 mo after the first reduction. Database lock: June 12, 2020, 5 y after the last pt enrolled. Results: In the BOS arm, dose reduction to 300 (without further reduction) or 200 mg QD was seen in 82 (31%) and 33 (12%) pts, and median time to dose reduction was 85 and 205 d. In the IMA arm, 50 (19%) pts had a dose reduction to 300 mg QD, and median time to dose reduction was 92 d. Most common (≥2% of pts) treatment-emergent adverse events (TEAEs) leading to dose reduction were increased alanine aminotransferase (8%), thrombocytopenia (7%), diarrhea (7%), increased lipase (6%), increased aspartate aminotransferase (4%), nausea (4%), neutropenia (3%), rash (3%) and abdominal pain (2%) with BOS, and neutropenia (4%) with IMA. Of the pts who remained on 400 mg QD BOS (n = 153) or IMA (n = 214), respectively, 120 (78%) and 139 (65%) achieved major molecular response (MMR). Among pts who had a BOS dose reduction to 300 mg QD, 51/82 (62%) had MMR > 6 mo after dose reduction: 14 (17%) maintained MMR before and after dose reduction and 37 (45%) achieved MMR for the first time after dose reduction. Seven (9%) pts had MMR before dose reduction but discontinued treatment before the next > 6 mo assessment. In the IMA arm, 32/50 (64%) pts had MMR > 6 mo after dose reduction: 9 (18%) maintained MMR before and after dose reduction and 23 (46%) achieved MMR for the first time after dose reduction. One (2%) pt had MMR before dose reduction but discontinued treatment before the next > 6 mo assessment and 1 (2%) pt lost a previously attained MMR after dose reduction. Among pts who had a BOS dose reduction to 200 mg QD, 12/33 (36%) had MMR > 6 mo after dose reduction: 7 (21%) maintained MMR before and after dose reduction and 5 (15%) achieved MMR for the first time after dose reduction. Six (18%) pts had MMR before dose reduction but discontinued treatment before the next > 6 mo assessment. Similar trends were seen for complete cytogenetic response. Conclusions: Management of TEAEs through BOS or IMA dose reduction enabled pts to continue treatment, with a substantial number of pts achieving MMR for the first time after dose reduction. Clinical trial information: NCT02130557.

7037 Background: Bosutinib (BOS) is approved for the treatment (Tx) of Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. Body mass index (BMI) was shown to influence Tx response with front-line dasatinib vs imatinib (IMA). We report the efficacy and safety of BOS and IMA by BMI in patients (pts) with newly diagnosed CP CML. Methods: In the open-label BFORE trial, pts were randomized to receive 400 mg once daily BOS or IMA. Outcomes were assessed according to baseline BMI ≥25 or = 25 kg/m2. This post hoc analysis was based on the final 5-y analysis (database lock: June 12, 2020). Results: In the BOS and IMA arms, respectively, 149 (56.4%) vs 115 (43.6%) pts and 145 (54.3%) vs 122 (45.7%) pts had BMI ≥25 vs = 25. In both the BOS and IMA arms, median Tx duration and time on study was 55 mo for pts with BMI ≥25 or = 25; respective median dose intensity was 394 vs 393 mg/d and 400 vs 400 mg/d. Molecular response (MR) rates are shown in the table. Cumulative incidence of major MR was similar in pts with ≥25 vs = 25 receiving BOS (HR 0.99; 95% CI 0.74−1.31) or IMA (HR 1.09; 95% CI 0.81−1.47). Event-free survival (EFS) and overall survival (OS) rates at 60 mo are shown in the table. Most common reasons for Tx discontinuation were adverse events (AEs) (BOS 28.2 vs 20.0%; IMA 13.3 vs 10.7%) and lack of efficacy (BOS 5.4 vs 5.2%; IMA 16.1 vs 19.8%). In pts with BMI ≥25 vs = 25, dose reductions and interruptions due to Tx-emergent AEs (TEAEs) occurred in 43.6 % vs 46.2% and 66.4% vs 69.7% of pts with BOS and 24.5% vs 24.6% and 40.6% vs 50.8% with IMA. Any grade TEAEs in ≥30% of pts with BMI ≥25 vs = 25 were diarrhea (73.8 vs 73.1%), nausea (40.9 vs 31.9%), thrombocytopenia (30.9 vs 41.2%), increased alanine (37.6 vs 28.6%) and aspartate aminotransferase (30.2 vs 20.2%) with BOS and diarrhea (49.0 vs 29.5%), nausea (46.2 vs 37.7%), muscle spasms (33.6 vs 26.2%), neutropenia (14.7 vs 32.0%) and thrombocytopenia (10.5% vs 30.3%) with IMA. Conclusions: Efficacy of BOS was consistent in pts with BMI ≥25 or = 25; however, with IMA a low (vs high) BMI appeared to be associated with worse survival outcomes. Differences in certain TEAEs were observed between BMI subgroups in both treatment arms. Clinical trial information: NCT02130557. [Table: see text]

7009 Background: BOS is approved for Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed Ph+ CP CML. In a phase 1/2 study, second-line BOS showed durable efficacy and manageable toxicity in pts with imatinib-resistant (IM-R) or -intolerant (IM-I) Ph+ CP CML. Methods: This final efficacy and safety analysis of the phase 1/2 study and extension study was based on ≥10 y of follow-up (FU). Ph+ CP CML pts who received BOS starting at 500 mg/d after prior treatment (Tx) with imatinib only were included. Results: 19% of pts were on BOS at y 10, and 13% were still on BOS at study completion after ≥10 y; 19% completed ≥10 y of FU. Median duration of Tx and FU were 26 and 54 mo, respectively. Median (range) dose intensity was 436 (87–599) mg/d. The most common primary reasons for permanent Tx discontinuation were lack of efficacy (unsatisfactory response or disease progression; 27%) and adverse events (AEs; 26%). In pts with a valid baseline assessment, cumulative complete cytogenetic response (CCyR), major molecular response (MMR) and MR4 rates (95% CI), respectively, were 50% (43–56), 42% (35–49) and 37% (30–44) (IM-R: 48% [41–56], 46% [37–55] and 39% [31–48]; IM-I: 53% [41–64], 36% [25–48] and 33% [22–45]). Responses were durable, with estimated probabilities of maintaining CCyR, MMR and MR4 > 50% after ≥10 y (Table). At 10 y, cumulative incidence of on-Tx progression/death was 24% and Kaplan-Meier (K-M) overall survival 72% (Table); 55 deaths (IM-R: n = 41; IM-I: n = 14) occurred on study, none BOS-related. Any grade Tx-emergent AEs (TEAEs) in ≥40% of pts were diarrhea (86%), nausea (46%) and thrombocytopenia (42%). Pleural effusion, cardiac and vascular TEAEs occurred in 13%, 12% and 11% of pts, respectively. 28% of pts had AEs leading to permanent Tx discontinuation; most common (≥2% of pts) were thrombocytopenia (6%), neutropenia (2%) and alanine aminotransferase increased (2%). Conclusions: These 10-y data are consistent with prior results of durable efficacy and manageable toxicity with second-line BOS and support long-term BOS use in CP CML pts after imatinib failure. Clinical trial information: NCT00261846 and NCT01903733. [Table: see text]

7549 Background: BOS is approved for newly diagnosed CP CML and CML resistant/intolerant to prior therapy. In a phase I/II study, BOS showed durable efficacy and manageable toxicity in patients (pts) with CP CML after IMA failure. We report an ≥8-y update of this phase I/II and ongoing extension study. Methods: Pts with CP CML resistant/intolerant to IMA (CP2L) or IMA + dasatinib and/or nilotinib (CP3L) or with accelerated/blast phase (AP/BP) CML or Philadelphia chromosome+ acute lymphoblastic leukemia with prior tyrosine kinase inhibitor (TKI) therapy (ADV) received BOS starting at 500 mg/d. Results: 54/284 (19%) CP2L pts were still on BOS after ≥9 y and 8/119 (7%) CP3L and 5/167 (3%) ADV pts after ≥8 y; 61 CP2L pts discontinued BOS since y 5 and 21 CP3L and 12 ADV pts since y 4. Overall, the most common reason for discontinuation was disease progression/lack of efficacy in CP2L (27%), CP3L (42%) and ADV (50%) pts; last dose before discontinuation was ≥500 mg/d in 59 (21%), 28 (24%) and 46 (28%) pts, respectively. In CP2L pts, median (range) of follow-up was 54 (1–155) mo, treatment duration 26 (

7551 Background: Bosutinib (BOS) is approved for patients (pts) with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and in newly diagnosed pts in chronic phase (CP). Methods: The ongoing phase 4 BYOND study is further evaluating efficacy and safety of BOS (starting dose 500 mg/d) for CML resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). We report findings in pts intolerant to all prior TKIs. Data are reported ≥1 y after the last enrolled pt (~85% TKI-intolerant pts had ≥2 y follow-up). Results: Of 163 pts who received BOS, 156 had Ph+ CP CML. 73 pts entered the study due to intolerance; 29, 26 and 18 had 1 (CP2L), 2 (CP3L) and 3 (CP4L) prior TKIs, respectively. After a median follow-up of 30.4 mo, median treatment duration across all 3 cohorts (CP2L, CP3L, CP4L, respectively) was 25.3 mo (29.2, 24.6, 17.6) and median dose intensity was 292.0 mg/d (304.5, 284.8, 272.1). Across CP CML cohorts (CP2L, CP3L, CP4L, respectively), 84.9% of patients (82.8%, 88.5%, 83.3%) had ≥1 dose reduction and 83.6% (79.3%, 84.6%, 88.9%) had ≥1 dose interruption due to adverse events (AEs). At the data cutoff, 53.4% (CP2L 65.5%, CP3L 42.3%, CP4L 50.0%) were still receiving BOS. The most common reason for discontinuation was AEs (28.8%). The most common ( > 40%) treatment-emergent AEs (TEAEs) were diarrhea (87.7%) and nausea (43.8%). Grade 3/4 TEAEs in > 10% of pts were diarrhea (16.4%), increased alanine aminotransferase (19.2%) and increased lipase (12.3%). Most pts with a valid baseline assessment achieved major molecular responses (MMR) across therapy lines (Table). Deaths occurred in 4 pts (CP2L 1, CP3L 3, CP4L 0); none were related to BOS or CML. Overall survival rate (95% CI) at 2 y in TKI-intolerant pts was 97.2% (89.2–99.3); rates were 96.4% (77.2–99.5), 96.0% (74.8–99.4) and 100% (100–100) in CP2L, CP3L and CP4L pts, respectively. Conclusions: A long duration of treatment and high response rate were observed in TKI-intolerant pts treated with BOS. Despite being intolerant to all prior therapies, ≥50% of pts in the overall intolerant cohort remained on BOS treatment at the data cutoff and > 80% achieved/maintained MMR. These results further support BOS use in pts with Ph+ CP CML and intolerance to all prior TKIs. Clinical trial information: NCT02228382 . [Table: see text]

7051 Background: Tyrosine kinase inhibitor therapy has been linked to cardiac and vascular events. Cardiac, vascular and hypertension treatment-emergent adverse events (TEAEs) with bosutinib or imatinib for newly diagnosed chronic phase chronic myeloid leukemia were analyzed. Methods: Patients (pts) who received ≥1 dose of bosutinib (n = 268) or imatinib (n = 265) 400 mg/d in the phase 3 BFORE trial were included. Prespecified MedDRA terms comprised the clusters of investigator assessed TEAEs. Exposure-adjusted TEAE rate was defined as the number of pts with TEAEs / total pt-yr (pt-yr = sum of total time to first TEAE for pts with TEAEs and treatment duration for pts without TEAEs). Results: After ≥36 mo follow-up, 65% vs 62% of pts in the bosutinib vs imatinib arm were still on treatment. Rates of TEAEs, treatment withdrawals and drug-related TEAEs in the clusters of interest were low in both arms (Table). The most common cardiac, vascular and hypertension TEAEs, respectively, were sinus bradycardia (2%), angina pectoris (3%) and hypertension (7%) vs prolonged QT (3%), peripheral coldness (1%) and hypertension (9%) with bosutinib vs imatinib; corresponding grade 3/4/5 TEAE rates in the respective clusters were 3%, 3% and 4% vs 1%, 0.4% and 4%. Hypertension was the only grade 3/4 TEAE occurring in ≥1% of pts in either arm (4% each); 1 grade 5 TEAE each was noted for bosutinib (cardiac failure) and imatinib (cerebrovascular accident). Exposure-adjusted rates of cardiac, vascular and hypertension TEAEs, respectively, were 0.04, 0.03 and 0.04 vs 0.03, 0.01 and 0.04 (grade 3/4/5 only: 0.01, 0.01 and 0.02 vs 0.01, 0.002 and 0.02) for bosutinib vs imatinib. Conclusions: Cardiac, vascular and hypertension TEAE rates were low with bosutinib and imatinib. A majority of TEAEs were low grade and few led to treatment withdrawal. Clinical trial information: NCT02130557. [Table: see text]

7062Background: Bosutinib has a distinct adverse event (AE) profile vs other TKIs used to treat Ph+ leukemia. Methods: Pts with chronic phase (CP) chronic myeloid leukemia (CML; n=403) or accelerat...

7002 Background: BOS is a potent, dual SRC/ABL tyrosine kinase inhibitor approved for treatment (tx) of adults with Ph+ CML resistant/intolerant to prior therapy. We assessed the efficacy and safety of BOS vs IM for first-line tx of chronic phase (CP) CML. Methods: In this ongoing, multinational, phase 3, open-label study, 536 patients (pts) with newly diagnosed CP CML were randomized 1:1 to BOS 400 mg QD (n = 268) or IM 400 mg QD (n = 268 [3 not treated]). Per protocol, efficacy was assessed in a modified intent-to-treat (ITT) population of 487 Ph+ pts (BOS, n = 246; IM, n = 241) with e13a2/e14a2 transcripts; results in full ITT will also be presented. Results: After≥12 mo of follow-up, 78% of BOS and 73.2% of IM pts remain on tx with median tx durations of 14.1 and 13.8 mo, respectively. Major molecular response (MMR) rate at 12 mo (primary endpoint) was significantly higher with BOS vs IM (47.2% vs 36.9%; P= 0.02). Time to MMR was shorter for BOS (hazard ratio [HR] 1.34; P< 0.02). Rate of complete cytogenetic response (CCyR) by 12 mo was also significantly higher with BOS vs IM (77.2% vs 66.4%; P< 0.008), with time to CCyR shorter for BOS (HR 1.38; P≤0.001). Rates of BCR-ABL transcripts≤10% (Intl Scale) at 3 mo (75.2% vs 57.3%), MR4 at 12 mo (20.7% vs 12%) and MR4.5 at 12 mo (8.1% vs 3.3%) were higher with BOS vs IM, respectively (all P< 0.025). 1 BOS pt and 4 IM pts discontinued tx due to progression to accelerated or blast phase. There were no deaths within 28 d of last dose of BOS and 4 with IM. Safety data were consistent with known safety profiles of BOS and IM. 12.7% of BOS and 8.7% of IM pts discontinued due to drug-related toxicity. Gr≥3 diarrhea (7.8% vs 0.8%) and increased alanine (19% vs 1.5%) and aspartate (9.7% vs 1.9%) aminotransferase levels were more common with BOS. Cardio-, peripheral- and cerebrovascular events were infrequent (3%, 1.5% and 0% BOS vs 0.4%, 1.1% and 0.4% IM; gr≥3: 1.5%, 0% and 0% vs 0%, 0% and 0.4%). Conclusions: Pts on BOS had significantly higher rates of 12-mo MMR and CCyR and achieved responses faster than those on IM, but had higher incidence of gastrointestinal events and transaminase elevations. Results suggest BOS may be an important tx option for pts with newly diagnosed CP CML. Funding. Avillion, Pfizer. Clinical trial information: NCT02130557 .

7076 Background: BOS is a Src/Abl tyrosine kinase inhibitor for adults with Ph+ CML resistant/intolerant to prior therapy. We assess long-term efficacy/tolerability of BOS after ≥5 y vs ≥2 y follow...

7068 Background: ADV Ph+ CML pts have worse outcomes vs chronic CML pts. In this first report of BOS activity in this cohort as fully enrolled, we evaluate long-term efficacy and safety of BOS in A...

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]

6511 Background: BOS is an oral dual Src/Abl kinase inhibitor with potent activity in Ph+ leukemia. Methods: Efficacy and safety of BOS 500 mg/d was evaluated in older (≥65 y; n = 119) and younger (

631 Background: Third-generation nonsteroidal aromatase inhibitors (AIs) are used as adjuvant and 1st-line metastatic therapy for postm HR+ ABC. However, many patients (pts) subsequently experience disease progression. A phase 2 study of the Src/Abl kinase inhibitor bosutinib (BOS) as monotherapy (400 mg) in unselected, heavily pretreated ABC pts revealed an overall response rate (ORR) of 9.4% and 16-wk progression-free survival (PFS) rate of 29.8%, with a median PFS of 9.9 wks. As all responses were seen in HR+ pts, combination BOS and endocrine therapy was explored. Methods: This randomized, open-label, multicenter, phase 2 trial evaluated BOS and EXE vs EXE alone as 2nd-line therapy after AI failure in postm HR+ HER2– ABC. The primary end point was PFS. Prior to randomization, a 28-day safety lead-in phase was conducted; BOS 400 mg/EXE 25 mg was administered orally once daily, with reduction to BOS 300 mg if the higher dose had unacceptable toxicity. Results: 42 pts participated in the safety lead-in p...

6535 Background: BOS is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). Methods: This open-label, phase 1/2 trial evaluated safety and efficacy of BOS as 3rd-line therapy in patient...