Dasatinib Arm Research Articles

Nilotinib vs dasatinib in achieving MR4.5 for de novo chronic myeloid leukemia: the randomized JALSG CML212 study

AbstractDeep molecular response (DMR) is a prerequite for treatment-free remission (TFR) in chronic myeloid leukemia in chronic phase (CML-CP). The JALSG (Japan Adult Leukemia Study Group) conducted a prospective randomized phase 3 CML212 study for de novo CML-CP to compare the cumulative achievement of molecular response 4.5 (MR4.5; international scale BCR::ABL1 ≤0.0032%) by 18 months between nilotinib and dasatinib treatment as a primary end point. A total of 454 patients were randomly assigned to the 300 mg nilotinib twice daily arm or to the 100 mg dasatinib daily arm (both n = 227). BCR::ABL1 messenger RNA levels were monitored every 3 months. Study treatment was stopped if the patients were judged as failure according to the European LekemiaNet 2009 criteria or showed intolerance. The cumulative achievement rates of MR4.5 by 18 months were 32.6% (95% confidence interval [CI], 26.5-39.1) in the nilotinib arm and 30.8% (95% CI, 24.9-37.3) in the dasatinib arm with no significant difference (P = .66). The cumulative achievement rates of early molecular response, complete cytogenetic response, and major molecular response by 12, 18, 24, and 36 months were almost the same between the 2 arms. There was no significant difference in progression-free survival (PFS) or overall survival (OS) between the 2 arms by log-rank tests (PFS, P = .58; OS, P = .64). These results suggest that nilotinib and dasatinib would be equally effective for patients with de novo CML-CP. This trial was registered in the University Hospital Medical Information Network Clinical Trials Registry as #UMIN000007909.

Feasibility and Outcome of Post-Induction Therapy Incorporating Dasatinib for Patients with Newly Diagnosed ABL-Class Fusion B-Lymphoblastic Leukemia (ABL-class Fusion B-ALL): Children's Oncology Group AALL1131

Background: Approximately 2-3% of B-ALL patients have Philadelphia chromosome like (Ph-like) B-ALL with an ABL-class fusion ( ABL1, ABL2, PDGFRB, or CSF1R fusions), but lacking BCR::ABL1. These patients are predicted to be sensitive to ABL-class tyrosine kinase inhibitors, such as imatinib or dasatinib. Ph-like B-ALL is associated with male sex, older age, higher initial white blood cell (WBC) count, elevated end of induction (EOI) minimal residual disease (MRD), and poor outcome. The AALL1131 Dasatinib arm was designed to evaluate response to therapy following induction of patients with ABL-class fusion B-ALL, when given dasatinib continuously on a modified Berlin-Frankfurt-Münster (MBFM) backbone. Methods: Between February 2012 and March 2019, AALL1131 enrolled patients 1-30 years with newly diagnosed high risk (HR) B-ALL. AALL1131 was amended in August 2016, to include the Dasatinib arm for patients with ABL-class fusions involving ABL1, ABL2, PDGFRB, and CSF1R. Patients with Down Syndrome were not eligible for the Dasatinib arm. ABL-class fusion B-ALL patients with a predicted TKI-sensitive mutation were screened by low density array (LDA) PCR and confirmed by additional molecular testing. Following 4-drug induction, patients with HR B-ALL and ABL-class fusions received MBFM with dasatinib (60 mg/m 2, maximum 140 mg) daily from start of consolidation through end of maintenance. Dasatinib was held only for toxicity. Results: Twenty-two evaluable patients with HR B-ALL were non-randomly assigned to the Dasatinib arm. ABL-class 3' partners included ABL1 (n=4), ABL2 (n=4), PDGFRB (n=12), and CSF1R (n=2). Compared to all patients on AALL1131, patients treated on the Dasatinib arm were older (median age at diagnosis 14 versus 10 years, p=0.008), more often male (77% versus 56%, p=0.046), and had a trend towards an increased initial WBC (median WBC at diagnosis 44,000/µL versus 19,000/µL, p=0.086). Patients with ABL-class fusions had EOI MRD > 0.01% in 20 of 22 patients and available end of consolidation MRD >0.01% in 6 of 10 patients. Only 5 of 22 (22.7%) patients completed prescribed protocol therapy. Reasons for therapy discontinuation included induction failure (n=2), relapse (n=1), alternate therapy (n=1), determined to be in the patient's best interest (n=10), death (n=1), unknown (n=2). Compared to all patients on AALL1131, four-year disease-free survival was 52.5+18.1% versus 86.8+0.7% (p<0.0001) and overall survival 79.4+13.6% versus 89.2+0.4% (p<0.0001). Dasatinib was well tolerated with no unexpected treatment related toxicities. Conclusion: Patients with ABL-class fusions were more likely male, EOI MRD+, and had poorer outcomes. Seventy-seven percent of patients enrolled on the Dasatinib arm did not complete prescribed therapy. While dasatinib was well tolerated, treatment failures occurred early, indicating alternate strategies are needed.

Asciminib (ASC) in Combination with Imatinib (IMA), Nilotinib (NIL), or Dasatinib (DAS) May be a Potential Treatment (Tx) Option in Patients (Pts) with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase or Accelerated Phase (Ph+ CML-CP/AP): Final Results from the Asciminib Phase 1 Study

Asciminib (ASC) in Combination with Imatinib (IMA), Nilotinib (NIL), or Dasatinib (DAS) May be a Potential Treatment (Tx) Option in Patients (Pts) with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase or Accelerated Phase (Ph+ CML-CP/AP): Final Results from the Asciminib Phase 1 Study

Biological medicines for diffuse intrinsic pontine glioma (DIPG) eradication (BIOMEDE): Final results of an international randomized phase II platform trial comparing 3 targeted therapies in combination with radiotherapy from ITCC, SIOPE-Brain and ANZCHOG.

10003 Background: DIPG is the most aggressive brain cancer in children and adolescents with a median survival of 9 months. Surgery is not possible due to the invasive nature of the disease in a critical area of the brain; only radiotherapy has shown a transient palliative effect on disease progression and no adjuvant therapy has proven to increase disease control. Methods: We launched a large randomized biomarker-driven platform trial to compare three targeted therapies (erlotinib, everolimus and dasatinib) in combination with 54 Gy radiotherapy, in newly diagnosed patients with DIPG (NCT02233049). A central pathological review was performed prior to study entry to confirm the diagnosis of DIPG with H3K27me3 loss (with or without H3K27M mutation) and assess biomarkers. The randomization was designed so that a drug could not be allocated if the corresponding biomarker was absent in the tumor (EGFR overexpression for erlotinib, mTOR activation for everolimus, no specific biomarker for dasatinib). Tumors underwent whole genome sequencing and RNAseq to evaluate prognostic and theranostic biomarkers. Primary endpoint was overall survival. Results: Among the 279 DIPG patients screened for the randomized trial between October 2014 and September 2019, 233 were enrolled in 45 centers in 7 countries; among the 46 screen failures, the diagnosis of DIPG could not be confirmed in 23 patients. No biopsy- or treatment-related death was reported. Serious adverse events > = 3 unrelated to disease progression were reported in 40% of patients, 34%, 36% and 46%, in the erlotinib, everolimus and dasatinib arms, respectively (p = 0.32). With a median follow-up of 5.3 years, median overall survival (OS) from the date of randomization was 9.0 (95% confidence interval, 7.4-14.4), 11.3 (10.3-13.4) and 9.4 (7.7-10.7) months for erlotinib, everolimus and dasatinib, respectively (p = 0.45). OS were not statistically different from those of a historical biopsy-proven cohort. The molecular profiling with copy number aberrations (CNA) had a strong impact on survival (log-rank test, p = 0.0001) as shown by the preliminary analysis of the first hundred patients identifying a group of tumors with very poor prognosis with a HR for death of 1.96 (1.07-3.64) characterized by TP53 mutations (p = 3.05e-11) associated with more CNA (p < 0.0001). Conclusions: This trial demonstrated the feasibility and safety of a large randomized trial for DIPG based on biomarker information from a stereotactic biopsy at diagnosis in an international multicenter setting and generated new tumor biological insights to further develop innovative therapies. Clinical trial information: NCT02233049 .

Attenuated Dose Dasatinib in Newly Diagnosed Chronic Myeloid Leukemia Chronic Phase Patients in India.

BCR-ABL Tyrosine kinase inhibitors (TKI's) are most successful of targeted therapies and are currently considered the cornerstone in the management of patients with chronic myeloid leukemia (CML). A recent study reported excellent outcomes of Dasatinib 50mg with better sustained response. Therefore, we aim to evaluate the molecular responses and safety of upfront Dasatinib 50mg in Indian CML-Chronic Phase patients. It was an observational single-centre study. CML-CP patients started on Dasatinib 50mg daily were offered to participate in this study. Data of imatinib was collected retrospectively as a comparator group. Between June 2020 to Feb 2022, fifty patients were included in the dasatinib 50mg once daily group. Median age was 40 yrs. ranging from (19 to73) years. At a median follow up of 9.2 months, 49 patients completed three months treatment, out of which 48 patients were evaluated as one patient stopped medication after a month due to financial constraints. The response rate at three months for dasatinib 50mg daily and Imatinib were 68.75% and 69.7% respectively. At 12 months, 68% and 66.6% patients achieved major molecular response [MMR] in dasatinib 50mg and imatinib groups respectively. In conclusion, low dose dasatinib is safe and effective as an upfront therapy in CML-CP. Early molecular response [EMR] rates were comparable in low dose dasatinib and imatinib arm but deep molecular responses were significantly higher in low dose dasatinib arm. Dasatinib, taken daily at a dose of 50mg, may offer a new, alternative choice as generic versions are available now for frontline therapy in CML-CP.

Comparison of Generic Dasatinib Versus Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia with Reference to Early Molecular Response: Results from a Single-Center, Randomized Controlled Study from India

Background: Chronic myeloid leukemia (CML) is the commonest leukemia in adult population in India. The advent of tyrosine kinase inhibitors (TKI) targeting BCR-ABL1 fusion transcript in CML has dramatically improved survival of CML patients. Generic formulations of imatinib mesylate have been the mainstay of TKI therapy in Indian CML patients for more than a decade, due to prohibitive costs of 2nd generation TKIs and poor socio-economic status of majority of patients. However, with the availability of generic dasatinib in India since March 2021, the cost of dasatinib therapy has become comparable to that of generic imatinib treatment, thereby enabling more extensive use of dasatinib as first-line TKI therapy in CML patients in India. Achievement of early molecular response (EMR) after 3 months of first-line TKI therapy, defined as blood BCR-ABL1 transcript level ≤ 10% [international scale (IS)], has emerged as an important predictor of favorable long-term outcome in CML-CP. There is scarcity of data on efficacy & safety of generic formulations of dasatinib vis-à-vis generic imatinib in CML-CP patients in India, which the present study has attempted to explore at a tertiary care hospital in India. Objectives: The objectives of the study were to compare early molecular response (EMR) [defined as BCR-ABL1 transcript level ≤ 10%, I.S.] at 3 months of therapy with generic dasatinib versus generic imatinib in newly diagnosed CML-CP patients and to compare treatment-related adverse effects in the two groups. Methods: This randomized controlled study enrolled newly diagnosed CML-CP patients after obtaining institutional ethics committee approval & informed consent. Inclusion Criteria:Newly diagnosed patients with chronic phase CML.Age ≥ 12 years. Exclusion Criteria:Patients with de novo accelerated phase or blast phase CML.Pregnancy & lactation.Patients with pre-existing pleural effusion, grade ≥ 3 lung disease, or pulmonary arterial hypertension.Patients with angina, or grade ≥ 3 cardiac disease [as defined by the New York Heart Association (NYHA) criteria] at diagnosis.Patients with prolonged QTc interval (> 480 msec) at baseline. The EUTOS long-term survival (ELTS) risk score was calculated at diagnosis. Patients were randomized to one of the two following treatment groups: Group A: Dasatinib 100 mg p.o. once daily (60 mg/m2/day for age <18 years). Group B: Imatinib 400 mg p.o. once daily (340 mg/m2/day for age < 18 years). Follow up & monitoring of patients was done every 2 weekly till completion of 3 months of TKI therapy, followed by assessment of hematological response & molecular response as per standard criteria. Results: A total of 61 consecutive CML patients were screened between June 2021 and March 2022, out of which 54 patients with confirmed diagnosis of CML-CP were enrolled in the study and were randomized to receive generic dasatinib or generic imatinib as first-line therapy and were followed up for 3 months for EMR and complete hematological response (CHR). Four patients were lost to follow up and data was analyzed for 50 patients for whom EMR results at 3 months was available. Out of these 50 patients, 24 patients received dasatinib & 26 patients received imatinib. The median age of patients was 33 years (range 18-64 years), with male: female ratio of 1.3: 1. Achievement of CHR was documented in 96% of patients in both dasatinib & imatinib treatment arms. EMR at 3 months was achieved in overall 72% patients in study [19/24 patients (79%) in dasatinib arm & 17/26 patients (65%) in imatinib arm]. However, the difference was not statistically significant (p = 0.27). Notably, EMR rates in ELTS intermediate-risk group was 86% in dasatinib arm versus 42% in imatinib arm, and EMR rates in ELTS high-risk group was 82% in dasatinib arm versus 57% in imatinib arm (p = 0.33). The incidence of grade 3-4 adverse events was not significantly different in the two treatment groups. The patient characteristics & treatment results are summarized in Table 1 & Figure 1. Conclusion: The results of the present study suggested that generic formulations of dasatinib were well-tolerated and were associated with improved early molecular response rates compared to generic imatinib in CML-CP patients in India. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ruxolitinib or Dasatinib in Combination with Chemotherapy for Patients with Relapsed/Refractory Philadelphia (Ph)-like Acute Lymphoblastic Leukemia: A Phase I-II Trial

Ruxolitinib or Dasatinib in Combination with Chemotherapy for Patients with Relapsed/Refractory Philadelphia (Ph)-like Acute Lymphoblastic Leukemia: A Phase I-II Trial

Use of tyrosine kinase inhibitors for paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia: a systematic review and meta-analysis

ObjectivesTo investigate the effectiveness and safety of tyrosine kinase inhibitors (TKIs) in the management of paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL).DesignA systematic review and meta-analysis.Data sourcesElectronic searches were conducted...

Nilotinib Vs. Dasatinib in Achieving MR4.5 for Newly Diagnosed Chronic Myeloid Leukemia: Results of the Prospective Randomized Phase 3 Study, JALSG CML212

Nilotinib Vs. Dasatinib in Achieving MR4.5 for Newly Diagnosed Chronic Myeloid Leukemia: Results of the Prospective Randomized Phase 3 Study, JALSG CML212

PCN24 TYROSINE KINASE INHIBITORS: REAL WORLD EVIDENCE ABOUT HEALTH OUTCOMES IN A MIDDLE INCOME COUNTRY

The high cost of antineoplastic therapies generates unprecedented pressure on the health systems in middle income countries; aditionally, the Knowledge Discovery in Databases allows to extract considerable value to evaluated health outcomes. This study assessed the association between adherence and a specific payment model called PGP (Global Prospective Payment, between insurer and provider). Observational retrospective study. Patients with Chronic Myeloid Leukemia (CML) were identified with ICD-10-C921 diagnoses obtained from 2018 High Cost Account database of the institutional cancer cohort. Positive Philadelphia chromosome patients who took Dasatinib or Nilotinib during 2018 were included (n=66). Imatinib was excluded because this drug is included in the health benefit plan in Colombia. Patients who took 100% of the prescribed medication were considered adherent (Morinsky Scale 4/4). Results were analyzed using SPSS version 24, chi-square independence test was used to determine P-value and bivariate analysis was made using binary logistic regression. Dasatinib arm (n=29, median age 65y; 52% female; 62% private regimen), 50% adherent to therapy. Nilotinib arm (n=37, median age 50y; 43% female; 63% private regimen), 59% adherent to therapy. Regardless payment model and TKI, 55% were adherent and 49% had an optimal molecular response. Patients under the PGP model were 100% adherent and, based on the latest available PCR BCR/ABL (real time) report, 89% had an optimal molecular response according to European Leukemia Net recommendations (both TKIs). Significant association were established between Adherence and PGP model (p<0.004; OR=0,49 IC 95% 0,37-0,64) and between optimal molecular response to both TKIs and GPP model (p<0.001; OR=0,43 IC 95% 0,24-0,95). This study provides contemporary real-world evidence about association between adherence to TKIs, optimal molecular response and a prospective payment model in an institution that provides oncological health services. Ensuring adherence to high-cost therapies in middle-income countries through a payment model, could improve health outcomes.

Spirit 2: Final 5 Year Analysis of the UK National Cancer Research Institute Randomized Study Comparing Imatinib with Dasatinib in Patients with Newly Diagnosed Chronic Phase CML

▪Objective. SPIRIT 2 is the largest phase 3 prospective randomized open-label trial comparing imatinib (I) 400mg with dasatinib (D) 100mg daily in newly diagnosed chronic phase CML. The primary endpoint was 5 year event-free survival. Methods. 812 (406 in each arm) of 814 patients recruited started study medication (median age 53.2, 275/812 (33.8%) were over 60 years old). Patients were recruited at 144 hospitals between August 2008 and March 2013 and randomized to receive either imatinib 400mg or dasatinib 100mg daily. Secondary endpoints included overall survival, rates of treatment failure, cytogenetic/molecular response - RT-PCR BCR-ABL/ABL ratio of <0.1%IS(major molecular response (MMR), 3 log reduction, MR3) and deeper. To address the potential confounding effect on the primary endpoint of patients switching from randomized treatment to an alternative TKI or other treatment, exploratory per-protocol analyses were performed using the inverse probability of censoring weighting (IPCW) method.Results. All patients have now completed 5 years of follow-up. 424/812 (52.2%) patients completed the study whilst still taking first line medication: 230/406 (56.7%) on dasatinib, 194/406 (47.8%) on imatinib. Of the patients who discontinued first line therapy, more patients on the imatinib arm switched due to suboptimal PCR response (as decided by the local investigator) than on dasatinib (D7/406, 1.7%; I71/406, 17.4%) but more patients on the dasatinib arm discontinued due to intolerance (D123/406, 30.3%; I68/406, 16.7%). More patients went on to transplant in the imatinib arm than in the dasatinib arm (D 6/406, 1.5%; I 30/406 7.6%) and in the imatinib patients undergoing transplant the reason for first line treatment failure was disease progression in 5/30 and suboptimal molecular response in 11/30. Using an intention to treat analysis cumulative incidence of MR3 and MR4 on first line therapy within 5 years was higher in the dasatinib arm than the imatinib arm (MR3: D 83.0%, I 63.0% - difference 20.0%, p<0.0001; MR4: D 77.5%, I 57.2% - difference 20.3%, p<0.0001).At 24 months the complete cytogenetic response rate was D 42.6%, I 31.8% - difference 10.8%, Chi-square test p=0.001.At 5 years the probability of treatment failure-free survival was higher with dasatinib than imatinib(D60.9%, I52.9% - HR: 0.73 (95%-CI:0.59-0.90), p=0.004) but there were no significant differences in event free survival (D91.0%, I89.0% - HR:0.80 (95%-CI:0.51-1.25), p=0.319) or overall survival (D91.9%, I91.2% - HR: 0.90 (95%-CI:0.56-1.47), p=0.690). IPCW modelling results will be presented at the meeting.The overall rate of pleural effusion over 5 years in the dasatinib arm was 36.0% with a higher incidence in older patients. 13 patients developed their first pleural effusion after 3 years on study. Conclusions. In SPIRIT 2 we observed a higher molecular and cytogenetic response rate and also a higher pleural effusion rate with dasatinib but a higher treatment failure rate with imatinib often because investigators were concerned about sub-optimal PCR responses. More imatinib-treated patients proceeded to transplant. There were no statistically significant differences in event free survival (the primary endpoint) or overall survival. Imatinib remains a highly effective first line therapy though subgroup analyses are planned to explore whether dasatinib may have advantages in particular clinical scenarios. DisclosuresO'Brien:Bristol Myers Squibb: Research Funding; CTI: Other: Chair of Independent Data Monitoring Committee; National Institute for Health and Care Excellence (NICE): Other: Chair of Technology Appraisal Committee. Osborne:Servier: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; MSD: Honoraria; Roche: Honoraria; Novartis: Honoraria. Bell-Gorrod:Bristol-Myers Squibb: Consultancy; Merck EDM Serono: Consultancy; PharmaMar: Consultancy; Novartis: Consultancy; GlaxoSmithKline: Consultancy. Latimer:Pfizer: Consultancy; BMS: Consultancy; Merck: Consultancy; Astra Zeneca: Consultancy; Bluebirdbio: Consultancy; Janssen: Consultancy. Apperley:Incyte: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Byrne:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Pocock:Kent & Canterbury Hospital: Employment. Copland:Incyte: Consultancy, 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, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Clark:Ariad/Incyte: Consultancy; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Dasatinib Versus Imatinib in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Who Have Not Achieved an Optimal Response to 3 Months of Imatinib Therapy: Dascern

Introduction: Treatment with dasatinib, a second-generation tyrosine kinase inhibitor (TKI), has resulted in high rates of cytogenetic and molecular responses for pts with CML-CP, both as initial therapy and after failure of other therapies. A reduction in BCR-ABL1 transcript levels to ≤ 10% on the International Scale (IS) at 3 mo is associated with an improved probability of deep molecular responses and superior progression-free and overall survival (PFS and OS). In DASISION, considerably more pts treated with dasatinib achieved BCR-ABL1 ≤ 10% IS compared to imatinib. BCR-ABL1 ≤ 10% IS at 3 mo is considered an optimal response by international guidelines; however, approximately one-third of pts with CML-CP on first-line (1L) imatinib will not achieve this threshold. Clinical studies exploring the potential benefit of early switching to dasatinib in pts with less than optimal responses on initial imatinib treatment have not been reported.Methods: DASCERN (NCT01593254) is a randomized, open-label, international phase 2b trial in adult pts with CML-CP who had achieved complete hematologic response (CHR) but who had BCR-ABL1 > 10% IS at 3 mo after initial treatment with 400 mg imatinib once daily (QD). Imatinib must have been started within 6 mo of the initial CML-CP diagnosis. Pts were randomized 2:1 to receive 100 mg dasatinib QD or continue imatinib at ≥ 400 mg daily with the option for dose escalation. Pts initially randomized in the imatinib cohort who met European LeukemiaNet 2013 failure criteria after randomization and without dasatinib-resistant mutations were crossed over to the dasatinib arm. The primary endpoint in DASCERN is the rate of MMR (BCR-ABL1 < 0.1% IS) at 12 mo after day 1 initiation of 1L imatinib (9 mo after randomization). Secondary endpoints include time to MMR, OS, and PFS (progression was defined as transformation to accelerated/blast phase or death). Tertiary endpoints include safety and tolerability profile of both treatment arms and cytogenetic response over time.Results: All 260 randomized pts (dasatinib: n = 174; imatinib: n = 86) had a minimum follow-up of ≥ 12 mo from the last pts 1st visit (Sokal scores: 28% low, 30% intermediate, 24% high, 18% unknown; median age 37 y [range 18-82, 95% were < 65 y]; 78% male; 73% Asian). All pts had e13a2 or e14a2 transcript types. At the time of analysis, 84% of pts were continuing in the study. Median daily dose was 100 mg QD (range 26-142) for dasatinib and 400 mg QD (range 129-825) for imatinib. Median treatment duration was 111 wk (774 d) in the dasatinib arm and 68 wk (477 d) in the imatinib arm; 42 (49%) imatinib-randomized pts crossed over to dasatinib. Rate of MMR at 12 mo in the intent-to-treat population was 29% (95% confidence interval [CI] 22, 36) for dasatinib and 13% (95% CI 7, 22) for imatinib (P = 0.005); median time to MMR was 14 mo (range 12-18) for dasatinib vs 20 mo (range 14-26) for imatinib (P = 0.053). No differences in the rate of progression or OS were observed between treatment arms. No new safety signals were observed for either treatment arm and the early switch to dasatinib did not increase the toxicity rate. Treatment-emergent pleural effusion (PE; any grade) occurred in 11 (6%) pts randomized to dasatinib and 3 (7%) imatinib-randomized pts who crossed over to dasatinib; treatment-emergent PE grade 3/4 occurred in 1 (1%) pt randomized to dasatinib and 2 (5%) pts randomized to imatinib who crossed over to dasatinib. Hematologic toxicity was similar between treatment arms: neutropenia grade 3/4 occurred in 18 (11%) pts randomized to dasatinib and 12 (29%) pts randomized to imatinib who crossed over to dasatinib; thrombocytopenia grade 3/4 occurred in 18 (11%) pts randomized to dasatinib and in 7 (17%) pts randomized to imatinib who crossed over to dasatinib. Two dasatinib-treated pts discontinued due to hematologic toxicity (1 neutropenia, 1 thrombocytopenia).Conclusions: Early results from DASCERN show that pts with suboptimal responses to imatinib at 3 mo who switched to dasatinib had a significantly increased rate of MMR at 12 mo compared to pts who remained on imatinib. Longer follow-up is required to assess the impact of early switching on PFS and OS, and achievement of deep molecular responses. DisclosuresCortes:Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Takeda: Research Funding. Kim:BMS: Research Funding; Ilyang: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Savona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Martin Regueira:Bristol-Myers Squibb: Employment, Equity Ownership. Sy:Bristol-Myers Squibb: Employment. Gurnani:Bristol-Myers Squibb: Employment.

Efficacy and Safety of Tyrosine Kinase Inhibitors for Treatment of Newly Diagnosed Chronic Myeloid Leukemia: Results Using Data Obtained with the New Target System from the Japanese Registry

Efficacy and Safety of Tyrosine Kinase Inhibitors for Treatment of Newly Diagnosed Chronic Myeloid Leukemia: Results Using Data Obtained with the New Target System from the Japanese Registry

Phase 2 placebo-controlled, double-blind trial of dasatinib added to gemcitabine for patients with locally-advanced pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate with limited treatment options. Gemcitabine provides a marginal survival benefit for patients with advanced PDAC. Dasatinib is a competitive inhibitor of Src kinase, which is overexpressed in PDAC tumors. Dasatinib and gemcitabine were combined in a phase 1 clinical trial where stable disease was achieved in two of eight patients with gemcitabine-refractory PDAC. This placebo-controlled, randomized, double-blind, phase II study compared the combination of gemcitabine plus dasatinib to gemcitabine plus placebo in patients with locally advanced, non-metastatic PDAC. Patients received gemcitabine 1000 mg/m2 (30-min IV infusion) on days 1, 8, 15 of a 28-day cycle combined with either 100 mg oral dasatinib or placebo tablets daily. The primary objective was overall survival (OS), with safety and progression-free survival (PFS) as secondary objectives. Exploratory endpoints included overall response rate, freedom from distant metastasis, pain and fatigue progression and response rate, and CA19-9 response rate. There was no statistically significant difference in OS between the two treatment groups (HR = 1.16; 95% confidence interval [CI]: 0.81-1.65; P = 0.5656). Secondary and exploratory endpoint analyses also showed no statistically significant differences. The burden of toxicity was higher in the dasatinib arm. Dasatinib failed to show increased OS or PFS in patients with locally advanced PDAC. Alternative combinations or trial designs may show a role for src inhibition in PDAC treatment.

The Role of Mutation Testing in Patients with Chronic Myeloid Leukemia in Chronic Phase after Imatinib Failure and Their Outcomes after Treatment Modification: Single-institutional Experience Over 13 Years.

Introduction:BCR-ABL1 kinase domain mutations represent the most frequent mechanism of resistance to tyrosine kinase inhibitor (TKI) therapy, being detected in 40%–50% of imatinib-resistant patients with chronic myeloid leukemia in chronic phase (CML-CP). Over 100 BCR-ABL1 single-point mutations have been reported in patients with imatinib-resistant CML. There were few studies reported from India on BCR-ABL kinase mutations in imatinib failure patients. We present our data on imatinib resistance mutation analysis (IRMA) and use of imatinib dose hike and 2nd-generation TKI at our institute.Materials and Methods:All patients with a diagnosis of CML in a university hospital from June 2003 to July 2016 and who were tested for IRMA in view of imatinib failure, those in CP, and age <18 years were included in the study.Results:A total of 2110 cases of CML reviewed and 269 cases of CML with imatinib failure were analyzed. The male to female ratio was 1.7:1. The median age at presentation was 36 years (range: 18–66 years). Among these, 26% were primary failures and 74% were secondary failures. The treatment was modified either as imatinib dose hike or nilotinib/dasatinib. Molecular response at 12 months was achieved in 25.7% in imatinib dose hike, 46.6% in nilotinib, and 53.8% in dasatinib arms. The 4-year overall survival in mutation detected group was 37.5% and in nonmutated group was 87.7%.Conclusion:Imatinib-resistant mutations were more common in the cases with secondary failure though not statistically significant. T315I mutation was the common mutation found in the study. Imatinib dose hike to the failure cases resulted in optimal hematological response rates.

Safety and Efficacy of Addition of Pegylated Interferon alpha2b to Standard Dose Dasatinib in Newly Diagnosed Chronic Phase CML Patients

▪Rationale: Dasatinib (DAS) and interferon have different modes of action and may have synergistic activity in CML, due to both antineoplastic and immunostimulatory mechanisms. Addition of pegylated interferon (PegIFN) to imatinib therapy in CP-CML has in previous clinical trials (French SPIRIT and NordCML002) resulted in deeper molecular responses. Thus, an optimal combination of DAS and PegIFN may increase the proportion of patients who reach deep molecular response with potential for treatment-free remission (TFR).Design: Newly diagnosed CP-CML patients were treated with DAS (Sprycel, BMS) 100 mg OD as single drug for three months. Thereafter weekly subcutaneous injections of Peg-IFN α2b (PegIntron, MSD) were added to DAS; from end of month 3 (M3) to M6, 15µg/week, thereafter 25µg/week until M15. Primary end points were safety and the rate of MMR at M12. The doses of PegIFN were lower than in the SPIRIT and NordCML002 studies to increase adherence.Population: Forty patients were included at 14 university centers. One patient was lost to follow-up after M6. All patients were included in analysis up to M12. Mean and median age was 48 years (range 19-71). The proportions of high risk patients were 25% (Sokal), 15% (Hasford), and 15% (EUTOS).Safety and dosing: Treatment was well tolerated with expected DAS and PegIFN related side effects. Six patients had seven serious adverse events (AEs), all hospitalizations. 1 episode each of bradycardia/atrial fibrillation (possibly PegIFN-related), headache (DAS), fever (PegIFN), anaphylaxis-like reaction (PegIFN), fever/malaise/headache (PegIFN), pneumonia and a knee effusion (both unrelated). One pleural effusion occurred (grade 2, 3%). Grade 3-4 neutropenia and thrombocytopenia occurred in 6 and 9 patients respectively. Prolonged hematological toxicity (>2 months) occurred in 8 patients, causing dosing problems in 5. One patient suffered grade 3 depression. Grade 3 flu-like symptoms occurred in 2 patients. One patient had lipase elevation grade 3 and one patient developed hypothyroidism attributed to PegIFN. Grade 2 dermal AEs like rash and acne occurred in about 20%, attributable to both drugs. 94% (DAS) and 76% (PegIFN) of assigned dose was given. Dose reductions occurred in 19 patients for DAS and 20 patients for PegIFN. Two patients discontinued DAS and switched to nilotinib, 1 for headache at M3 and 1 at M12 for lack of efficacy/hematological toxicity. Two patients could not start PegIFN for hematological toxicity (one lost to follow-up after M6). PegIFN was discontinued because of bradycardia/atrial fibrillation (1 patient), anaphylaxis (1 patient), flu-like syndrome (2 patients) and long-term hematological toxicity (2 patients). At 12 months 31/38 pats (82%) were still on PegIFN, a higher proportion than in the French Spirit or NordCML002 studies.Efficacy: We have used the DAS arm of the Dasision study (Kantarjian NEJM 2010) as a historical control. Early response at M3 was very similar between studies. In the present and the Dasision cohorts respectively, 18% vs 16% missed the 10% BCR-ABLIS landmark, 66% vs 56% achieved a CCyR and 8% vs 8% achieved MMR. At M6, three months after introduction of PegIFN, a steep increase in MMR rate was observed compared with Dasision. This was also reflected in deep responses, MR4.0 (see tables) and MR4.5 at M12, 18% vs 5%. The primary efficacy endpoint was MMR at M12, 82% vs 46%. Table 1MMRDAS+PegIFN (%)DAS (Dasision)(%)Difference (%)M3880M6532726M9663927M12824636Table 2MR4.0DAS+PegIFN (%)DAS (Dasision) (%)Difference (%)M3303M620614M938830M12481236Progressions and treatment failure defined by ELN 2013: Failures: No progression was noted. At M3, 2 patients still had >95% Ph+ metaphases (MF). At M6, four patients (11%) had > 35% Ph+MF or >10% BCR-ABL levels. At M12, one patient failed CCgR and two more patients failed <1% BCR-ABL. No BCR-ABL mutations were detected in "failure" patients.Conclusion: The combination of DAS and low dose PegIFN could be safely administered in newly diagnosed CP CML. No unexpected autoimmune phenomena were observed, and pleural effusions were rare. Efficacy appears very promising with high early MMR rates and deep molecular responses. A randomized comparison DAS +/- PegIFN is warranted.Support: Study drug from BMS and MSD. Grant from BMS. [Display omitted] DisclosuresHjorth-Hansen:Ariad: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Off Label Use: Dasatinib and Pegylated IFN combination in CML. Richter:Ariad: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Porkka:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding.

Model-Based Characterization of the Molecular Response Dynamics of Tyrosine Kinase Inhibitor (TKI)-Treated CML Patients – a Comparison of Imatinib and Dasatinib First-Line Therapy

▪Background: Chronic myeloid leukemia (CML) is characterized by the expression of the BCR-ABL fusion protein in virtually all malignant cells in the vast majority of patients. This molecular specificity forms the basis of a highly efficient, targeted therapy by TKIs. The success of this therapeutic approach is the reason that CML has developed into a showcase example for an efficient, targeted tumor therapy.Methods: As previously shown, the application of a single-cell–based mathematical model, which describes CML as a clonal competition between normal and leukemic hematopoietic stem cells, can consistently describe the median long-term BCR-ABL transcript levels in response to the first-generation TKI imatinib [1]. Furthermore, it has been demonstrated that a similar modeling approach also allows predicting the molecular long-term response to imatinib in individual patients [2]. Specifically, we showed that these predictions, including the determination of an optimal, patient-specific time point for potential treatment cessation, can be derived directly from time course data of the BCR-ABL transcript levels. Here we present novel results on the application of a similar analysis strategy for CML patients, treated with the second-generation TKI dasatinib. Based on unpublished data describing the 4-year molecular response dynamics (ie, BCR-ABL transcript levels) observed in a randomized, controlled clinical trial (DASISION [3]), we directly compare the effects of dasatinib (n=253) and imatinib (n=255).Results: These data show an accelerated and deeper median molecular response in the dasatinib arm (Figure 1). We confirmed this observation by statistical analysis, describing the BCR-ABL response kinetics by a bi-phasic exponential model. Comparing different characteristic parameters of this model, we could demonstrate a significantly steeper initial decline in the dasatinib arm compared to imatinib (P < 0.001, t-test on mean initial decline). Beyond the statistical analysis, we apply the above-mentioned single-cell–based mathematical model. Adapting its parameters to the specific kinetic characteristics observed under the different treatment conditions, model predictions for both the population and individual patients are derived for both treatment scenarios. In our presentation we will compare the model predictions of long-term BCR-ABL kinetics under first line imatinib and dasatinib treatment. The population and patient-specific model predictions will include BCR-ABL levels in the peripheral blood and bone marrow, as well as the estimated risk of molecular relapses after stopping treatment and, related to this, optimal time points for potential treatment cessation.Conclusion: Our analysis suggests that the application of model-prediction tools, previously used for the first-generation TKI imatinib, can be applied to other TKIs. The steeper initial decline in the dasatinib arm may be relevant in estimating relapse risk, which will be determined from long-term outcome of ongoing discontinuation trials.[1] Roeder I et al. (2006) Nat. Med.[2] Horn M et al. (2013) Blood.[3] Cortes JE et al. ASH 2013, Abstract #653. [Display omitted] DisclosuresGlauche:Bristol-Myers Squibb: Research Funding. Fröhlich:Bristol-Myers Squibb: Employment. Roy:Bristol-Myers Squibb: Employment, Equity Ownership. Subar:Bristol-Myers Squibb: Employment. Wang:Bristol-Myers Squibb: Employment.

Spirit 2: An NCRI Randomised Study Comparing Dasatinib with Imatinib in Patients with Newly Diagnosed CML

▪Objective. SPIRIT 2 is the largest phase 3 prospective randomized open-label trial comparing imatinib 400mg with dasatinib 100mg daily: this is the first presentation of data comparing the two arms.Methods. 814 patients were recruited at 144 hospitals between August 2008 and March 2013. 812 started study medication (406 in each arm). The primary endpoint is event-free survival at 5 years. A key secondary endpoint is the rate of achievement of a BCR-ABL/ABL ratio of <0.1%IS (major molecular response (MMR), 3 log reduction or MR3).Results. Discontinuations. With a median follow up of 34 months a total of 289/812 (35.6%) patients have discontinued study medication. 118/812 (14.5%) patients have discontinued due to non-haematological toxicity: imatinib 47/406 (11.6%); dasatinib 71/406 (17.5%). 40 patients discontinued due to sub optimal response as assessed by the treating physician: imatinib 37/406 (9.1%); dasatinib 3/406 (0.7%). Side effects. Patients receiving imatinib experienced GI toxicity more often than patients receiving dasatinib; fatigue, rash and headache were more common with dasatinib. A higher rate of grade 3/4 thrombocytopenia was observed in the dasatinib arm: imatinib 17/406 (4.2%); dasatinib 52/406 (12.8%). Pleural effusions occurred in 78/406 (19.2%) patients on dasatinib; 13 of 78 (16.7%) patients required drainage. Arterial cardiovascular events (excluding hypertension) were experienced by 10/812 (1.2%) patients: imatinib 2/406 (0.5%; myocardial infarction (MI) x2); dasatinib 8/406 (2.0%; MI x1; angina/acute coronary syndrome x5; peripheral arterial disease x2). Hypertension was observed in 10/812 (1.2%) patients: imatinib 3/406 (0.7%); dasatinib 7/406 (1.7%). Venous CV events occurred in 7/812 (0.9%) patients: imatinib 3/406 (0.7%); dasatinib 4/406 (1.0%). Efficacy. For both PCR and cytogenetic analyses patients that had discontinued their allocated therapy or that did not have a 12 month sample were analysed as not having achieved MR3/CCR. The MR3 (PCR <0.1%IS) rate at 12 months in all treated patients is significantly different (p<0.001) between the two treatment arms: imatinib 173/406 (42.6%); dasatinib 236/406 (58.1%). The MR3 rate at 12 months in patients treated with dasatinib is 51/78 (65.4%) in those with a pleural effusion and 185/328 (56.4%) in those without (p=0.148, NS).The complete cytogenetic response (CCR) rate at 12 months is: imatinib 163/406 (40.1%); dasatinib 207/406 (51.0%). The difference between the two treatment arms is statistically significant (p=0.002) but caution is required in interpreting these data as there were missing analyses in 367 of 812 (45.2%) patients: imatinib 191 of 406 (47.0%), dasatinib 176 of 406 (43.3%). The difference in major cytogenetic response (MCR) rate between the two treatment arms at 12 months is not statistically significant: imatinib 200/406 (49.3%); dasatinib 218/406 (53.7%), p=0.206. Disease progression and deaths. 16 patients have progressed to either accelerated phase or blast crisis and 13 of those progressions were within the first year. Accelerated phase: imatinib 3/406 (0.7%); dasatinib 2/406 (0.5%). Blast crisis: imatinib 7/406 (1.7%); dasatinib 4/406 (1.0%).Conclusions. Dasatinib-treated patients have a higher rate of molecular response at 1 year but, with a median of 34 months follow up, there is no significant difference in rates of disease progression or overall survival. More patients abandoned imatinib than dasatinib due to investigator concerns about sub optimal responses. Further follow up is required to evaluate whether there will be differences in event free survival at five years. DisclosuresO’Brien:Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Hedgley:BMS: Research Funding; ARIAD: Research Funding. Adams:BMS: Research Funding. Apperley:Ariad Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Holyoake:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Byrne:BMS: Honoraria; Novartis: Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy. Osborne:ARIAD: Research Funding. Copland:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Clark:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Honoraria, Research Funding.

Twelve-Month Cost per Responder (CPR) Analysis of Nilotinib and Dasatinib As Front-Line Therapy in Patients with Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Introduction: Nilotinib and dasatinib, two second-generation tyrosine kinase inhibitors (TKIs), have been associated with higher rates of molecular response compared to imatinib in the treatment of newly diagnosed CML-CP patients based on the ENESTnd and DASISION trials. A published indirect comparison study of efficacy outcomes between nilotinib and dasatinib showed that nilotinib had significantly higher rates of molecular response by 12 months compared to dasatinib: major molecular response (MMR; defined as BCR/ABL1 level ≤0.1% on International Scale [IS]): 56.1% vs. 45.9%; MR4.0 (BCR/ABL1 level ≤0.01% on IS): 20.6% vs.12.0%; and MR4.5 (BCR/ABL1 level ≤0.0032% on IS): 10.2% vs. 3.1% for nilotinib and dasatinib, respectively. However, little is known about the costs associated with achieving molecular response. This study estimated and compared the CPR for the first 12 months of nilotinib and dasatinib for the treatment of Ph+ CML-CP in a front-line setting from a US payer’s perspective.Methods: A 12 month CPR model of nilotinib and dasatinib was constructed, where MMR by 12 months was used to define a responder and the rates were from the published indirect comparison study. The two model cost components were 12 month treatment costs and treatment-related grade 3/4 adverse event (AE) costs. Treatment costs were estimated based on drug price (wholesale acquisition cost), median dose and discontinuation rate. Drug prices by dose were extracted from the Red Book Online®. Median doses and discontinuation rates were from the ENESTnd, DASISION and the 2nd-line trials of nilotinib and dasatinib. Discontinuation was assumed to occur at a constant rate over the 12 months. Patients who discontinued the initial treatment were assumed to switch to the other second-generation TKI and remain on this for the rest of the first year. No patient was assumed to die within the first 12 months, i.e. no patients discontinued due to death. AE costs were estimated based on AE rates and the costs of treating the AE: treatment-related rates of grade 3/4 AEs were obtained from the clinical trials and direct medical costs were obtained from published literature. Because the definition of AEs may differ across the two trials, AE rates were adjusted relative to the AE rates observed in the imatinib arms of the two trials. The 12 month CPR for each treatment was calculated as the sum of the 1st-line treatment costs, the 2nd-line treatment costs (after a switch), and the grade 3/4 AE costs incurred by responders and non-responders, divided by the MMR rate. All costs were presented in 2014 USD. One-way sensitivity analyses varying the response definition (including MR4.0 and MR4.5) and AE costs were conducted.Results: The 12 month CPR was $202,840 for nilotinib and $248,919 for dasatinib (difference=$46,079; p <0.05). Costs of neutropenia, thrombocytopenia and anemia were the driving factor behind AE costs; these costs in the nilotinib arm were about half (53%) of the costs for of these AEs in the dasatinib arm. In one-way sensitivity analyses with responders defined based on MR4.0 and MR4.5, the differences in CPR between the two drugs were even greater: CPR for nilotinib was 42% and 70% (both p<0.05) lower than that for dasatinib for MR4.0 and MR4.5, respectively. In one-way sensitivity analyses that varied the costs of AEs to their lower and upper bounds, CPR ranged from $201,277 to $217,298 for nilotinib and $245,245 to $280,568 for dasatnib. Nilotinib’s CPR was 17.9% and 22.6% (both p<0.05) lower than dasatinib’s CPR for the low and high AE cost estimates, respectively.Conclusion: This analysis demonstrates that, compared to dasatinib, front-line therapy with nilotinib is associated with a lower CPR during the first 12 months in patients with newly diagnosed CML-CP from a US payer’s perspectiveAbstract 1304. Table 1CPR ResultsResponse Rates*Treatment CostsGrade 3 / 4 AE CostsCPRCPR Difference(Nilo – Dasa)NiloDasaNiloDasaNiloDasaNiloDasaMMR56.1%45.9%$112,024$110,901$1,769$3,353$202,840 $248,919 -$46,079 p <0.05MR4.020.6%12.0%$552,394$952,117-$399,723 p <0.05MR4.510.2%3.1%$1,115,619$3,685,613 -$2,569,994 p <0.05Nilo: Nilotinib; Dasa: Dasatinib*Signorovitch, J.E., et al. One-year and longer-term molecular responses to nilotinib and dasatinib for newly diagnosed chronic myeloid leukemia: a matching-adjusted indirect comparison. Abstract presented at American Society for Clinical Oncology, Chicago, May 30-June 3, 2014. DisclosuresGuerin:Novartis Pharmaceuticals Corporation: Consultancy, I am an employee of Analysis Group, Inc., which received consultancy fees from Novartis Other. Revol:Novartis Pharmaceuticals Corporation: Consultancy, I am an employee of Analysis Group, Inc., which received consultancy fees from Novartis Other. Ramanakumar:Novartis Pharmaceuticals Corporation: Consultancy, I am an employee of Analysis Group, Inc., which received consultancy fees from Novartis Other. Foster:Novartis Pharmaceuticals Corporation: Consultancy, I am an employee of Analysis Group, Inc., which received consultancy fees from Novartis Other. Wu:Novartis Pharmaceuticals Corporation: Consultancy, I am an employee of Analysis Group, Inc., which received consultancy fees from Novartis Other. Mhatre:Novartis Pharmaceuticals Corporation: Employment. Chen:Novartis Pharmaceuticals Corporation: Employment, Stock options Other.

The Observed and Expected Incidence of Cardiovascular (CV) Ischemic Events in Dasatinib (DAS)-Treated Patients (pts) Across a Clinical Trial Program

▪Background: The safety profile of each BCR-ABL1– targeted tyrosine kinase inhibitor (TKI) used to treat chronic myeloid leukemia (CML) is unique and should be considered when choosing therapy. Although rare, potentially severe adverse events have been reported in CML pts treated with TKIs, particularly pulmonary arterial hypertension with DAS (Montani, Circulation 2012), peripheral arterial occlusive disease with nilotinib (Kim, Leukemia 2013), and arterial and venous occlusive events with ponatinib (Cortes, N Engl J Med 2013). The incidence of CV ischemic events in DAS-treated pts from clinical trials was assessed. Standardized incidence rates (SIRs) were calculated to determine if the number of observed events was different than expected compared with reference populations.Methods: Incidence of CV ischemic events (Table 1) were assessed in a pooled population of DAS-treated pts with any phase CML or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia from 11 first- and second-line clinical trials (N=2712; median age, 54 years [y]), newly diagnosed CML pts treated with DAS (n=258; median age, 46 y) or imatinib (IM; n=258; median age, 49 y) from the phase 3 DASISION trial only (CA180-056, NCT 00481247), and prostate cancer pts from the phase 3 READY trial treated with DAS or placebo in combination with docetaxel and prednisone (CA180-227, NCT 00744497; N=1518; about 66% of pts were >65 y of age). Reference populations for SIR analyses were a general population (total N=116,000,000; males N=56,000,000), CML pts (N=16,000), and prostate cancer pts (N=530,000) derived from Truven’s MarketScan Commercial Claims and Medicare Supplemental database, 2008–2013, narrowed to mimic clinical trial eligibility. SIRs were calculated by dividing the observed number of events in DAS-treated pts by the expected number of events, based on the DAS exposure and reference population event rates.Results: Within the pooled population, 96 pts (4%) had CV ischemic events. In DASISION, 10 DAS- and 4 IM-treated pts had any grade CV ischemic events. In READY, 18 pts in the DAS arm and 9 pts in the placebo arm had any grade CV ischemic events. The majority of pts with a CV event had a history and/or risk factors for atherosclerosis (77/96 [80%] in the pooled population; 8/10 with DAS and 3/4 with IM in DASISION). Time-to-event analysis revealed that, in the pooled population, CV ischemic events occurred in 69/96 pts (72%) within 1 y, 11 pts (11%) in 1–2 y, and 16 pts (17%) in 3–7 y. Over 70% tolerated continued DAS therapy without a recurrent CV event. In DASISION, CV events occurred in 7/10 pts within 1 y of DAS initiation, 2 pts in 1–3 y, and 1 pt after 5 y. Based on SIRs, the observed number of CV events in DAS-treated pts was not higher than expected, given the rates of reference populations (Table 1). SIR results should be interpreted with caution due to the limitations of the indirect comparison between clinical data and claims data (eg, coding differences and surveillance bias).Conclusion: CV ischemic events were reported in 4% of DAS- and 2% of IM-treated pts in DASISION, 4% of DAS-treated pts in the pooled population, and 2% of DAS- and 1% of placebo-treated pts in READY. In all populations, among pts who experienced an event, the majority had a history of arterial ischemic events and/or risk factors for atherosclerosis, and most events occurred early. SIRs suggest that the total number of CV ischemic events among DAS-treated pts was not higher than expected, and in contrast to what has been observed with other TKIs, largely restricted to 1 y after initiating therapy. [Display omitted] DisclosuresSaglio:Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; BMS: Consultancy, Fees for occasional speeches Other. Off Label Use: Dasatinib is approved for first line use in adults with chronic phase Ph+ CML, and in adult AP- or BP-CML, and Ph+ ALL patients who are resistant or intolerant to prior therapy. le Coutre:ARIAD: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Cortes:Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Mayer:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Mahon:ARIAD: Consultancy, Research Funding; Pfizer : Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Kroog:Bristol-Myers Squibb: Employment. Gooden:Bristol Myers Squibb: Employment. Subar:Bristol Myers Squibb: Employment. Preston:Bristol-Myers Squibb: Employment. Shah:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding.