Efficacy Of Dasatinib Research Articles

Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model.

BackgroundDysregulation of the Src pathway has been shown to be important at various stages of cancer. Dasatinib is a potent Src/Abl inhibitor and has demonstrated to have anti-proliferative and anti-invasive activity in many preclinical models. The objective of this study was to determine the anti-tumor activity of dasatinib using in vitro and in vivo preclinical colorectal (CRC) models.MethodsCRC cell lines and patient-derived tumor explant (PDX) models were used to investigate the efficacy of dasatinib. We treated 50 CRC cell lines with dasatinib for 72 hours and proliferation was assayed by a sulforhodamine B (SRB) assay; an IC50 ≤ 0.08 μmol/L was considered sensitive. We treated 17 patient-derived CRC explants with dasatinib (50 mg/kg/day, administered once-daily) for 28 days to determine in vivo efficacy. Tumor growth inhibition (TGI) ≥ 50% was considered sensitive.ResultsWe found that 8 out of 50 CRC cell lines reached an IC50 ≤ 0.08 μmol/L with dasatinib treatment. In addition, of 17 CRC explants grown in the xenograft mouse model, 2 showed sensitivity to dasatinib. The anti-tumor effects observed in this study were a result of G1 cell cycle arrest as the dasatinib sensitive CRC cell lines exhibited G1 inhibition. Moreover, those CRC cell lines that were responsive (0.08 μmol/L) to treatment demonstrated a significant baseline increase in Src and FAK gene expression.ConclusionDasatinib demonstrated significant anti-proliferative activity in a subset of CRC cell lines in vitro, especially in those with increased Src expression at baseline, but only showed modest efficacy in CRC explants. Dasatinib is currently being studied in combination with chemotherapy in patients with advanced CRC, as its use as a single agent appears limited.

T790M-Selective EGFR-TKI Combined with Dasatinib as an Optimal Strategy for Overcoming EGFR-TKI Resistance in T790M-Positive Non-Small Cell Lung Cancer.

T790M mutation-selective EGFR tyrosine kinase inhibitors (EGFR-TKI) have demonstrated clinical benefits in non-small cell lung cancer (NSCLC) patients harboring T790M mutation, which is the major cause of resistance to EGFR-TKI. However, their efficacy is limited, possibly due to the emergence of apoptosis resistance in T790M-positive NSCLC. We previously identified Src family kinases as cooncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced antitumor activity in T790M-positive cells. In the current study, we evaluated the efficacy of dasatinib combined with the clinically relevant T790M-selective EGFR-TKI ASP8273 or osimertinib in EGFR mutation-positive NSCLC with or without T790M mutation. A cell viability assay revealed that dasatinib had synergistic effects with these TKIs in T790M-positive cells and simultaneously inhibited Src, Akt, and Erk, which remained activated upon single-agent treatment. Dasatinib also increased the rate of apoptosis in T790M-positive cells induced by T790M-selective EGFR-TKIs, as determined by the Annexin-V binding assay; this was associated with downregulation of the antiapoptotic Bcl-2 family member Bcl-xL, a finding that was confirmed in mice bearing T790M-positive xenografts. Our results suggest that Bcl-xL plays a key role in the apoptosis resistance of T790M-positive NSCLC, and that dasatinib combined with clinically relevant T790M-selective EGFR-TKIs is potentially effective in overcoming resistance to first-generation EGFR-TKIs in NSCLC patients with acquired T790M. Mol Cancer Ther; 16(11); 2563-71. ©2017 AACR.

The Efficacy of Reduced-dose Dasatinib as a Subsequent Therapy in Patients with Chronic Myeloid Leukemia in the Chronic Phase: The LD-CML Study of the Kanto CML Study Group.

Objective The aim of this study was to prospectively investigate the efficacy and safety profiles of low-dose dasatinib therapy (50 mg once daily). Methods Patients with chronic myeloid leukemia in the chronic phase (CML-CP) who were being treated with low-dose imatinib (≤200 mg/day), but were resistant to this agent were enrolled in the current study (referred to as the LD-CML study). Results There subjects included 9 patients (4 men and 5 women); all were treated with dasatinib at a dose of 50 mg once daily. Among 8 patients who had not experienced major molecular response (MMR; BCR-ABL1 transcript ≤0.1% according to International Scale [IS]) at study enrollment, 5 attained MMR by 12 months. In particular, 3 of 9 patients demonstrated a deep molecular response (DMR; IS ≤0.0069%) by 18 months. Five patients developed lymphocytosis accompanied by cytotoxic lymphocyte predominance. There was no mortality or disease progression, and all continue to receive dasatinib therapy at 18 months with only 2 patients requiring dose reduction. Toxicities were mild-to-moderate, and pleural effusion was observed in 1 patient (grade 1). Conclusion Low-dose dasatinib can attain MMR and DMR without severe toxicity in patients with CML-CP who are unable to achieve MMR with low-dose imatinib. Switching to low-dose dasatinib should therefore be considered for patients in this setting, especially if they are otherwise considering a cessation of treatment.

Five-Year Efficacy and Safety of Dasatinib and Imatinib by Baseline Comorbidity and Age in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) from DASISION

Five-Year Efficacy and Safety of Dasatinib and Imatinib by Baseline Comorbidity and Age in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) from DASISION

Effect of Dose Modifications on 5-Year Efficacy of Dasatinib and Imatinib in Newly Diagnosed Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) From DASISION

Effect of Dose Modifications on 5-Year Efficacy of Dasatinib and Imatinib in Newly Diagnosed Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) From DASISION

Dasatinib and chemotherapy in a patient with early T-cell precursor acute lymphoblastic leukemia and NUP214-ABL1 fusion: A case report.

The present study aimed to evaluate the therapeutic efficacy of dasatinib in a patient with nucleoporin 214-tyrosine protein kinase ABL1 proto-oncogene 1 (NUP214-ABL1)-positive early T-cell precursor-acute lymphoblastic leukemia (ETP-ALL), as well as that of selinexor and dasatinib for NUP214-ABL1-positive ETP-ALL in vitro. ETP leukemia is a form of T-cell ALL (T-ALL) with poor prognosis. The NUP214-ABL1 gene is present in ~6% of T-ALL cases, however the prevalence of NUP214-ABL1 gene expression in ETP-ALL in particular has not yet been verified. The current study reports the rare case of a 29-year-old man with ETP-ALL harboring the NUP214-ABL1 fusion gene, presenting with low-grade fever, stomachache and splenomegaly. The patient was successfully treated with dasatinib and vincristine, idarubicin, cyclophosphamide and prednisone (VICP) chemotherapy. The therapeutic efficacy of selinexor and dasatinib was also evaluated in vitro. Apoptosis was analyzed using Annexin V/propidium iodide staining and flow cytometry, and poly ADP-ribose polymerase (PARP) cleavage was detected using western blot analysis. The results demonstrated that the apoptotic cell population significantly increased following selinexor or dasatinib treatment compared with the control (P<0.05). Furthermore, combined selinexor and dasatinib treatment led to a significant increase in cell apoptosis compared with either treatment alone (P<0.05). The apoptosis results were confirmed by PARP cleavage. Thus, NUP214-ABL1 fusion gene expression should be tested in T-ALL, including ETP-ALL. Dasatinib used in combination with traditional induction chemotherapy may reverse the high induction failure of ETP-ALL with NUP214-ABL1 fusion gene; however, further prospective studies are required to confirm this. Therefore, selinexor with or without dasatinib may serve as a potential salvage therapy in the case of relapse and may be developed as a novel treatment for ETP-ALL with the NUP214-ABL1 fusion gene.

Early results of lower-dose dasatinib, 50 mg daily, in newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase.

e18551 Background: Dasatinib, a potent BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase CML (CML-CP) in the frontline and salvage settings. The approved dose in chronic phase is 100mg orally daily. Notable side effects include pleural effusions and myelosuppression.We evaluated the efficacy and toxicity profile of dasatinib 50mg orally daily in patients with newly diagnosed CML-CP. Methods: Adults with newly diagnosed CML-CP were eligible. Prior TKI therapy for up to 1 month was allowed. Eligibility criteria were standard. Patients received dasatinib 50mg daily. Responses were defined according to the European LeukemiaNet guidelines (Baccarani et al. Blood 2013 122:872-884). Results: From March 2016 until January 2017, 30 patients were enrolled. Median age was 47 years (22 to 84). Sokal risk was low in 17 patients, intermediate in 10, and high in 3. Response data are shown below. Among 7 patients not in CCyR at 3 months by FISH (% FISH + 3, 3.5, 4.5, 5.5, 7, 9 and 83%), the respective BCR-ABL transcripts (IS) were 0.49, 0.08, 0.1, 0.09, 0.60, 0.69 and 9.2%. Thus, 6/7 patients with FISH + disease at 3 months had BCR-ABL transcripts (IS) &lt; 1%, and 17/18 patients evaluable at 3 months had BCR-ABL transcripts (IS) &lt; 1% (equivalent to CCyR). Significant myelosuppression requiring treatment interruption occurred in only 1 patient. No patients so far had pleural effusions requiring intervention. To date, there have been no dose modifications. Conclusions: Dasatinib 50mg daily is active and well-tolerated in newly diagnosed CML-CP. It should be further explored as a new potential dose-schedule standard-of-care in CML. [Table: see text]

Abstract P6-08-04: Preclinical efficacy of dasatinib in combination with PARP inhibitor plus standard cytotoxic agent in triple-negative breast cancer xenograft model

Abstract Background: Dasatinib is an orally-active ATP-competitive small molecule kinase inhibitor that potently inhibits Abl kinase, Src family kinases and other kinases (Lombardo et al., 2004). Src, one of the key targets of dasatinib is involved in the regulation of cell proliferation, survival and apoptotic ability of cancer cells (Tryfonopoulos et al., 2011; Pusztai et al., 2014). Dasatinib has shown its anti-proliferative and anti-metastatic effectiveness against triple-negative breast cancer (TNBC) in both preclinical and clinical studies (Finn et al., 2011). Several molecular targets including poly ADP ribose polymerase (PARP) are under clinical investigation for the treatment of TNBC. Recently, PARP inhibitors in combination with chemotherapy have shown promising results in this disease in clinical and preclinical studies (Tutt et al., 2010; Kim et al., 2013; De et al., 2014). Here, we hypothesize that dasatinib in combination with PARP inhibitor (ABT888) plus standard cytotoxic agent (carboplatin) will attenuate the growth of both TNBC cell lines and xenograft tumors. Methodology:We have used BT-20 (PIK3CA mutated, H1047R), HCC70 (PTEN null), HCC1937 (BRCA1 mutated, PTEN null), MDA-MB-231 (KRAS/BRAF mutated), MDA-MB-468 (PTEN null) and SUM149PT (BRCA1 mutated, PTEN null) cells for in vitro study. Survival/proliferation, colony formation and apoptosis were examined by using 2D proliferative/growth assay, 3D-ON-TOP assays, and annexinV staining respectively. We next studied the activation status of Src and its downstream signaling. We also have evaluated the effects on tumor growth inhibition of dasatinib/ABT888/carboplatin as a single agent or in combination by using mouse xenograft model. Results: We observed that 1) Dasatinib inhibited Src activation in all tested lines, induced dephosphorylation of ERK1/2 and S6 RP; 2) level of Cyclin D1 was decreased by dasatinib treatment; 3) high anti-proliferative activities were observed following the treatment of dasatinib along with ABT888 plus carboplatin in both 2D proliferation assay and 3D-ON TOP colony formation assay; 4) dasatinib in combination with ABT888 plus carboplatin inducing early stage apoptosis was seen by Annexin V staining in all tested cell lines; 5) dasatinib alone or combined with ABT888 or carboplatin or in triple combination inhibited tumor growth in TNBC xenograft models, the best tumor inhibition result was induced by triple combination (comparing to no treatment control, the mean tumor volume was decreased ~ 87% ). Conclusion: Our in vitro and in vivo studies suggest that dasatinib may enhance the antitumor activity of PARP inhibitor plus standard cytotoxic agent in TNBC. Mechanistic studies of xenograft tumor samples are ongoing, the results of which will be presented in the meeting. Citation Format: Sun Y, Lin X, Carlson JH, De P, Dey N, Jepperson T, R &amp; D NCI, Williams C, Leyland-Jones B. Preclinical efficacy of dasatinib in combination with PARP inhibitor plus standard cytotoxic agent in triple-negative breast cancer xenograft model [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-08-04.

Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia

AbstractPhiladelphia chromosome (Ph)–like B-cell acute lymphoblastic leukemia (Ph-like ALL) is associated with activated JAK/STAT, Abelson kinase (ABL), and/or phosphatidylinositol 3-kinase (PI3K) signaling and poor clinical outcomes. PI3K pathway signaling inhibitors have been minimally investigated in Ph-like ALL. We hypothesized that targeted inhibition of PI3Kα, PI3Kδ, PI3K/mTOR, or target of rapamycin complex 1/2 (TORC1/TORC2) would decrease leukemia proliferation and abrogate aberrant kinase signaling and that combined PI3K pathway and JAK inhibition or PI3K pathway and SRC/ABL inhibition would have superior efficacy compared to inhibitor monotherapy. We treated 10 childhood ALL patient-derived xenograft models harboring various Ph-like genomic alterations with 4 discrete PI3K pathway protein inhibitors and observed marked leukemia reduction and in vivo signaling inhibition in all models. Treatment with dual PI3K/mTOR inhibitor gedatolisib resulted in near eradication of ALL in cytokine receptor-like factor 2 (CRLF2)/JAK-mutant models with mean 92.2% (range, 86.0%-99.4%) reduction vs vehicle controls (P < .0001) and in prolonged animal survival. Gedatolisib also inhibited ALL proliferation in ABL/platelet-derived growth factor receptor (PDGFR)-mutant models with mean 66.9% (range, 42.0%-87.6%) reduction vs vehicle (P < .0001). Combined gedatolisib and ruxolitinib treatment of CRLF2/JAK-mutant models more effectively inhibited ALL proliferation than either inhibitor alone (P < .001) and further enhanced survival. Similarly, superior efficacy of combined gedatolisib and dasatinib was observed in ABL/PDGFR-mutant models (P < .001). Overall, PI3K/mTOR inhibition potently decreased ALL burden in vivo; antileukemia activity was further enhanced with combination inhibitor therapy. Clinical trials testing combinations of kinase inhibitors in Ph-like ALL patients are indicated.

First-Line Dasatinib Treatment of CML-CP Leads to Earlier Achievement of MMR and MR4.5 with High Safety

(INTRODUCTION) Several clinical studies have revealed that dasatinib demonstrated deep and fast responses. We report a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan (IMIDAS PART2 study).(PATIRNTS AND METHODS) Between July 2011 and June 2013, a total of 79 consecutive patients with CML-CP received 100 mg dasatinib daily as a first-line therapy. Treatment was continued until disease progression or until toxicity became unacceptable. The primary end-point was the rate of major molecular response by 12 months. Secondary end-points included the rate of complete cytogenetic response, rate of molecular responses with a 4.5 log reduction (MR4.5) by 12 months, and adverse events. The median age was 62 years, ranging from 27 to 80 years. Patients older than 65 years comprised 41.7% of all patients. Two-thirds of patients (68.4%) were male. Nearly all patients were ECOG performance status 0. Most patients (83.6%) had low and intermediate Sokal scores. The BCR-ABL1 International Scale (BCR-ABL1 IS) in the peripheral blood was measured by the central laboratory center (BML, Tokyo, Japan).(RESULTS) The median BCR-ABL1 IS before therapy was 54.0% (7.8-230.2). Seventy patients (88.6%) received dasatinib therapy for 12 months. The median BCR-ABL1 ISs were 0.25 % at 3 months (range 0.0002-52.2 %, n =77), 0.03 % at 6 months (range not detected-29.2 %, n = 75) and 0.008 % at 12 months (not detected -0.86 %, n = 70). MMR rate was 77.2% (95% CI, 67.9-86.5 %) by 12 months. The rates of CCyR and MR4.5 by 12 months were 88.6% (95% CI; 81.5-95.7 %) and 35.4% (95% CI; 24.8-46.1 %), respectively (Figure 1). Multivariate analysis of MMR or MR4.5 by 12 months showed that female sex (odds ratio 1.1, P = 0.92, odds ratio 1.7, P = 0.35, respectively), low and intermediate Sokal score (odds ratio 0.9, P = 0.90, odds ratio 3.2, P =0.23, respectively), and BCR-ABL1 IS less than 54% at diagnosis (RR =odds ratio 0.8, P = 0.74, odds ratio 0.7, P = 0.55, respectively) were not significantly correlated with MMR by 12 months nor MR4.5 by 12 months (Table 1). However, patients who were more than 62 years old were significantly correlated with MR4.0 and MR4.5 by 12 months (odds ratio 2.8, P =0.04, odds ratio 3.5, P =0.01). Treatment-related all AEs were reported in 98.7% patients (78 of 79). Grade 3/4 non-hematologic AEs were observed in only a few cases. Lymphocytosis (more than 4x 109/L) was observed in 34.1% of patients, which was within grade 2. Only 9 patients withdrew the study because of adverse events (4 patients), ineffectiveness (3 patients), and others (2 patients).(DISCUSSION AND CONCLUSION) The incidence of lymphocyte predominance may depend on a history of previous cytomegalovirus (CMV) infection in CML-CP patients (Leukemia. 2011 25(10): 1587-97). Although the frequency of CMV-positive patients was unknown in this study, that of blood donors in Japan was almost positive in the ages with 60s or older. The median age of CML-CP patients in this study was 62 years. Therefore, we assumed that some immunological effects induced by dasatinib might have improved the clinical efficacy in Japanese CML-CP patients compared to those worldwide. Our phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed CML-CP in Japan revealed that the first-line dasatinib treatment of CML-CP leads to earlier achievement of MMR and MR4.5 with high safety. Elder age patients (>62 years) were significantly associated with achievement of MR4.5. [Display omitted] [Display omitted] DisclosuresShindo:Sysmex Corporation: Research Funding. Sakamoto:Yakult: Other: Remuneration; Takeda Pharmaceutical: Consultancy.

Safety and Efficacy of Dasatinib Treatment Change for Patients Previosly Treated with Imatinib with Late Warning Response. Results from the Phase II, Open, Multicenter Dasapost Study

Background: Current European LeukemiaNet (ELN) recommendations (ELN 2013) endorse closely monitoring, due to risk of failure, for patients with so called late warning response (patients with complete cytogenetic response without major molecular response after 12 months of treatment). In this situation, for patients initially treated with imatinib, previous studies have shown a benefit of treatment change to nilotinib in terms of the achievement of deeper molecular responses. However, the role of treatment change to dasatinib in this group of patients have not been evaluated.DASAPOST is the first clinical trial evaluating efficacy and safety of dasatinib in patients with late warning responses.Methods: We are presenting results of the 18 patients enrolled in the phase II, open, multicenter DASAPOST study (NCT01802450). Main inclusion criteria were patients previously treated with imatinib with late suboptimal response by ELN2009 (CCyR without MMR after 18 months of treatment). The primary end point was rate of MMR by 6 moths after treatment change to dasatinib. Secondary end points were rate of MMR by 12 months, rate of deep molecular responses, progression free survival and safety of treatment change. Results were expressed as the proportion of patients who achieved molecular responses in the intention-to-treat (ITT) population, considering as failure if the evaluation was not performed in a specific time point. All BCR-ABL/ABL (IS) measurements were centralized in an EUTOS laboratory.Results: From April 2013 to May 2015, 18 patients were enrolled in 12 Spanish centers. Median age was 59 years (39-77). The ratio of men to women was 13/5, and the risk groups according to Sokal Score were 48%, 30% and 22% for low, intermediate and high risk, respectively. Median time from diagnosis to treatment change to dasatinib was 2.6 years (1.6-23) and median time while on imatinib to achieve CCyR 1.4 years (0.2-12). Median exposure to imatinib was 2.4 years (1.6-14). Seventy-two percent of the patients achieved MMR by 6 months (primary endpoint). Rates of MMR and deeper molecular responses at different time points are shown in table 1. Of interest 9/18 patients (50%) achieved MR4 by 12 months. Treatment change to dasatinib was safe, with only 3 study discontinuations (16%), due to adverse events (AE) and 4 serious AE (congestive heart failure, acute gastroenteritis, pyelonephritis and pancreatitis (only congestive heart failure was related to dasatinib). Most commonly reported (>5%) drug-related AEs are shown in table 1.Conclusions: Our study shows, for the first time, that in patients treated with imatinib and with late warning responses, switching to Dasatinib induced MMR in 2 out every 3 patients, and MR4 in half of the patients by 6 months, with a good safety profile. [Display omitted] [Display omitted] DisclosuresGarcía-Gutierrez:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Casado:Ariad: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Sánchez-Guijo:Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers-Squib: Consultancy, Honoraria. Martinez-Lopez:BMS: Research Funding. Steegmann:Ariad: Honoraria, Other: Research funding for the Spanish CML Group; Pfizer: Honoraria, Other: Research funding for the Spanish CML Group; BMS: Honoraria, Other: Research funding for the Spanish CML Group; Novartis: Honoraria, Other: Research funding for the Spanish CML Group.

Baseline Characteristics and Early Monitoring of Chinese CML Patients Treated with Dasatinib: Report from a Multicenter, Observational, Registry-Based Study

Background: Previously, real-world baseline characteristics and response monitoring pattern of Chinese CML patients treated with dasatinib were poorly studied and rarely reported. The Chinese dasatinib registry CA180-518 is a multicenter, observational study that provides us with a unique opportunity to obtain such information. Here we reported baseline characteristics and monitoring adherence of patients enrolled in this study.Methods: Imatinib-resistant/-intolerant CML adult patients in any phase, who planned to receive or were receiving dasatinib therapy based on physician's clinical judgement, were enrolled in this study and were separated into 3 cohorts based on their disease phases: chronic phase (CP), accelerated phase (AP) and blast phase (BP). Patients were to be followed until death, withdrawal of consent, end of study or loss of follow-up. Patient visit schedule, evaluation and treatment decision were determined solely by the physician in their real-world clinical practice. The first and the second patient visits were designed at Month 0 and Month 3.Results: From April 2013 to June 2015, a total number of 126 patients from hematology division of 28 hospitals in China were enrolled. Of these, 116 were included in the full analysis set (FAS), including 69 patients with CML-CP, 22 patients with CML-AP and 25 patients with CML-BP. Patients in the FAS had a median age of 43 years. 60.34% (70/116) were male. ECOG performance status (PS) at diagnosis was available for 81.90% (21/116) patients and most of them (75.00%, 87/116) had a good PS (PS0-PS1). Median disease duration was 33.00 months (Q1-Q3:14.00-71.50). 37.38% (40/116) of the patients had received imatinib treatment for ≥ 24 months. 75% (87/116) of the patients used dasatinib due to primary or secondary imatinib resistance and 25% (29/116) due to imatinib intolerance. 69 of 116 patients had undergone genetic mutation test at baseline, among which, 76.80% (53/69) were detected with genetic mutations. Y253F/H (15.94%; 11/69), E255K/V (11.59%; 8/69) and F359V/I (10.14%; 7/69) were the three most common mutation types, which also happened to be the mutations associated with nilotinib-resistance.18.97% (22/116) patients had baseline comorbidities and 50% (11/22) of them had ≥2 comorbidities. The most common comorbidity was cardiovascular diseases (CVD)/metabolic syndrome (MS) (54.54%, 12/22). It is also important to note that 22.72% (5/22) patients had a history of hepatitis B virus (HBV) infection.For 62 CML-CP patients who completed the second visit, 64.52% (40/62) had taken routine blood test, 72.58% (45/62) had taken PCR test and 22.58% (14/62) had taken cytogenetic test. It is noteworthy that there were still 19.35% (12/62) patients who took none of the laboratory tests mentioned above. The efficacy of dasatinib is being assessed based on the test results and will be reported in the further.Conclusion: The results from this analysis provided real-world data about baseline characteristics and response monitoring pattern of Chinese CML patients treated with dasatinib. Although less than 20% patients had baseline comorbidities, the fact that the most common comorbidity was CVD/MS should raise awareness, because TKI-related vascular AEs (VAEs) may develop preferentially in patients with these preexisting risk factors. Although the frequency of VAEs is lower in patients receiving dasatinib compared with nilotinib or ponatinib, for these patients, it is still important to closely monitor metabolic and cardiovascular parameters during the follow-up to reduce the vascular risk. Meanwhile, for patients who are carriers of HBV, EMA recently recommended that signs and symptoms of active HBV infection should be closely monitored throughout therapy and for several months following termination of therapy, given the risk of HBV reactivation for all TKIs.Besides, patient adherence to monitoring is a concerning problem for CML management in China. This data indicates a considerable amount of CML patients, who do not follow current recommended guidelines on response monitoring.Acknowledgment: BMS funded this research and medical writing support [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Matching-Adjusted Indirect Treatment Comparison of Bosutinib, Dasatinib, Nilotinib and Ponatinib on Survival for Second Line Chronic Phase Chronic Myeloid Leukemia Patients

Background: In clinical trials of second line and later line therapies for chronic myeloid leukemia (CML), to date only single arm trials have been conducted for the available treatments (i.e. Bosutinib, Dasatinib, Nilotinib and Ponatinib). These trials included heterogeneous patient populations in terms of line of treatment, stage of disease and other patient- and disease baseline characteristics that may impact the outcomes of the treatment. This hampers any direct or indirect comparisons of these second line CML treatments in terms of efficacy measures such as progression-free survival (PFS) and overall survival (OS). In this situation (i.e. lack of common comparator), matching-adjusted indirect treatment comparisons (MAICs) can be applied.Objective: The aim of this research was to compare the efficacy (PFS and OS) of Bosutinib, Dasatinib, Nilotinib and Ponatinib in second line chronic phase CML patients by means of MAICs. Patient data are reweighted such that their medians on demographic and clinical characteristics match those of the aggregated comparator trial, in order to adjust for cross-trial differences in those baseline characteristics. Outcomes of the reweighted patient level dataset are then compared with those of the aggregated comparator trial.Methods: A systematic literature review of second-line or later CML Phase II and Phase III clinical trials identified 2 trials for Bosutinib, 11 trials for Dasatinib, 8 trials for Nilotinib and 2 trials for Ponatinib. For the MAIC, only second line chronic phase trials with three or more years of follow-up (to allow for sufficient differentiation of treatments over time) were considered, resulting in 1 trial for Bosutinib (NCT00261846), 1 trial for Dasatinib (CA180-034), 1 trial for Nilotinib (NCT00109707) and no trials for Ponatinib. To adjust for cross-trial differences, patient data from the Bosutinib trial were subject to the inclusion and exclusion criteria reported in the comparator trials, and were weighted to match all available summary baseline characteristics reported in the 1 Dasatinib trial and the 1 Nilotinib trial. The baseline characteristics considered for reweighing were as follows: age, gender, Imatinib resistant/intolerant, disease duration, and prior stem cell transplantation. After the MAICs, PFS and OS were compared based on hazard ratios (HR) derived by Cox proportional hazard (PH) regressions using the reweighed Bosutinib dataset. The Cox PH assumption was tested with log cumulative hazard plots, Schoenfeld residuals and its corresponding statistical test. In case the PH assumption did not hold, Cox regressions with time varying coefficients were tested and the relative restricted mean survival time (RMST) was estimated.Results: Comparing Bosutinib to Nilotinib resulted in HRs for PFS and OS of 2.0 (<0.01) and 1.4 (p=0.109) respectively. When compared to Dasatinib, Bosutinib showed a non-significant HR of 1.3 (p=0.30) in favor of Bosutinib for OS and a significant 1.6 HR (p<0.01) for PFS. In the PFS and OS analyses compared to Dasatinib, the PH assumption was violated based on the statistical test or almost violated according to the visual plots. Therefore, we examined the relative restricted mean survival times, which were 1.123 (p=0.02) for PFS and 1.025 (p=0.41) for OS.Discussion: After performing MAICs to adjust for cross-trial differences in baseline characteristics, Bosutinib appeared to have a significantly greater PFS than Nilotinib (p<0.01). Based on the relative RMST analyses, Bosutinib also appeared to have a significantly greater PFS than Dasatinib, at the p<0.05 level. For OS the findings were numerically positive in favor of Bosutinib, but not statistically significant, compared to both. However, qualitatively, Bosutinib appears to be an equally effective second line chronic phase CML therapy. The greater PFS compared to Nilotinib and Dasatinib, especially at the end of the follow up period for Bosutinib, may translate into future OS benefits not yet observed.A limitation of our study is that we could only correct for observed differences between the trials, and not for unobserved ones. Also, the reweighing was performed for all relevant reported baseline characteristics; not all baseline characteristics were reported in all trials. Both limitations could have an impact on the outcomes and therefore the study conclusions. DisclosuresMuresan:Ingress-health Nederland BV: Employment. Mamolo:Pfizer Inc: Employment, Equity Ownership. Cappelleri:Pfizer Inc: Employment, Equity Ownership. Shapiro:Pfizer Inc: Employment, Equity Ownership. Crescenzo:Pfizer Inc: Employment. Su:Pfizer: Employment, Equity Ownership; Bristol Myers Squibb: Equity Ownership. Heeg:Ingress-health Nederland BV: Employment, Equity Ownership, Research Funding.

PTPN11 Mutations in JMML Confer Dasatinib Sensitivity in a TNK2-Dependent Manner

Introduction: Juvenile myelomonocytic leukemia (JMML) is a rare disease characterized by an overproduction of granulocytes and monocytes, with cells displaying hypersensitivity to stimulation by the cytokine GM-CSF in culture. The only curative approach for JMML is allogeneic hematopoietic stem cell transplant, and disease recurrence is the leading cause of death in these patients, occurring within two years in 50% of patients. New therapeutic strategies are needed to improve treatment and survival.Methods: In order to better identify therapeutic strategies, our lab has developed ex vivo functional assays with small-molecule inhibitors and RNAi for the profiling of actionable targets in primary patient samples. In these assays, mononuclear cells from patient bone marrow or blood are cultured in the presence of small molecule inhibitor or RNAi libraries and cell viability is measured by colorimetric assay. To investigate targets identified in these assays, gene constructs are transfected into HEK293 T17 cells for immunoblots or transduced into mouse bone marrow cells for methylcellulose-based colony formation assays.Results: Mononuclear white blood cells from a patient with recurrent JMML were found to be sensitive to the multi-family kinase inhibitor dasatinib as well as siRNA targeting the dasatinib target tyrosine kinase non-receptor 2 (TNK2, also known as ACK1), suggesting an over-reliance on TNK2 for cell viability. TNK2 was recently demonstrated by our lab and others to regulate signaling downstream of signaling pathways including EGFR, ER, Src, and CSF3R. Based on the ex vivo functional data for this JMML specimen, the patient was placed on daily dasatinib and achieved marked improvement, which bridged the patient to an additional bone marrow transplant, resulting in disease-free survival for another year.This patient had a mutation in PTPN11 (also known as SHP2), which encodes a protein tyrosine phosphatase that is mutated in approximately 35% of JMML patients. PTPN11 is an auto-inhibited phosphatase that dephosphorylates targets in many signaling pathways including RAS-MAPK, with an overall positive effect on pathway activity and cellular proliferation. In JMML, mutations in residues of the N-terminal SH2 domain of PTPN11 result in a constitutively active form of the protein, which increases proliferation and cell survival and is linked to dysregulation of RAS/MAPK.Results of in vitro experiments demonstrate, for the first time, an interaction of TNK2 with mutant PTPN11. Co-expression of mutant-PTPN11 and TNK2 results in increased phospho-PTPN11 at two sites associated with activation of PTPN11 (Y542 and Y580), and co-immunoprecipitation experiments indicate direct interaction of TNK2 with PTPN11. These phosphorylation events coincide with significantly increased MEK/ERK signaling in the context of TNK2/mutant PTPN11 co-expression relative to expression of either gene alone. Expression of a TNK2 mutant harboring a loss-of-function mutation at a key activating residue (TNK2 Y284F) reduces PTPN11/MAPK activation, whereas expression of a gain-of-function, drug-resistant TNK2 gatekeeper mutant increases PTPN11/MAPK activation when compared to wild-type TNK2. Inhibition of TNK2 with either dasatinib or the TNK2-specific inhibitor AIM100 also reduces PTPN11/MAPK activation. Interestingly, phospho-TNK2 levels are significantly reduced in the presence of mutant-PTPN11, suggesting a feedback mechanism that has yet to be fully elucidated.Functional experiments suggest that mutant-PTPN11 and TNK2 work in a synergistic fashion to increase cell transformation and cytokine hypersensitivity. Mouse bone marrow cells transduced with both mutant PTPN11 and TNK2 have significantly more colonies in methylcellulose colony formation assays than with mutant- PTPN11 alone or with wild-type PTPN11 and TNK2. Treatment of cells in colony formation assays with either dasatinib or AIM100 inhibits colony formation, suggesting a dependence on TNK2 kinase activity for cell transformation.Conclusions: Taken together, the preliminary data suggest that PTPN11 mutations may be a functional marker for dasatinib sensitivity, and that the underlying mechanism for this sensitivity may be through the inhibition of TNK2 activity by dasatinib. Our aim is further validate the role of PTPN11 mutations as a marker for efficacy of dasatinib or other TNK2 inhibitors. DisclosuresNo relevant conflicts of interest to declare.

Similar Efficacy of Dasatinib and Nilotinib As Second-Line Therapy in Patients with Chronic Phase Chronic Myeloid Leukemia Failing Imatinib: A Retrospective, Real-Life Study

Background. Use of 2nd generation tyrosine kinase inhibitors (2G-TKIs) dasatinib (DAS) and nilotinib (NIL) in chronic phase (CP) chronic myeloid leukemia (CML) patients failing imatinib (IM) results in around 50% of sustained cytogenetic response, and around 40% major molecular response (MMR). However, these are historical data and it's unclear if there's a significant difference in efficacy of the two 2G-TKIs, especially in the long-term.Aims and methods. We retrospectively analysed 163 CP-CML patients resistant or intolerant to IM that received either DAS (n=95) or NIL (n=68) as second-line therapy. We compared the characteristics of the two groups at the time of CML diagnosis and at the time of IM failure, including the cause of switch to 2G-TKI, duration of IM therapy, IM dose escalation and Hammersmith score to predict the probability of response to 2G-TKIs. Cytogenetic and molecular responses were evaluated according to the ELN recommendations. Sustained deep molecular response (DMR) was defined as MR4 or better lasting ≥ 2 years, ongoing at the last contact, and with at least a Q-PCR test every 6 months. Time to treatment failure (TTF) was calculated from the start of 2G-TKI to any of the followings: progression to accelerated or blast phase (ABP), death for any cause at any time, treatment discontinuation for primary or secondary resistance or intolerance. Progression free survival (PFS) was calculated from the start of 2G-TKI to ABP or death. Overall survival (OS) was calculated from the start of 2G-TKI to death.Results. DAS and NIL cohorts were comparable for age, sex and risk score (Sokal and EUTOS) at diagnosis. Median duration of IM therapy was similar (DAS 19 months, NIL 14 months), but 27/95 patients (28%) had IM dose escalation before DAS compared to only 9/68 (13%) before NIL (p=0.03). There was a higher rate of switch to DAS than to NIL for secondary resistance (26/95, 27% vs 7/68, 10%; p=0.01) while more patients changed from IM to NIL due to intolerance (31/68, 46%, vs 21/95, 22% for DAS; p=0.002). Rates of primary resistance did not differ (47/95, 49% for DAS vs 28/68, 41% for NIL; p=0.37), as well as other causes of switch (1/95, 1% for DAS vs 2/68, 3% for NIL; p=0.77). Hammersmith score was almost identical in the two groups.Complete cytogenetic response (CCyR) was attained in 53/73 (73%) patients not in CCyR at the time of DAS start, and in 31/48 (65%) patients not in CCyR at the time of NIL start (p=0.46). Mean time to CCyR was similar (7.1 months for DAS and 5.3 months for NIL; p=0.30).MMR was achieved in 55/89 (65%) patients not in MMR at the time of DAS start and in 39/61 (65%) patients not in MMR at the time of NIL start (p=0.82). Again, mean time to MMR was not different in the DAS e NIL cohorts (12.4 vs. 8.5 months; p=0.14).DMR was obtained in 39/88 (44%) patients not in DMR at the time of DAS start and in 30/65 (46%) patients not in DMR at the time of NIL start (p=0.95). Sustained DMR was evaluable in 127 patients: 37 patients (29%) achieved sustained DMR, without difference between DAS (24/82, 29%) and NIL (13/45, 29%; p=1.00).With a median follow-up of 44 months (range 1-124), 5-year TTF was similar for DAS (65%, 95%CI 52-75%) and NIL (61%, 95%CI 43-74%; p=0.40) [Figure 1a]. Thirty-two of 95 patients (34%) stopped DAS due to toxicity (19/32, 59%), resistance (11/32, 31%) or other causes (3/32, 10%); 22/68 patients (32%) interrupted NIL for toxicity (11/22, 50%), resistance (8/22, 36%) or other causes (3/22, 14%). Probability of survival and progression were almost identical, with a 5-year PFS of 84% (95%CI 68-89%) for DAS and 92% (95%CI 79-97%) for NIL (p=0.27) [Figure 1b] and a 5-year OS of 89% (95%CI 78-95%) and 96% (95%CI 85-99%) (p=0.31), respectively.Conclusions. With the limits of a retrospective analysis, our data suggest similar efficacy of DAS and NIL after IM failure in CP-CML, with rates of cytogenetic and molecular responses higher than those previously reported and excellent long-term survival. Around 30% achieved sustained DMR with second-line therapy, thus being potentially candidate for TKI discontinuation. DisclosuresTiribelli:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau. Bonifacio:Ariad Pharmaceuticals: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Amgen: Consultancy. Fanin:Novartis: Speakers Bureau.

BP1001, a Novel Therapeutic for Chronic Myelogenous Leukemia

Background: The Growth factor receptor bound protein-2 (Grb2) is essential to cancer cell signaling. Grb2 binds to numerous tyrosine kinases, including the Bcr-Abl chimeric oncogene found in Philadelphia chromosome positive chronic myelogenous leukemia (CML) cells. Upon binding to tyrosine kinases, Grb2 transduces the kinases signals to the activation of Ras and its downstream protein, Extracellular signals regulated protein kinases-1,2 (Erk1,2). The direct binding of Grb2 to Bcr-Abl is required for Bcr-Abl to transform fibroblasts and induce CML-like diseases in mice. We hypothesize that Grb2 is a potential therapeutic target against CML. BP1001, a liposome-incorporated antisense oligodeoxynucleotide targeted against the Grb2 mRNA, was developed to inhibit Grb2 expression. Previously we demonstrated that BP1001 suppressed the growth of CML cell lines and CML xenografts.Aim: Since the clinical activity of BP1001 will be investigated in gleevec-resistant CML patients, preclinical studies were conducted to determine whether BP1001 could suppress the proliferation of gleevec-resistant CML cells. Additionally, whether BP1001 could enhance the inhibitory effects of dasatinib in CML cells was determined. The clinical activity of BP1001 was studied in CML blast patients, who were part of a larger Phase I clinical study.Methods: The alamarBlue dye incorporation method and the CellTiter Glow method were used to determine cell viability. Flow cytometry was utilized to analyze cell cycling and Grb2 expression. The clinical study was a standard 3+3 dose-finding study in which BP1001 was given twice weekly, IV over 2-3 hours for 28 days. The clinical activity of BP1001 was evaluated in its ability to reduce target Grb2 protein in CD33-expressing cells and to reduce leukemia blast counts.Results: BP1001 decreased the proliferation of gleevec-resistant CML cells in a dose-dependent manner. Furthermore, BP1001 pretreatment enhanced the inhibitory effects of dasatinib in CML cells, by about 2-6 fold. The major inhibition mechanism of the BP1001 + dasatinib combination was cell death. A total of39 patients with refractory/relapsed hematologic malignancies was enrolled in the clinical trial. Five were CML blast phase patients; they were enrolled in the first cohort (5 mg/m2BP1001). Two CML patients, who had T315I mutation, showed significant reductions in circulating blasts during treatment. One patient’s blasts were reduced from 89% to 9%, while another patient’s blasts were reduced from 17% to 8%. BP1001 decreased >25% Grb2 levels in 10 of 12 samples (average decrease: 49%) and >25% phosphorylated Erk1,2 levels in 7 of 12 samples (average decrease: 52%).Conclusions: BP1001 was active against gleevec-resistant CML cells and enhanced dasatinib efficacy in preclinical studies. BP1001 may have therapeutic activity against CML. We are planning a Phase I/II trial to study the safety and efficacy of BP1001 in combination with dasatinib in accelerated or blast phase CML patients. DisclosuresTari Ashizawa:Bio-Path Holdings, Inc.: Employment, Equity Ownership.

LYN expression predicts the response to dasatinib in a subpopulation of lung adenocarcinoma patients.

Therapies targeting SRC family kinases (SFKs) have shown efficacy in treating non-small cell lung cancer (NSCLC). However, recent clinical trials have found that the SFK inhibitor dasatinib is ineffective in some patient cohorts. Regardless, dasatinib treatment may benefit some NSCLC patient subgroups. Here, we investigated whether expression of LYN, a member of the SFK family, is associated with patient survival, the efficacy of dasatinib, and/or NSCLC cell viability. LYN expression was associated with poor overall survival in a multivariate analysis, and this association was strongest in non-smoker female patients with adenocarcinoma (ADC). In lung ADC cells, LYN expression enhanced cell proliferation, migration, and invasion. Dasatinib inhibited LYN activity and decreased cell viability in LYN-positive ADC cell lines and xenografts. Additionally, we identified the SFKs SRC and YES as candidate dasatinib targets in LYN-negative ADC cell lines. Our findings suggest that LYN is a useful prognostic marker and a selective target of dasatinib therapy in the lung ADC subpopulation especially in female non-smokers with lung ADC.

Abstract CT060: Efficacy, safety and tolerability of dasatinib combined with afatinib: a phase I trial in patients with epidermal growth factor receptor mutant (EGFRm) advanced non-small-cell lung cancer (NSCLC) after acquired tyrosine kinase inhibitor (TKI) resistance

Abstract Background: Combining the Src family kinase inhibitor dasatinib and irreversible EGFR inhibitor afatinib results in enhanced antitumor activity in proliferation and apoptosis assays with EGFRm, TKI-resistant cell lines. Moreover, this combination results in higher tumor regression than either drug alone in PC9GR xenograft studies. We hypothesized that this drug combination would arrest progression in EGFRm NSCLC with acquired resistance. Therefore, we initiated a phase I open-label trial (NCT01999985) to evaluate dasatinib in combination with afatinib for patients (pts) with EGFRm advanced NSCLC who had progressed on previous EGFR TKIs. Methods: A phase I dose-escalation cohort with 3+3 design included patients (pts) with refractory NSCLC and ECOG performance status (PS) ? 1. Pts received continuous oral afatinib daily followed by addition of continuous oral dasatinib daily beginning on Day 8. After determination of maximum tolerated dose (MTD), a phase I cohort was expanded to include only pts with activating EGFR mutation who had acquired resistance to previous EGFR TKI. Safety, median progression-free survival (PFS), and tumor response were investigated. Plasma before and during treatment was collected for sequencing of circulating cell-free tumor DNA. Cox regression was performed. All statistical tests were 2-sided. Interim results are reported. Results: Of 31 pts screened, 25 were treated. Characteristics: 63% were female, median age was 66.8 years (range 53 - 81), and 72% were ECOG PS 1. Race: 75% Caucasian, 16% African-american. Median prior lines of therapy was 3. For EGFRm pts (n = 16), 56% had exon 19 deletion, 43% exon 21 mutation. In addition, 31% also had T790M detected in tumor prior to treatment. No significant interactions were observed with dasatinib and afatinib. Dose escalation halted at 40 mg afatinib and 100 mg dasatinib when 2 patients at this level experienced grade 2 or 3 diarrhea despite optimal supportive care. The most common drug-related adverse events of any grade from dose escalation included 63% diarrhea, 45% rash, 27% nausea, 18% oral mucositis, and fatigue. The MTD was 30 mg afatinib with 100 mg dasatinib. The PFS for EGFRm pts was 5.5 months (95% confidence interval 2.6 - 8.5). A trend toward more favorable PFS for T790M was observed (7.0 vs. 2.8 months, p = 0.06) in evaluable subjects. No confirmed partial or complete responses have been observed. Conclusions: Afatinib plus dasatinib was acceptably tolerated in pts with NSCLC in the escalation phase. Clinical benefit has been observed in the expansion phase, although without objective radiologic responses. Preliminary data support continued evaluation of afatinib 30 mg plus dasatinib 100 mg as the expansion phase dose in pts with EGFRm NSCLC with acquired TKI resistance. Citation Format: Ben Creelan, Jhanelle Gray, Diana Lima, Scott Antonia, Alberto Chiappori, Tawee Tanvetyanon, Rebecca DeVane, Charles Williams, Eric Haura. Efficacy, safety and tolerability of dasatinib combined with afatinib: a phase I trial in patients with epidermal growth factor receptor mutant (EGFRm) advanced non-small-cell lung cancer (NSCLC) after acquired tyrosine kinase inhibitor (TKI) resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT060.

Abstract 4417: In vitro efficacy of dasatinib alone or in combination with PARP inhibitor plus standard cytotoxic agent in triple-negative breast cancer cell lines

Abstract Background: Patients presenting with triple-negative breast cancer (TNBC) have the poorest prognosis of all breast cancer (BC) subtypes and there are limited treatment options, with no efficacious targeted therapies. Therefore, improved approaches to treatment of these cancers are an unmet need. Several molecular targets including: epidermal growth factor receptor (EGFR), poly ADP ribose polymerase (PARP), and Src family tyrosine kinases are under clinical investigation for the treatment of this disease (De et al., 2014; Kim et al., 2013). Src family tyrosine kinases play a critical role in signal transduction downstream of growth factor receptors and integrin family members. Preclinical studies have established a role for Src family kinases in proliferation, angiogenesis and invasion in prostate cancer model (Varcaris et al., 2014). Dasatinib is an rally-active ATP-competitive small molecule kinase inhibitor that potently inhibits Abl kinase, Src family kinases and other kinases (Lombardo et al., 2004), and has shown its anti-proliferative and anti-metastatic effectiveness against TNBC in both preclinical and clinical studies (Finn et al., 2011). Recently, PARP inhibitors in combination with chemotherapy have shown promising results in TNBC in clinical and preclinical studies (Tutt et al., 2010; De et al., 2014). We hypothesize that the inhibitor of Src family of kinases (dasatinib) in combination with PARP inhibitor (ABT888) plus standard cytotoxic agent (carboplatin) will attenuate the growth of TNBC cell lines. Methodology: BT-20 (PIK3CA mutated, H1047R), HCC70 (PTEN null), HCC1937 (PTEN null), MDA-MB-231 (KRAS/BRAF mutated), MDA-MB-468 (PTEN null) and SUM149PT (BRCA1 mutated, PTEN null) cells were used for this study. Growth inhibition, survival/proliferation, colony formation and apoptosis were examined using MTT assay, 2D proliferative/growth assay, 3D-ON-TOP assays, and annexinV staining respectively. Results: Our data showed that 1) High anti-proliferative activities were observed following the treatment of dasatinib along with ABT888 plus carboplatin in both 2D proliferation assay and 3D-ON TOP colony formation assay. 2) In the same line, dasatinib in combination with ABT888 plus carboplatin inducing early stage apoptosis was seen by Annexin V staining in all tested cell lines. 3) Our MTT data showed that anti-proliferative activity of dasatinib as a single agent is highly variable in different genetic background of TNBC cell lines. Conclusion: Our data suggest that the combination of Src inhibitor may enhance the antitumor activity of PARP inhibitor plus standard cytotoxic agent in TNBC models. Mechanistic studies are ongoing, the results of which will be presented in the meeting. Citation Format: Yuliang Sun, Jennifer Carlson, Xiaoqian Lin, Pradip De, Casey Williams, Sally Hausman, Nandini Dey, Brian Leyland-Jones. In vitro efficacy of dasatinib alone or in combination with PARP inhibitor plus standard cytotoxic agent in triple-negative breast cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4417.

Retrospektywna analiza skuteczności nilotynibu i dazatynibu w drugiej linii terapii przewlekłej białaczki szpikowej w polskich ośrodkach hematologicznych

Until now, there has been no randomized study directly comparing the activity of second-generation BCR-ABL tyrosine kinase inhibitors (TKI-2G) nilotinib and dasatinib in chronic myeloid leukemia (CML). The aim of our study was to retrospectively analyze efficacy of nilotinib and dasatinib in the real life setting of CML with resistance or intolerance of imatinib. Of 108 included patients treated in polish hematology centers, 75 received dasatinib and 33 patients received nilotinib. Rates of complete cytogenetic response (CCyR) did not differ between the two groups of patients. After six months of therapy, CCyR was achieved in 34.7% of patients treated with dasatinib and 38.7% treated with nilotinib (p=0.86), while after 12 months, the CCyR rates were 60.0% and 77.0% in dasatinib and nilotinib groups, respectively (p=0.11). Moreover, we have not observed any significant difference in the probability of progression-free survival (p=0.89) or overall survival (p=0.99) between patients treated with these two TKI-2G. In conclusion, the results of our analysis indicate that nilotinib and dasatinib have comparable and satisfactory efficacy in the treatment of CML patients refractory or intolerant to imatinib. Our findings support current strategy of choice of IKT-2G according to drug toxicity profile and risk of specific adverse events in an individual patient.