Targeted Tyrosine Kinase Inhibitor Therapy Research Articles

Disparities in frontline treatment and overall survival in the era of targeted tyrosine kinase inhibitor therapy for chronic myeloid leukemia: 2004-2021.

11187 Background: The treatment of chronic myeloid leukemia (CML) was revolutionized in 2001 with the introduction of the BCR::ABL tyrosine kinase inhibitor (TKI), imatinib. In 2006, dasatinib was approved, followed by nilotinib in 2007. Two other TKIs, bosutinib & ponatinib were approved in 2012, followed by the allosteric ABL myristoyl inhibitor asciminib in 2021, providing multiple options for patients (pts) who have refractory disease. In this study we examine how survival has improved in CML pts with the availability of multiple TKI’s and identify disadvantaged socioeconomic & demographic groups which continue to have disparate survival. Methods: The National Cancer Database was used to identify CML pts diagnosed (dx) from 2004-2021. Demographic, treatment, & overall survival (OS) were compared by era of TKI availability, with pts dx from 2004-2005 considered to be treated in the imatinib era, 2006-2011 for dasatinib & nilotinib, 2012-2020 with access to bosutinib & ponatinib, and 2021 for asciminib. Results: Of 44,993 CML pts identified, 55.8% were male & 82.5% were White, with median age of 58 years. The portion of pts who were untreated (due to contraindication or early death) decreased by each time period, from 17.8% in the imatinib era to only 7.8% in 2021. The rate of upfront transplant decreased from 2.5% from 2004-2005, to 0.8% in 2021. For dx 2004-2005 median OS was 11.5 yrs (95% CI 10.6-12.5). This increased to 13.6 yrs (CI 13.1-14.1), with age-adjusted hazard ratio (HR) of 0.86 (CI 0.81-0.91) for pts dx 2006-2011, with median OS unreached for 2012-2020, HR 0.67 (CI 0.63-0.71, p<0.001); referenced to 2004-2006. Survival at 1-, 5- & 10-yrs was improved for each subsequent time period of dx, with 5-yr OS of 65%, 71%, & 76%, respectively, p<0.001. On multivariate cox regression adjusted for yr of dx, features associated with reduced OS included age (HR 1.06 [95% CI 1.05-1.06], p<0.001 for each yr), Black race (HR 1.11 [95% CI 1.05-1.18], p<0.001), increased comorbidity index (HR 1.94 [95% CI 1.84-2.04], p<0.001 for index ≥2), uninsured (HR 2.20 [95% CI 2.01-2.41], p<0.001), or insured through Medicaid (HR 2.40 [95% CI 2.23-2.58], p<0.001). Conclusions: Survival for CML pts has significantly improved during the last 20 yrs with the availability of each additional TKI, likely related to increased treatment options for pts with resistance or intolerance. Additional TKI options, particularly approval of ponatinib for patients with T315I mutation, have a secondary benefit of decreasing the utilization of allogenic transplant. Though survival has improved for all pts, pts from traditionally underserved populations, including pts who are underinsured or from racial minority groups, have reduced OS. Continued advances in treatment & efforts to improve access to care for underserved populations is vital to achieve equitable survival outcomes in CML.

Disparities in Frontline Treatment and Overall Survival in the Era of Targeted Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia: 2004-2021

Disparities in Frontline Treatment and Overall Survival in the Era of Targeted Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia: 2004-2021

Radiomics of metastatic brain tumor as a predictive image biomarker of progression-free survival in patients with non-small-cell lung cancer with brain metastasis receiving tyrosine kinase inhibitors

Background and objectiveEpidermal growth factor receptor (EGFR)–targeted tyrosine kinase inhibitors (TKIs) are the first-line therapy for EGFR-mutant non-small-cell lung cancer (NSCLC). Early prediction of treatment failure in patients with brain metastases treated with EGFR–TKIs may help in making decisions for systemic drug therapy or local brain tumor control. This study examined the predictive power of the radiomics of both brain metastasis tumors and primary lung tumors. We propose a deep learning based CoxCC model based on quantitative brain magnetic resonance imaging (MRI), a prognostic index and clinical data; the model can be used to predict progression-free survival (PFS) after EGFR–TKI therapy in advanced EGFR-mutant NSCLC. MethodsThis retrospective single-center study included 271 patients receiving first-line EGFR–TKI targeted therapy in 2018–2019. Among them, 72 patients who had brain metastases before receiving first-line EGFR–TKI treatment. Three radiomic features were extracted from pretreatment brain MRI images. A CoxCC model for the progression risk stratification of EGFR–TKI treatment was proposed on the basis of MRI radiomics, clinical features, and a prognostic index. We performed time-dependent PFS predictions to evaluate the performance of the CoxCC model. ResultsThe CoxCC model based on a prognostic index, clinical features, and radiomic features of brain metastasis exhibited higher performance than clinical features combined with indexes previously proposed for determining the prognosis of brain metastasis, including recursive partitioning analysis, diagnostic-specific graded prognostic assessment, graded prognostic assessment for lung cancer using molecular markers (lung-molGPA), and modified lung-molGPA, with c-index values of 0.75, 0.67, 0.66, 0.65, and 0.65, respectively. The model achieved areas under the curve of 0.88, 0.73, 0.92, and 0.90 for predicting PFS at 3, 6, 9 and 12 months, respectively. PFS significantly differed between the high- and low-risk groups (p < 0.001). ConclusionsFor patients with advanced-stage NSCLC with brain metastasis, MRI radiomics of brain metastases may predict PFS. The CoxCC model integrating brain metastasis radiomics, clinical features, and a prognostic index provided reliable multi-time-point PFS predictions for patients with advanced NSCLC and brain metastases receiving EGFR–TKI treatment.

A phase 1, multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of HS-10382 (TERN-701) in patients (pts) with chronic myeloid leukemia (CML).

TPS7081 Background: There is a need for new treatment options for pts with CML who are intolerant/resistant to currently available BCR-ABL1 ATP-binding site targeted tyrosine kinase inhibitors (TKIs). HS-10382 (TERN-701) is a potent, oral small molecule allosteric inhibitor of BCR-ABL. By binding to the myristoyl site of the BCR-ABL1 protein, HS-10382 (TERN-701) locks BCR-ABL1 into an inactive conformation. This results in a mutation-driven resistance profile different from that of ATP-binding site TKIs, providing potential for both monotherapy and combination therapy with ATP-binding site TKIs. In preliminary nonclinical assays, HS-10382 (TERN-701) was highly potent against wild type BCR-ABL1 as well as most common mutations acquired by pts treated with second generation active site TKIs. This ongoing first-in-human phase 1 study is evaluating HS-10382 (TERN-701) in pts with CML. Methods: Eligible adult CML chronic phase (CP) or advanced phase (AP) pts who are resistant or intolerant to prior BCR-ABL-1 TKI therapy are enrolled in an open-label Phase 1 study to evaluate the safety, tolerability, PK and efficacy of HS-10382 (TERN-701). This study is being conducted in two parts: Part 1 dose escalation utilizing a rolling six design and Part 2 dose expansion. In the dose escalation stage, CML-CP/AP pts who are resistant or intolerant to prior BCR-ABL-1 therapy are being enrolled to determine the maximum tolerated dose (MTD) or maximum applicable dose. Doses selected from the escalation part will be evaluated in the expansion stage in CML-CP pts who are resistant or intolerant to prior BCR-ABL-1 TKI therapy and have no T315I mutation. All pts will be carefully followed for adverse events for the duration of study treatment and for 28 days after the last dose of study drug. Pts will be permitted to continue therapy with assessments for progression if the study drug is well-tolerated and the pt has no objective evidence of disease progression. This study is ongoing (enrollment underway for Part 1, dose 3 as of February 2023) with 7 participating study sites in China. Clinical trial information: NCT05367700 .

Integrated survival analysis.

e14695 Background: Clinical trial efficacy may be determined by the primary endpoint(s) of median progression free survival (mPFS) and/or median overall survival (mOS) from the Kaplan-Meier estimate, and secondary endpoints of overall response rate (ORR) and duration of response (DOR). In the treatment of metastatic cancers, single agent immunotherapy tends to have lower ORR and longer DOR in comparison to chemotherapy or targeted tyrosine kinase inhibitor therapy, which tends to have higher ORR and shorter DOR. This leads to intersecting or crossing Kaplan-Meier survival curves, which are harder to interpret. In immunotherapy trials, mPFS is a poor surrogate for mOS, and both may underrepresent the clinical benefit over time. Methods: We aimed to develop novel metrics that more effectively represent the Kaplan-Meier estimate. The graphical curve of the Kaplan-Meier estimate may be represented by the equation as a function of time. The integration of f ( x), which mathematically represents the area under the curve and clinically the cumulative or integrated survival benefit with time, is: ∫0t f( x) dx = F(t) − F(0). Kaplan-Meier curve equation with constants C and A may be approximated by: ∫0t C e-A x dx = C e-A t ]0 t = C( e-A t – 1). The average integrated clinical benefit with time is: 1/ t ∫0t f( x) dx = [ F( t) − F(0)]/ t. Results: The Phase 3 KeyNote-061 trial of metastatic gastric cancer treated with single agent Pembrolizumab immunotherapy versus Paclitaxel chemotherapy was use for integrated PFS and iOS calculation. The Kaplan-Meier curves intersected or crossed in KeyNote-061 trial. We show the established ORR, mPFS, mOS, DOR. Integrated PFS (iPFS) and iOS were calculated with greater increase in iOS and much less decrease in iPFS for Pembrolizumab than Paclitaxel treatment. Conclusions: Integrated survival is a novel analysis that integrate the Kaplan Meier estimates and better represent the entire median survival and drug DOR may be combined into a single useful metric for overall clinical benefit. [Table: see text]

Predicting survival of NSCLC patients treated with immune checkpoint inhibitors: Impact and timing of immune-related adverse events and prior tyrosine kinase inhibitor therapy.

Immune checkpoint inhibitors (ICIs) produce a broad spectrum of immune-related adverse events (irAEs) affecting various organ systems. While ICIs are established as a therapeutic option in non-small cell lung cancer (NSCLC) treatment, most patients receiving ICI relapse. Additionally, the role of ICIs on survival in patients receiving prior targeted tyrosine kinase inhibitor (TKI) therapy has not been well-defined. To investigate the impact of irAEs, the relative time of occurrence, and prior TKI therapy to predict clinical outcomes in NSCLC patients treated with ICIs. A single center retrospective cohort study identified 354 adult patients with NSCLC receiving ICI therapy between 2014 and 2018. Survival analysis utilized overall survival (OS) and real-world progression free survival (rwPFS) outcomes. Model performance matrices for predicting 1-year OS and 6-month rwPFS using linear regression baseline, optimal, and machine learning modeling approaches. Patients experiencing an irAE were found to have a significantly longer OS and rwPFS compared to patients who did not (median OS 25.1 vs. 11.1 months; hazard ratio [HR] 0.51, confidence interval [CI] 0.39- 0.68, P-value <0.001, median rwPFS 5.7 months vs. 2.3; HR 0.52, CI 0.41- 0.66, P-value <0.001, respectively). Patients who received TKI therapy before initiation of ICI experienced significantly shorter OS than patients without prior TKI therapy (median OS 7.6 months vs. 18.5 months; P-value < 0.01). After adjusting for other variables, irAEs and prior TKI therapy significantly impacted OS and rwPFS. Lastly, the performances of models implementing logistic regression and machine learning approaches were comparable in predicting 1-year OS and 6-month rwPFS. The occurrence of irAEs, the timing of the events, and prior TKI therapy were significant predictors of survival in NSCLC patients on ICI therapy. Therefore, our study supports future prospective studies to investigate the impact of irAEs, and sequence of therapy on the survival of NSCLC patients taking ICIs.

Trends in Frontline Treatment and Overall Survival in the Era of Targeted Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia

Introduction The treatment of chronic myeloid leukemia (CML) was revolutionized in 2001 with the introduction of the BCR-ABL tyrosine kinase inhibitor (TKI), imatinib. In 2006, dasatinib was approved, shortly followed by nilotinib in 2007 for the treatment of CML patients (pts) who developed resistance or intolerance to imatinib. In the following years, dasatinib and nilotinib were approved for newly diagnosed CML. Two other TKIs, bosutinib and ponatinib were approved in 2012. Dasatinib, nilotinib and bosutinib are effective against all imatinib resistant mutations except the gatekeeper mutation, T315I. Ponatinib approval provided a TKI option for pts with T315I mutation. In this study we examine how survival has improved in CML pts over time with the availability of multiple TKI options and identify traditionally disadvantaged socioeconomic and demographic groups which continue to have disparate survival outcomes. Methods The National Cancer Database was used to identify CML pts by histology code 9863 & 9875, who were diagnosed between 2004-2019. Demographic and treatment characteristics were compared by era of TKI availability. Pts diagnosed from 2004-2005 were considered to be treated in the imatinib era, 2006-2011 as having access to dasatinib and nilotinib, and from 2012 on to have access to bosutinib and ponatinib. Pts who received allogeneic transplant were excluded in survival analysis. Kaplan Meier and Cox regression analysis were used to compare overall survival (OS) for the entire cohort and by year (yr) of diagnosis, with adjustment by age, Charleson-Deyo comorbidity, race, sex, insurance, and quartile of income and education level of the patient's zip code to identify demographic and socioeconomic features associated with poor survival outcomes. Results Of the 38,763 CML pts identified, 55.5% were male and 81% were white, with a median age of 57 yrs (interquartile range 44-70). The portion of pts who were untreated, either due to comorbidity, death, or contraindication, decreased from 17.4% in the imatinib era to only 8.6% from 2012 on, p<0.001. Though the rate of upfront transplant was low (1.6%), it decreased with the advent of new therapies, from a rate of 3.4% from 2004-2005, to 1.4% from 2012 on, p<0.001. The median OS of CML pts since 2004 is 14.4 years (yrs) (95% confidence interval (CI) 14.0-14.9). For pts diagnosed from 2004-2005 median OS was 12.0 yrs (95% CI 11.1-13.0). This increased to 13.8 yrs (95% CI 13.4-14.2), with a hazard ratio (HR) of 0.88 (95% CI 0.84-0.94) for pts diagnosed 2006-2011 when referenced to the initial time period, p<0.001. Median OS was not reached for the latest time period, with a HR of 0.71 (95% CI 0.66-0.75, p<0.001) referenced to 2004-2006. Survival at 1-, 5- & 10-yrs was improved for each subsequent time period of diagnosis, with a 5-yr OS of 66%, 71%, and 76% for each subsequent diagnosis period, p<0.001. On multivariate cox regression adjusted for yr of diagnosis, features associated with reduced OS included age (HR 1.05 [95% CI 1.05-1.06], p<0.001), increased comorbidity burden (HR 1.34 [95% CI 1.30-1.37], p<0.001), uninsured status (HR 1.95 [95% CI 1.75-2.16], p<0.001), Medicaid (HR 2.2 [95% CI 2.0-2.4], p<0.001), and living in a zip code with median income in the lowest quartile (HR 1.15 [95% CI 1.06-1.25], p<0.001) and lowest education quartile (HR 1.19 [95% CI 1.10-1.29], p<0.001). Features associated with improved survival include female sex (HR 0.80 [0.77-0.84], p<0.001), and subsequent diagnosis year (HR 0.96 [95% CI 0.95-0.96], p<0.001). Discussion Overall survival for CML pts has significantly improved during the last 18 years, with improvements seen with the availability of each additional TKI. While treatment data is very limited in this dataset, this improvement is likely related to increased availability of multiple TKIs for pts with resistance or intolerance to prior TKI therapies. Additional TKI options, particularly approval of ponatinib for pts with T315I mutation also have a secondary benefit of decreasing the utilization of allogenic transplant, a high-risk procedure in itself. Though survival has improved for all pts, pts from traditionally underserved populations, including those who are underinsured or from low-income or low-education areas, have reduced survival. Continued advances in treatment and efforts to improve access to care for underserved populations is vital in the goal to achieve equitable survival outcomes in CML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chronic Myeloid Leukemia: who should get a treatment-free trial and how?

Treatment with a BCR::ABL1 targeted tyrosine kinase inhibitor (TKI) has afforded a near-normal life expectancy for most patients with chronic myelogenous leukemia (CML). Approximately half of CML patients achieve a deep molecular response with TKI therapy and can discontinue treatment. In these patients, the CML can remain in prolonged remission, and patients can experience an improvement in quality of life.&#x0D; The European Leukemia Network (ELN) and the National Comprehensive Cancer Network (NCCN) provide the most up-to-date frameworks for treatment-free trials (TFTs), reflecting best practices from over 13 clinical trials published since the concept first entered the CML vernacular around 2010. Provincial guidelines also exist, such as those published in Quebec by the Groupe Québécois de Recherche en LMC-NMP (the Chronic Myeloid Leukemia and Myeloproliferative Neoplasms Quebec Research Group).&#x0D; The discontinuation of therapy for patients with CML in deep remission marks a potential shift from the management of CML as a chronic illness to the potential for a curative approach to CML. However, for now, only 50% of eligible patients have undergone successful TFT; optimal patient selection and monitoring is required to ensure the best outcomes with such a management strategy.

Abstract 3260: Enhanced lineage plasticity in RTK-independent TKI-resistant EGFR-mutant NSCLC

Abstract Background: Resistance to targeted tyrosine kinase inhibitors (TKI) inevitably develops in metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Resistance mechanisms are diverse, and mechanisms beyond receptor tyrosine kinase (RTK) pathway mutations are poorly understood. We hypothesized that the use of osimertinib as first-line therapy is increasing the prevalence of RTK-independent resistance mechanisms, and that RTK-independent resistant tumors undergo enhanced tumor cell lineage plasticity as an escape mechanism to EGFR TKI therapy. Methods: We identified patients who developed osimertinib resistance (OR) after first line (1L, n=54) and second line (2L, n=42) treatments and determined the resistance mechanisms based on clinical sequencing and histopathology. We also performed single-cell RNA-seq of 24 samples from 13 patients with EGFRm NSCLC at TKI treatment-naïve (TN, n=2), residual disease (RD, n=4), and progression disease (PD, n=7) stages. Results: Compared to 2L OR tumors, 1L OR tumors had increased RTK-independent mechanisms of resistance (76% vs. 46%, p=0.002), including 8% with small cell transformation (n=4), 2% with squamous transformation (n=1) and 66% with unknown mechanisms (n=34). To understand inter- and intra-tumor heterogeneity, we analyzed transcriptomic profiles of 76,266 single cells. Lung developmental lineages were assigned to 10,250 EpCAM+ cells, including 4,735 cells classified as malignant cells by inferCNV and RTK signaling analysis. In the two EGFRm TN tumors, the malignant cells demonstrated bronchoalveolar lineage and moderate EGFR expression. In the TKI resistant cases (PD, n=7), both RTK-dependent and RTK-independent resistance were observed. The RTK-dependent tumors (EGFR T790M n=1; ERBB2 amplification n=1) demonstrated preserved bronchoalveolar lineage identity. In the RTK-independent resistant tumors (n=5), one had complete lineage switch from epithelial to small cell neuroendocrine and very low expression level of EGFR. The remaining 4 PD tumors displayed varying expression of epithelial-to-mesenchymal transformation (EMT) features. One tumor had sarcomatoid histology and a high proportion of cells having positive VIM expression (84%) and 92% of cells having complete loss of NAPSA expression; 3 tumors had partial EMT demonstrated by heterogeneous proportion of cells having VIM expression (18-56%) and loss of NAPSA (26-67%). Interestingly, some of the cells with EMT and partial-EMT had moderate levels of EGFR expression, similar to the levels in the TN tumors. Conclusion: With osimertinib use at 1L, the incidence of RTK-independent resistance has increased to become the dominant mechanism, whereas RTK-dependent resistance has decreased. Increased lineage plasticity (small cell neuroendocrine, squamous and EMT) potentially serves as an RTK-independent TKI-resistance mechanism in EGFRm NSCLC. Citation Format: Xiuning Le, Ruiping Wang, Natalie Vokes, Yasir Elamin, Neda Kalhor, Daniel McGrail, Yuanxin Xi, Santiago Treviño III, Lingzhi Hong, Robyn Du, George Blumenschein, Carl Gay, Marcelo Negrao, Mehmet Altan, Hai Tran, Limei Hu, Jing Wang, Simon Heeke, Monique Nilsson, Jacqulyne Robichaux, Minghao Dang, Guangchun Han, Lauren Byers, Anne Tsao, Boris Sepesi, Chantale Bernatchez, Jianjun Zhang, Linghua Wang, John Heymach. Enhanced lineage plasticity in RTK-independent TKI-resistant EGFR-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3260.

In Vitro Cell Density Determines the Sensitivity of Hepatocarcinoma Cells to Ascorbate.

Hepatocellular carcinoma (HCC) is the primary histological subtype of liver cancer, and its incidence rates increase with age. Recently, systemic therapies, such as immune checkpoint inhibitors, monoclonal antibodies, and tyrosine kinase inhibitors (TKIs), have been more beneficial than conventional therapies for treating HCC. Nonetheless, the prognosis of late-stage HCC remains dismal because of its high recurrence rates, even with substantial advances in current therapeutic strategies. A new treatment, such as a combination of current systemic therapies, is urgently required. Therefore, we adopted a repurposing strategy and tried to combine ascorbate with TKIs, including lenvatinib and regorafenib, in HepG2 and Hep3B cells. We investigated the potential functional impact of pharmacological concentrations of ascorbate on the cell-cycle profiles, mitochondrial membrane potential, oxidative response, synergistic effects of lenvatinib or regorafenib, and differential responsiveness between HepG2 and Hep3B cells. Our data suggest that the relative level of cell density is an important determinant for ascorbate cytotoxicity in HCC. Furthermore, the data also revealed that the cytotoxic effect of pharmacological concentrations of ascorbate might not be mediated via our proposed elevation of ROS generation. Ascorbate might be involved in redox homeostasis to enhance the efficacy of TKIs in HepG2 and Hep3B cells. The synergistic effects of ascorbate with TKIs (lenvatinib and regorafenib) support their potential as an adjuvant for HCC targeted TKI therapy. This research provides a cheap and new combinatory therapy for HCC treatment.

NTRK-rearranged spindle cell neoplasm of the lower extremity: radiologic-pathologic correlation.

Neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell neoplasm is a recently characterized soft tissue tumor and has been classified as provisional by the World Health Organization. Detection of the genetic rearrangement is important because these tumors are amenable to targeted tyrosine kinase inhibitor therapy, which can play a key role in patients with unresectable or advanced disease. Although the spectrum of histopathology associated with this entity is broad, one notable feature is the infiltrative growth pattern, which is most reminiscent of lipofibromatosis-like neural tumor. Description of their diverse histologic attributes has aided recognition, but so far little attention has been paid to correlating the gross appearance and imaging features of these lesions. In this report, we describe the clinical, imaging, histopathological, and genetic features of a soft tissue NTRK-rearranged spindle cell neoplasm. Inclusion of this more recently identified entity into the imaging differential of tumors with intratumoral relatively hypovascular nodules and infiltrative margins is important because testing for NTRK rearrangement is not routinely performed.

Upfront Targeted Tyrosine Kinase Inhibitor Therapy Improves Outcome in Patients with Myeloid/Lymphoid Neoplasms with Eosinophilia

▪BackgroundTo recognize the growing list of recurrent genetically defined eosinophilia driven by constitutively active tyrosine kinase fusion genes, the World Health Organization (WHO) created a provisional entity of myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) with rearrangement of PFGFRA, PDGFRB or FGFR1, or with PCM1- JAK2. These eosinophilic disorders are clinically and genetically heterogeneous. Annotating additional somatic mutations and relevant clinical features may have an impact on treatment selection and refine prognostication. In this study, we aim to describe the clinicopathologic characteristics and outcome with upfront targeted tyrosine kinase inhibitor (TKI) therapy in patients (pts) with MLN-Eo.MethodsWe retrospectively reviewed clinical and molecular data on 39 pts with newly diagnosed MLN-Eo with PDGFRA, PDGFRB, FGFR1, JAK2 or FLT3 rearrangement at Moffitt Cancer Center, Duke Cancer Center, and the UCSF Comprehensive Cancer Center. Clinical data was abstracted in accordance with institutional review board approved protocol. Pts were divided to two categories based on morphologic classification of the disease at diagnosis or at transformation: chronic phase and blastic phase disease. Each category was then divided into two subgroups: Cohort A) upfront TKI +/- other systemic therapy and Cohort B) no upfront TKI arm. Median time from chronic phase disease to blastic phase and median overall survival (mOS) (in whole cohort) were calculated using Kaplan Meier method and compared with log-rank test. Cox proportional hazards (PH) model was used to calculate hazard ratio (HR) in univariate analyses.ResultAmong the 39 pts included in the analysis, 22 pts had PDGFRA fusion (20)/activating mutations (2), 4 had PDGFRB, 7 had FGFR1, 2 had JAK2 (PCM1-JAK2 and BCR-JAK2), and 4 had FLT3 (3 ETV6-FLT3 and 1 FLT-3-TRIP11). Median age at first diagnosis of myeloid/lymphoid neoplasm was 54.5 years (range 9-76). Seventy-seven percents (30/39) were male. Chronic eosinophilic leukemia (CEL) was the most common clinical diagnosis and occurred in 11 pts (28%). Seven (18%) pts had both myeloid and lymphoid neoplasms either concurrently or sequentially. Sixteen (41%) pts presented with de-novo blastic phase at time of initial diagnosis.Among 23 pts who presented with chronic phase disease at diagnosis, nine patients did not receive TKI upfront. Five out of the nine patients (55%) developed blastic phase disease with a median follow up of 73 months. The median time to blastic phase was 45 months. No patients in the upfront TKI arm (n=14) had blastic transformation during follow up (Figure 1a, p<0.001).Among 21 pts who had blastic phase disease (16 pts with de-novo diagnosis and 5 pts with blastic transformations), 95% of them (20/21 pts) had treatment information and follow-up data available. At a median follow up of 37 months, 11 pts (55%) were deceased, and median OS was 44 months. Seven pts (35%) underwent allogeneic stem cell transplant (alloHSCT). Four patients received upfront TKI, and all of them achieved complete remission and were alive at the time of the study (Figure 1b). Among those pts, 2 had FLT3-ETV6 rearrangement, 1 with PDGFRA rearrangement and 1 with FGFR1 rearrangement. Two pts received single agent TKI only and two pts received TKIs followed by alloHSCT.In the univariate analysis, upfront TKI use was significantly associated with improved OS (HR 0.067, 95% CI [0.009-0.512], p=0.009). Complex cytogenetics at the time of initial diagnosis was associated with inferior OS, though statistical significance was not reached (table II).ConclusionOur data suggests that upfront TKI therapy is associated improved survival outcomes in pts with MLN-eo and is effective in preventing blastic transformation from chronic phase disease. As proposed, the driver oncogene most likely occurs in hematopoietic stem cells/progenitor cells in this entity. Upfront TKI can potentially suppress, even in some cases eradicate the malignant clone. The study is limited due to small sample size and retrospective nature, and larger study is needed to validate our observation. [Display omitted] DisclosuresSokol: Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Membership on an entity's Board of Directors or advisory committees. Shah: Novartis: Consultancy, Other: Expenses; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy. Lancet: Agios: Consultancy; AbbVie: Consultancy; Celgene/BMS: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; BerGenBio: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Jazz: Consultancy. Kuykendall: Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BluePrint Medicines: Honoraria, Speakers Bureau; Prelude: Research Funding; Abbvie: Honoraria; Incyte: Consultancy; Novartis: Honoraria, Speakers Bureau; PharmaEssentia: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; CTI Biopharma: Honoraria. Padron: Stemline: Honoraria; BMS: Research Funding; Kura: Research Funding; Blueprint: Honoraria; Incyte: Research Funding; Taiho: Honoraria.

Immune Checkpoint Blockade in Oncogene-Driven Non-Small-Cell Lung Cancer.

Patients with oncogene-driven lung cancer have limited therapeutic options after progressing on their targeted tyrosine kinase inhibitor (TKI) therapy. Given the growing role of immune checkpoint inhibitor (ICI) therapy in the treatment of lung cancer, oncogene-driven cancer has warranted further evaluation regarding ICI therapy. However, initial ICI studies have suggested that ICI monotherapy is not only lacking in efficacy, but that it may be less tolerable in oncogene-driven non-small-cell lung cancer (NSCLC). We performed a detailed review of the literature using Pubmed, and present the current and impactful findings here. Studies evaluating the use of concurrent ICI therapy and TKI therapy have also suggested increased toxicity and lack of increased activity in these patients. Larger studies have suggested that the sequence of ICI therapy and TKI, such as utilizing ICI therapy after TKI as opposed to before TKI, may play a role in reducing toxicity (hepatotoxicity, pneumonitis); however, these studies are limited in number. Novel methods of patient selection, including low tumor mutational burden, inflamed phenotyping, and high CD8 + tumor infiltrating lymphocytes, may aid in determining ideal patients to give ICI therapy. Novel therapeutic combinations including the addition of anti-VEGF (vascular endothelial growth factor) therapy or radiotherapy show promising findings for these patients. Given the growing unmet need for therapeutic options in patients with oncogene-driven NSCLC who have failed TKI therapy, further research is warranted.

ED08.04 Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC

ED08.04 Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC

Outcomes of Adult Philadelphia Positive Acute Lymphoblastic Leukemia Patients Treated with Pediatric Multi-Agent Chemotherapy and Imatinib and the Impact of Residual Disease Monitoring on Survival

The prognosis of Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) has improved markedly after the introduction of BCR ABL1 targeted tyrosine kinase inhibitors (TKI). With the addition of upfront TKI, ~90 % of patient will achieve complete remission (CR). Allogenic stem cell transplant (alloSCT) remains the cornerstone of post remission therapy based on large trials that predate the introduction of TKIs. This approach has since been challenged in more recent studies in which similar outcomes were observed with lifetime TKI therapy. Several reports have suggested a correlation between achieving a molecular negativity with chemotherapy + TKI and long term outcome, in patients who did not receive alloSCT, suggesting that a monitoring strategy might spare some patients with excellent response to chemotherapy and TKI the toxicity of (alloSCT), and with comparable outcome.We previously reported good overall survival and event free survival in patients treated with a TKI-modified version of the Dana Farber Cancer Institute (DFCI) pediatric ALL protocol. In this retrospective analysis we compared the long term outcome of Ph+ ALL patients who were transplanted and those who were not, mainly due to the unavailability of a donor. In addition, we reviewed the effect of residual disease monitoring (RDM) at post induction, 3, 6, 9 and 12 months, and correlated the achievement of complete and major molecular responses with survival.In the present study, 167 patients diagnosed with Ph+ ALL in our center were evaluated from year 2001-2015. One hundred and thirty three (133) received DFCI chemotherapy + imatinib. One hundred and nineteen (119; 89%) patients achieved CR following the induction phase. Fifty nine (59; 44.3 %) subsequently received an allogenic stem cell transplant from a sibling or matched unrelated donor, leaving 74 patients who were not transplanted and were evaluated for RDM.While there was no significant difference between the overall survival (OS) for the transplanted and not transplanted cohorts (median survival 3.3 years vs 5.3 years, and 5 year- OS 40% vs 50 %, respectively; p value = 0.40), there was an improved relapse free survival (RFS) in the transplanted group (5- year RFS, 55% vs 75%, respectively; p value= 0.033).Achieving CMR with un-detectable transcripts post-induction, and at 3 and 6 months, showed superior OS compared to those not achieving CMR (p values of 0.029, 0.0086 and 0.028, respectively), whereas superior RFS was associated with molecular negativity at 3, 6 and 9 months ( p values of 0.0076,0.0023 and 0.03, respectively). Molecular negativity at 12 months had no impact on survival.In conclusion, our data confirm that while the RFS of patients with Ph+ ALL who did not undergo alloSCT as post remission therapy was inferior to that of those who did, OS was similar in the two groups. Monitoring of residual disease at early time points during therapy, and especially at 3 and 6 months, appears to identify patients with a lower chance of relapse who can likely be spared the toxicity of alloSCT, and receive chemotherapy + TKI, followed by ongoing TKI maintenance. Further RDM studies are needed to better stratify such patients and to facilitate alloSCT decision making. [Display omitted] DisclosuresGupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schimmer:Novartis: Honoraria. Schuh:Amgen: Membership on an entity's Board of Directors or advisory committees.

In Vitro Modeling of Ph-like ALL Fusions Identifies Novel Kinase-Domain Mutations As Mode of TKI-Resistance - Implications for Targeted Therapy

IntroductionTreatment-resistant acute lymphoblastic leukemia (ALL) remains a significant clinical issue. Recently, genomic profiling has identified a new subtype of high-risk ALL termed Philadelphia-chromosome-like (Ph-like) ALL, associated with a poor outcome1. Ph-like ALL has a gene expression profile similar to Ph+ (BCR-ABL1+) ALL, characterized by the presence of fusion genes converging on kinase and cytokine signaling pathways. These pathways have been shown to be targetable both in vitro and in case reports by tyrosine kinase inhibitors (TKIs). Despite well-documented efficacy profiles, it is known from TKI-use in chronic myeloid leukemia (CML) andPh+ ALL that resistance is likely, resulting in relapse. Our study aims to model and understand mechanisms of TKI-resistance inPh-like ALL, informing future therapeutic strategies that may avert or overcome resistance, potentially improving patient outcomes.MethodsThree Ph-like ALL lines were generated via retroviral-transduction from plasmids of fusion genes identified in patient cohorts (RANBP2-ABL1, SSBP2-CSF1R and PAX5-JAK2, a kind gift from C. Mullighan)2 into Ba/F3 pro-B cells. Transformation was confirmed via growth of cells in the absence of IL-3. Cells were tested for sensitivity to a panel of TKIs (imatinib, dasatinib, ponatinib, ruxolitinib and BMS-911543) via Annexin-V/7-AAD flow-cytometry and western blotting of downstream effector proteins. Drug resistance was generated through exposure of cells to incrementally increasing concentrations of TKIs over a period of 3-6 months, and cell death LD50 determined byAnnexin-V/7-AAD. Sanger sequencing of the 3-prime partner gene of each fusion was performed to identify the emergence of any kinase-domain mutations.ResultsBa/F3 Ph-like cells demonstrated sensitivity to TKIs at clinically relevant doses (RANBP2-ABL1: 1 μM imatinib, 5 nM dasatinib & 5 nM ponatinib; SSBP2-CSF1R: 1 μM imatinib, 6 nM dasatinib; PAX5-JAK2: 1 μM ruxolitinib & 2 μM BMS-911543). This correlated with decreased levels of relevant downstream signaling proteins including p-Stat5, p-Erk and p-CrkL. TKI-resistant Ph-like ALL lines were tolerant to a significantly higher concentration of TKIs compared to control (RANBP2-ABL1: 10 μM imatinib, 200 nM dasatinib & 200 nM ponatinib; SSBP2-CSF1R: 10 μM imatinib, 200 nM dasatinib; PAX5-JAK2: 10μMruxolitinib & 10μM BMS-911543; Table 1).Sequencing analysis revealed that Ba/F3 RANBP2-ABL1 imatinib and dasatinib resistant cells acquired the clinically significant ABL1 T315I (c.944C>T) kinase-domain mutation, which was ultimately targetable using the third-generation TKI ponatinib (LD50: 25 nM). An ABL1 E255K (c.763G>A) and c-terminus deletion was discovered in the ponatinib-resistant line. In Ba/F3 SSBP2-CSF1R cells, a novel CSF1R L785M (c.2566C>A) mutation was identified in imatinib-resistant cells whereas a deletion spanning the SSBP2-CSF1R breakpoint was acquired in the dasatinib-resistant line. A JAK2 Y931C (c.3286A>G) point mutation previously associated with resistance to ATP-competitive inhibitors was acquired in Ba/F3 PAX5-JAK2ruxolitinib and BMS-911543 resistant lines.ConclusionIn vitro modeling of Ph-like ALL resistance has identified novel kinase domain mutations and deletions that may arise as a result of targeted TKI therapy. In addition, previously identified mutations (T315I and E255K) were also identified. Detection of these mutations is important because alterations in drug-binding regions are known to result in significantly reduced TKI sensitivity, leading clinically to relapse3. This study describes an in vitro platform that can be utilized to inform future clinical approachesincluding the development of rational therapeutic approaches (and/or combination therapies) to avert resistance inPh-like ALL cases treated with rationally targeted therapies.Abbreviations:ABL1 - Abelson tyrosine protein kinase 1CSF1R - Colony stimulating factor 1 receptorJAK2 - Janus kinase 2PAX5 - Paired box 5RANBP2 - RAN-binding protein 2SSBP2 - Single-stranded DNA binding protein 2

Treatment of Lung Cancer Patients With Actionable Mutations in the Intensive Care Unit

BackgroundPatients with advanced-stage non–small-cell lung cancer (NSCLC) have high mortality rates in the intensive care unit (ICU). Although the benefit of chemotherapy for hematologic malignancies in the ICU has previously been explored, few data exist regarding the use of targeted therapy for NSCLC in such settings. The primary objective of the present study was to report our experience with the use of targeted therapy in patients with NSCLC in the ICU. Materials and MethodsWe performed a single-institution, retrospective medical record review. The eligibility criteria included patients with NSCLC with targetable mutations who had received tyrosine kinase inhibitors (TKIs) in the ICU. Cases were identified by queries of our institution's information warehouse database and pharmacy dispensary records from 2010 to 2015. ResultsAll 9 patients who had received TKIs in the ICU had acute respiratory failure. Three patients were successfully extubated after initiating TKI therapy, although 1 required later tracheostomy. TKI therapy stabilized another patient's refractory disseminated intravascular coagulation. The remaining 5 patients showed no measurable clinical improvement and were transitioned to comfort care. The overall ICU mortality rate was 56%. ConclusionPatients with metastatic NSCLC requiring mechanical ventilation have high mortality rates. Cytotoxic chemotherapy is generally contraindicated for poor performance status patients. However, targeted TKI therapy should be considered, given its proven efficacy and few systemic side effects. We recommend the empiric use of targeted therapy for NSCLC patients with suspected and/or known actionable mutations presenting with multifactorial respiratory failure to the ICU, with aggressive determination of the mutation status if not known.

Optimal Molecular Methods in Detecting p190 (BCR-ABL) Fusion Variants in Hematologic Malignancies: A Case Report and Review of the Literature.

Patients with BCR-ABL1 positive hematologic malignancies and Philadelphia-like B-lymphoblastic leukemia (B-ALL) are potential candidates for targeted therapy with tyrosine kinase inhibitors (TKI). Before TKIs, patients with B-ALL had a much worse prognosis and current treatments with targeted TKI therapy have improved outcomes. Thus, the detection of BCR-ABL1 is crucial and a false negative BCR-ABL1 result may adversely affect patient care. We report a case of a 76-year-old male with a new diagnosis of B-ALL who was initially found to be BCR-ABL1 negative by quantitative polymerase chain reaction (PCR). A concurrent qualitative PCR was performed which detected a positive BCR-ABL1 result that was confirmed by a next generation sequencing (NGS) based assay and identified as the rare fusion variant e1a3 of p190BCR-ABL. Based on this result, the patient was placed on dasatinib as a targeted therapy. In the era of molecular diagnostic medicine and targeted therapy, it is essential to have an understanding of the limitations of molecular assays and to follow a comprehensive diagnostic approach in order to detect common abnormalities and rare variants. Incorporating NGS methods in an algorithmic manner into the standard diagnostic PCR-based approach for BCR-ABL1 will aid in minimizing false negative results.

Personalizing Therapy in Advanced Non–Small Cell Lung Cancer

The recognition that non-small cell lung cancer (NSCLC) is not a single disease entity, but rather a collection of distinct molecularly driven neoplasms, has permanently shifted the therapeutic landscape of NSCLC to a personalized approach. This personalization of NSCLC therapy is typified by the dramatic response rates seen in EGFR mutant NSCLC when treated with targeted tyrosine kinase inhibitor therapy and in ALK translocation-driven NSCLC when treated with ALK inhibitors. Targeted therapeutic approaches in NSCLC necessitate consideration of more invasive biopsy techniques aimed at providing sufficient tissue for both histological determination and molecular profiling in all patients with stage IV disease both at the time of diagnosis and at the time of disease progression. Comprehensive genotyping efforts have identified oncogenic drivers in 62% lung adenocarcinomas and an increasing proportion of squamous cell carcinomas of the lung. The identification of these oncogenic drivers and the triage of patients to clinical trials evaluating novel targeted therapeutic approaches will increasingly mold a landscape of personalized lung cancer therapy where each genotype has an associated targeted therapy. This review outlines the state of personalized lung cancer therapy as it pertains to individual NSCLC genotypes.

A Role for Adjuvant RFA in Managing Hepatic Metastases from Gastrointestinal Stromal Tumors (GIST) After Treatment with Targeted Systemic Therapy Using Kinase Inhibitors

This study was designed to assess the role of radiofrequency ablation (RFA) in the multimodality management of gastrointestinal stromal tumors (GIST) in patients undergoing targeted tyrosine kinase inhibitor therapy (TKI) for liver metastases. Outcomes of 17 patients who underwent liver RFA for 27 metastatic GIST after TKI therapy, from January 2004 to March 2012, were retrospectively analyzed. Mean maximum tumor diameter was 2.5 ± 1 cm (range 0.9-4.5 cm). In seven patients (group A), RFA of all residual tumors was performed, with curative intent, and TKI therapy was discontinued. In five patients (group B), RFA of all residual tumors was performed upon achieving the best morphological response with TKI therapy, which was maintained after RFA. In another five patients (group C), RFA was performed on individual liver metastases which were progressive under TKI therapy. All 27 targeted tumors were completely ablated, without local recurrence during the mean follow-up period of 49 months. No major complications occurred. Two minor complications were reported (11 %). Only two patients (both in group C) died at 20 and 48 months. Two-year progression-free survival (PFS) after RFA was 29 % in group A, 75 % in group B, and 20 % in group C. RFA in patients, previously treated with TKI, is feasible and safe. Our data suggest that RFA is a useful therapeutic option in patients with metastatic GIST and should be performed at the time of best clinical response with patient maintained under TKI after the procedure.