E7050 treatment also decreased the expression of CD31 and p-VEGFR2 in MES-SA/Dx5 tumor tissue sections in comparison with the vehicle control. Collectively, E7050 may serve as a potential agent for the treatment of cancer and angiogenesis-related disorders.

By multivariate analysis, third-line therapy with ponatinib was the only independent factor associated with better survival (P =?0.003). In conclusion, ponatinib is an optimal treatment for patients with CML-CP failing 2 prior TKIs.

More recently, a chemotherapy-free regimen with blinatumomab and ponatinib resulted in a complete molecular remission rate of 85% and an estimated 3-year survival rate of 90%, potentially reducing the role of, and need for allogeneic stem cell transplantation (SCT) in remission. In younger patients with pre-B Philadelphia chromosome-negative ALL, the integration of blinatumomab and inotuzumab into the frontline therapy has improved the estimated 3-year survival rate to 85% across all risk categories...In summary, the management of ALL has witnessed significant progress during the past four decades. Novel combination regimens including newer-generation BCR::ABL1 TKIs and novel antibodies are questioning the need and duration of intensive chemotherapy and allogeneic SCT.

Outcomes of this trial using a personalised approach will provide clinical and patient-reported data to guide future dose reduction of TKIs in CML. If the strategy appears to be effective, it may be implemented as another valid option to offer next to standard of care to prevent potential unnecessary exposure to higher TKI doses in this selected group of patients.

This analysis in Italian real-life clinical practice reported economic expenditure for patients with CML in 2nd or ≥ 3rd lines with TKIs, mostly burdened by hospitalizations. Such clinical complexity suggests that further efforts are needed to improve the therapeutic management of later lines of CML.

P1, N=193, Completed, Mirati Therapeutics Inc. | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Apr 2022

Sitravatinib with nivolumab had a manageable safety profile. Although ORR was not met, this combination demonstrated antitumor activity and encouraging survival in CPI-experienced patients with non-squamous NSCLC.

P=N/A, N=1769, Completed, Takeda

In this study, we demonstrated that the inhibition of Src activity by ponatinib effectively suppressed several malignant phenotypes of esophageal squamous cell carcinoma (ESCC) both in vitro and in vivo, whereas it did not produce growth-inhibitory effects on normal esophageal epithelial cells (NEECs)...Furthermore, results of the clinical ESCC samples showed that the hyperactivation of pSrc Tyr, Fyn Tyr or Tyr, and Lyn Tyr or Tyr could be biomarkers of ESCC prognosis. This study illustrates that Src/Fyn and Src/Lyn heterodimers serve as targets for the treatment of ESCC.

Initially, the incorporation of the first-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) imatinib into intensive chemotherapy regimens improved outcomes compared with chemotherapy alone. In particular, encouraging early results have been seen with the combination of blinatumomab plus ponatinib, suggesting that this regimen may represent a chemotherapy-free and SCT-sparing strategy for patients with Ph-positive ALL. Herein, we discuss the current evidence for frontline therapies of Ph-positive ALL, the treatment de-escalation strategies over time, and the role of allogeneic SCT in view of the emergence of newer chemotherapy-free regimens using potent TKIs.

P2, N=80, Active, not recruiting, Fundacion CRIS de Investigación para Vencer el Cáncer | Recruiting --> Active, not recruiting

There are therefore risks in the management of FLT3i DDIs (i.e., sorafenib, ponatinib, crenolanib, midostaurin, quizartinib, and gilteritinib) and ignoring them can compromise therapeutic success in acute myeloid leukemia (AML) treatment, in complex patients and secondary pathologies. FLT3i will be combined with other therapeutic agents (supportive care, doublet, or triplet therapy) and in different clinical settings, which means a greater chance of controlling and even eradicating the disease effectively, but also an increased risk to patients due to potential DDIs. Healthcare professionals should be aware of the potential interactions that may occur and be vigilant in monitoring those patients who are receiving any potentially interacting drug.

P2, N=24, Active, not recruiting, Versailles Hospital | Recruiting --> Active, not recruiting | N=77 --> 24 | Trial primary completion date: Dec 2021 --> Dec 2022

Our study reveals the potential therapeutic role of sitravatinib in FLT3 mutant AML and provides an alternative inhibitor for the treatment of AML patients who are resistant to current FLT3 inhibitors.

P2, N=3, Terminated, C. Kent Osborne, MD | N=30 --> 3 | Trial completion date: Feb 2026 --> Jan 2023 | Recruiting --> Terminated | Trial primary completion date: Feb 2024 --> Jan 2023; Terminated by sponsor due to lack of interest

Furthermore, the top five drugs (AP.24534, BX.795, Midostaurin, WO2009093927 and CCT007093) were significantly higher in cluster 1 than in cluster 2. Finally, three genes (AOX1, NNMT and PTGIS) were acquired as prognostic, and their expressions were consistent with the results of bioinformatics analysis. Three prognostic genes related to NAD metabolism in STAD were screened out, which provides a theoretical basis and reference value for future treatment and prognosis of STAD.

Taken together, these findings uncover a novel mechanism of ponatinib-induced cardiac inflammation leading to cardiac dysfunction. From a translational perspective, our results provide critical preclinical data and rationale for a clinical investigation into immunosuppressive interventions for managing ponatinib-induced cardiotoxicity.

PCa is the most prevalent cancer in US males and there is an urgent need for more accurate biomarkers that can predict disease severity and suggest actionable targeted therapy. In this retrospective analysis, we confirm that higher RIPK2 expression is associated with more advanced PCa. We extend these findings to a predominantly AA cohort, which may promote improvements in personalized medicine for this population at higher risk for PCa if RIPK2-targeting drugs such as Ponatinib can be utilized.

Maintenance therapy consisted of daily ponatinib and vincristine-prednisone monthly for 2 years, followed by daily ponatinib indefinitely. Twelve intrathecal injections of cytarabine alternating with methotrexate were given as central nervous system prophylaxis...Two ponatinib-related deaths from myocardial infarction (3%; at months 2.6 and 4.3, respectively; both in CR) in the first 37 patients treated led to the ponatinib dose-modifications mentioned earlier, with no further ponatinib-related deaths observed. The long-term results of ponatinib and hyper-CVAD continue to demonstrate excellent outcome results and acceptable safety data, indicating that this strategy is another standard of care approach in frontline Ph-positive ALL.

The median (95% CI) CSF -to-C ratio of ponatinib in four patients with the combination of ABCB1 variants 1236T/T-2677T/T+T/A-3435T/T was 2.62 (1.42 - 3.42)%; this ratio was significantly higher than that in subjects with other genotypes [1.08 (0.89 - 1.47)%; P = 0.006]. The brain distribution of ponatinib was affected by ABCB1 polymorphisms and therefore seems to be modulated by P-glycoprotein at the blood-brain and blood-CSF barriers.

These findings contribute to understanding of the function of m6A-related lncRNAs in UCEC and provide promising therapeutic strategies for UCEC.

P3, N=420, Ongoing, BeiGene, Ltd.

E7050 treatment also decreased the expression of Ki-67 and p-Met, and increased the expression of cleaved caspase-3 in MES-SA/Dx5 tumor sections. Therefore, E7050 is a promising drug that can be developed for the treatment of multidrug-resistant uterine sarcoma.

With improvements in TKI efficacy and allogeneic hematopoietic cell transplantation (HCT), survival has improved over the past 3 decades, and the role of chemotherapy and allogeneic HCT is now changing. Better risk stratification, the application of the third-generation TKI ponatinib, and the use of immunotherapy with the CD19-CD3 bifunctional T-cell engaging antibody blinatumomab in place of chemotherapy has made therapy for Ph+ ALL more tolerable and arguably more efficacious, especially for older patients who comprise most patients with Ph+ ALL.

This was first shown with the addition of the first-generation TKI imatinib, which allowed more patients to be bridged to an allogeneic stem cell transplant (SCT) and led to superior long-term outcomes compared with chemotherapy alone. The use of second-generation TKIs (eg, dasatinib and nilotinib) has led to further improvement in outcomes of patients with Ph- positive ALL, with a long-term survival of 40% to 60% in several studies. Ponatinib is a third-generation, more potent TKI that results in high rates of molecular response and promising long-term survival even when allogeneic SCT is not routinely performed. While randomized data to support the TKI selection in Ph-positive ALL are lacking, data from single-arm studies suggest deeper molecular responses and superior survival outcomes with each successive generation of TKI. More recently, chemotherapy-free regimens with blinatumomab and TKIs have shown excellent results in the frontline setting and may represent an emerging paradigm shift in the treatment of Ph-positive ALL.

P1/2, N=11, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=38 --> 11 | Trial completion date: Jan 2023 --> Aug 2023 | Trial primary completion date: Jan 2023 --> Aug 2023

These results suggested that the beneficial effects of ponatinib on metabolic disorders are achieved by inhibiting the inflammatory phenotypic transformation of ATMs, thereby maintaining the physiological function of adipose tissue under excessive obesity. The data here not only revealed the novel therapeutic function of ponatinib, but also provided a theoretical basis for the application of multi-target tyrosine kinase inhibitors in metabolic diseases.

P2, N=32, Active, not recruiting, Institute of Hematology and Blood Transfusion, Czech Republic | Recruiting --> Active, not recruiting

He was treated with Mini-CVD and Ponatinib, achieved complete remission with negative MRD by flow cytometry, however molecular studies showed BCR-ABL1 level at 58% IS indicating a persistent cytogenetic abnormality. De novo lymphoid blastic-phase CML can therefore be difficult to differentiate from Philadelphia positive B-ALL due to their overlapping clinical and laboratory picture, implying the need to do myeloid compartment evaluation at the time of diagnosis. With recent progress in the treatment of Philadelphia positive B-ALL, including the role of transplant with the use of novel agents, a better characterization of this disease entity in retrospective and prospective trials is warranted.

Treatment agents such as tyrosine kinase inhibitors (Imatinib, Dasatinib, Nilotinib, Bosutinib, Ponatinib, Radotinib), Omacetaxine and Asciminib have been used in the treatment of Bcr abl positive CML according to the patient's clinic and mutation status. All patients responded well to imatinib therapy. During follow up patients who maintained their MMR achieve had a better clinical course and prognosis compared to other CML patients.

Imatinib was used in front line in 45 /74 patients. Dasatinib and nilotinib were used as first line 18 vs 5, second line in 19 vs 6 and third line in 3 vs 7 patients. Ponatinib was used second line in 2 patients vs. third, forth and fifth line in 1 patient each.A total of 8 patients received allogeneic transplant ( 1 cord ) and all 8/8 achieved CMR remained in CR for medan of 12 years...second cancers were seen in 9% (n=6) patients.Conclusion : Allogeneic transplant still appears to have role to achieve long term CR. Use of drugs targeting CML leukemia stem cells along with TKIs may be needed to yield more complete metabolic responses (CMR) cure CML.

Bone marrow (BM) samples were collected at the end of the induction phase (day +70) with ponatinib in the experimental arm or with a chemotherapy backbone plus imatinib in the control arm. These findings suggest that the BCR/ABL1 fusion transcript remains the main sensitive target in adult Ph+ ALL and lead to hypothesize that in in this setting IG/TR clonal rearrangements represent a surrogate marker. Cohort expansion is warranted and clinical correlations are ongoing.

First-line treatments were imatinib (n=3), dasatinib (n=9), or nilotinib (n=6).The median duration of ponatinib treatment was 14.5 months (2.4-26.3). Only 1 grade 3 cardiovascular event (aphasia) occurred.Data on toxicity prevention including echocardiography, duplex or ankle brachial index of lower extremities, blood sugar metabolism, and fundoscopy will be presented.Conclusion In patients failing first-line second-generation TKI therapy with nilotinib or dasatinib, we observed robust responses and fewer cardiovascular events in patients treated with a reduced dose of ponatinib. Importantly, strict preventative measures of cardiovascular risk factors may reduce the occurrence of such AEs, providing durable disease control.

Olverembatinib, a novel BCR-ABL tyrosine kinase inhibitor, has anti-tumor activity in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia cells(CML) and tumor models, is currently approved for treating resistant CML patients with T315I mutation by the National Medical Products Administration in China, and in phase Ib clinical trials in the US for ponatinib resistant and/or intolerant CML patients...Of 5 patients with ph+ ALL that relapsed after transplantation, 1patient was treated with blinatumomab and olverembatinib, 2 patients were treated with intensive chemotherapy and olverembatinib followed by donor lymphocyte infusion(DLI), The treatment for the remaining 2 patients was Anti-CD19 chimeric antigen receptor T cell (CAR-T) technology followed by olverembatinib, and this 5 Ph+ ALL patients achieved complete molecular remission(CMR). In addition, treatment-related adverse reactions included cytopenias, skin pigmentation, proteinuria and high triglycerides, all grades less than 2. No deaths have occurred.Conclusion Olverembatinib-based regimens show encouraging activity and safety in very heavily pre-treated, advanced Ph+ leukemias.

The previous TKI treatment consisted of imatinib (n=34), nilotinib (n=6), dasatinib (n=34), two lines of imatinib because of pregnancy (n=1), imatinib dasatinib (n=3), imatinib nilotinib (n=1), dasatinib imatinib (n=1), dasatinib ponatinib (n=1), imatinib dasatinib nilotinib (n=1), nilotinib dasatinib nilotinib (n=1), imatinib dasatinib imatinib dasatinib (n=1), imatinib nilotinib dasatinib dasatinib+asciminib (n=1), imatinib nilotinib dasatinib nilotinib (n=1). 6 patients had a follow-up of more than 8 years without treatment, which is still ongoing. These data confirm the applicability and safety of TKI discontinuation.

P1/2, N=68, Active, not recruiting, Takeda | Recruiting --> Active, not recruiting

However, the multi-tyrosine kinase inhibitors ponatinib and dasatinib, as well as the anti-sarcoma compound trabectedin, revealed promising activity against SFT growth. In conclusion, this study identified novel trabectedin-based treatment combinations with clinically approved tyrosine kinase inhibitors, using two newly established NAB2-STAT6 fusion-positive cell models. These findings can be the basis for anti-SFT drug repurposing approaches in this rare and therapy-refractory disease.

Combination experiments with CEL_Amide and BCR::ABL TKIs imatinib, dasatinib, nilotinib, and ponatinib were synergistic for the treatment of both TOM-1 and BV-173 cells. CDKN2A/BCR::ABL1+ B-ALL cells were transplanted in mice, which were treated with combinations of CEL_Amide and nilotinib or ponatinib, which significantly prolonged their survival. Altogether, the LIMKi CEL_Amide yields activity in Ph+ ALL models when combined with BCR::ABL-targeting TKIs, showing promising synergy that warrants further investigation.

We examined the cost-effectiveness ratio (CER) of dasatinib and ponatinib for Ph AL and the cost-effectiveness of gilteritinib and quizartinib for FLT3-AML in elderly patients. Although TKIs and FLT3 inhibitors have an inferior CER than does conventional CT, their promising survival benefit with better QOL can offer a profound advantage. TKI or FLT3 inhibitor monotherapy is recommended as an alternative treatment option for unfit (vulnerable) elderly patients with Ph AL or FLT3-AML.

P1, N=193, Active, not recruiting, Mirati Therapeutics Inc. | Unknown status --> Active, not recruiting | Trial completion date: Nov 2020 --> Dec 2022 | Trial primary completion date: Aug 2020 --> Apr 2022

Although patient numbers were small, this real-world evidence study with patients with CML confirms that ELN guidelines are generally implemented in Swiss clinical practice, with a large proportion of patients achieving ELN 2013 milestones. While TKI use involved all inhibitors approved at the time of the study, an unexpectedly high number of TKI therapy switches suggests a clear difference in TKI use between registration trials and clinical practice.