Tyrosine Kinase Inhibitors Group Research Articles

Treatment outcomes of differentiated thyroid cancer with distant metastasis improve by tyrosine kinase inhibitors.

In patients with distant metastasis, treatment for differentiated thyroid cancer (DTC) includes complete total thyroidectomy, followed by radioactive iodine (RAI) therapy for metastatic lesions. Tyrosine kinase inhibitor (TKI) treatment is the final treatment option for metastatic lesions, which is incurable with surgery/RAI therapy. The present study examined whether treatment outcomes for DTC in patients with distant metastasis improved following TKI treatment. This study included 147 patients (median age, 71; range, 33-91 years) who underwent surgery in our hospitals and were diagnosed with distant metastasis. Disease progression was observed in 70 patients, of whom 56 were treated with TKI (TKI group); 14 refused TKI treatment or showed no treatment indication [untreated (UT) group]. Disease progression and treatment outcomes were assessed using imaging evaluations. The present study investigated thyroglobulin doubling time (Tg-DT) and Tg antibody presence/absence and their relation to disease progression. Overall survival following disease progression between the two groups was compared. The study included 22 cases of sorafenib, 49 of lenvatinib, and 15 involving TKIs. The mean dosing period for sorafenib was 153 days and for lenvatinib was 462 days. In the TKI group, 16, 26, and 9 patients exhibited partial responses (PRs), stable disease (SD), and progressive disease (PD), respectively, whereas 5 patients were not evaluable. The disease control rate (DCR) (PR+SD) was 75.0%. A total of 16 patients died in the TKI group, whereas 10/14 patients in the UT group died. Survival curves for the groups were significantly different. TKI treatment improved the prognosis of patients with distant metastasis and PD.

Optimal Sequence of Local and EGFR-TKI Therapy for EGFR-Mutant Non-Small Cell Lung Cancer With Brain Metastases Stratified by Number of Brain Metastases

It is unclear whether local therapy (LT) or epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) should take precedence for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases (BMs). The number of BMs is important in the choice of LT, including whole-brain radiation therapy, stereotactic radiosurgery, and surgery. We retrospectively evaluated cases of EGFR-mutant non-small cell lung cancer with BMs from a single site. Patients were divided into 2 groups based on upfront therapy-EGFR-TKI (TKI) or LTs-and subsequently stratified by the number of BMs. Among 176 patients, 61% received upfront EGFR-TKI, and 39% received upfront LT. The number of patients with 1 to 4 BMs was similar (56% vs 52%; P=.61). All patients with 1 to 4 BMs in the LT group, except for surgical cases, received stereotactic radiosurgery (n=31). Among those with ≥5 BMs, most (n=27; 82%) received whole-brain radiation therapy. There was no significant difference in OS between LT and TKI groups (median overall survival, 28 vs 23months; hazard ratio, 0.75; 95% confidence interval, 0.52-1.07). In patients with 1 to 4 BMs, the LT group showed significantly better OS compared with the TKI group (median overall survival, 35 vs 23months; hazard ratio, 0.54; 95% confidence interval, 0.32-0.90). There was no difference in OS between the LT and TKI groups for patients with ≥5 BMs. Multivariable analysis showed that upfront LT yielded significantly better OS for patients with 1 to 4 BMs. Upfront LT followed by EGFR-TKI is more effective than upfront EGFR-TKI for the survival of untreated patients harboring EGFR mutations with 1 to 4 BMs.

Health Care and out-of-Pocket (OOP) Costs Among Medicare Beneficiaries Diagnosed with Chronic Myeloid Leukemia (CML)

Background: Patients with CML require treatment with Tyrosine Kinase Inhibitors (TKIs) for extended periods of time. Given a median age at diagnosis of 67, it is important to understand the costs incurred by the healthcare system (i.e., Medicare) as well as OOP costs incurred by the older CML patients treated with TKI. Previous studies have focused on the younger patient population (<65y) or have used simulation to estimate costs in older adults. We examined costs to Medicare and OOP costs in older CML patients over the first 2y from CML diagnosis in the TKI era.Methods: We used SEER-Medicare data to identify 805 Medicare beneficiaries with incident CML diagnosed between 2007 and 2012 at age >65. A non-cancer Medicare beneficiary sample (n=805) was age, sex, and race frequency-matched to CML patients. Patients were followed until 2y from diagnosis; death or 12/31/2014, whichever came first. Therapeutic exposures were classified as: i) TKIs (Imatinib, dasatinib, nilotinib); ii) other outpatient chemotherapy (CT) without TKI; iii) no treatment. Primary outcomes were healthcare costs reimbursed by Medicare and patient-paid OOP costs. Statistical Analysis: Survival was estimated using Kaplan-Meier method and Cox survival models for adjusted analyses (age, sex, race/ethnicity, treatment, State-buy in coverage and comorbidity). Costs were estimated monthly using generalized linear models with log link (gamma distribution) with bootstrapping to obtain 95% confidence intervals (95%CI). To accommodate censoring, each one-month cost was weighted by inverse probability of not being censored. Monthly costs were summed over 24 mo and averaged to generate annual costs. Predictors of high cost were calculated. Proportion of resource-specific costs (inpatient, outpatient, Part D [prescription drug coverage], home health, and durable medical equipment costs) were compared across treatment categories. Costs were adjusted to reflect 2018 pricing. Models were evaluated for the following 3 eras: 2007-2008 (35%), 2009-2010 (32%), and 2011-2012 (33%).Results: Median age at diagnosis was 76y (66-102) and 5yr survival was 56%. Majority of patients were white (83%) and male (53%); 20% had State-buy in coverage; 36.6% had ≥1 comorbidity. Overall, 52.4% received TKI therapy (43% received Imatinib alone); 27% received other CT; 21% received no treatment. Patients receiving TKI were 57% less likely to die than patients receiving no CT over 3y from diagnosis (HR=0.43, 95%CI, 0.31-0.62), and 65% less likely to die compared to patients receiving other CT (HR=0.36, 95%CI, 0.26-0.49). Medicare costs: Annual Medicare cost/patients was significantly higher for TKI-treated patients ($83,037) vs. patients with other CT ($35,996), patients with no CT ($22,813), and non-cancer controls ($11,506) (Fig 1). The average annual cost/patient increased significantly across the 3 eras for TKI patients ($65,102 to $112,118, p<0.001), but declined for patients treated with other CT ($42,575 to $27,533, p<0.01). Predictors of being >90th percentile in cost ($150,241) included having State-buy in coverage (RR=1.9, p<0.001); and receiving Imatinib alone (RR=5.4, p=0.004), or other multiple TKIs (RR=10.9, p<0.001) (ref grp: no treatment). As shown in Fig 2, the largest proportion of annual costs was Part D (2007-2008: 56%; 2009-2010 60%; 2011-2012: 70%) for the TKI-treated patients but was inpatient care for those treated with other CT. Patient-paid OOP costs: Total annual OOP costs were ~2-times higher for TKI patients vs. other CT patients ($7,404 vs. $3,900), ~3-times higher vs. no CT patients, and 3.5-times higher vs. non-cancer controls (Fig 3). OOP costs for TKI patient remained consistently high across the 3 eras ($6,913 to $7,867), but declined for the other CT group ($4,929 to $2,996).Conclusion: The superior survival in Medicare beneficiaries with CML is accompanied with significantly increasing costs to Medicare. Highest cost groups include those receiving multiple TKIs (i.e., dasatinib or nilotinib along with imatinib). The high costs are largely attributable to Part D in the TKI group. Patients receiving TKIs continue to experience a significant personal financial burden, with 3.5 times higher costs than non-cancer controls. DisclosuresNo relevant conflicts of interest to declare.

Upfront Radiation Therapy with TKI Improved the Intracranial PFS but Not OS in the NSCLC Patients Harboring EGFR Mutation and Brain Metastases

Patients with epidermal growth factor receptor (EGFR) mutation have a 50-70% risk for developing brain metastasis (BM) in non-small cell lung cancer (NSCLC). The tyrosine kinase inhibitors (TKI) have more than 70% intracranial response rate, which challenge the role of upfront intracranial radiation therapy (RT) in BM. Therefore, we conducted a retrospective analysis to demonstrate the value of adding upfront RT to TKI in the treatment. We retrospectively reviewed the patients treated in our institution from 2010 to 2016. Patients had histologically confirmed NSCLC, EGFR mutation, CT or MRI confirmed brain metastases, treated with TKI or upfront RT concurrent with/followed by TKI, were included in this study. Of note, patients had TKI use before brain metastases were excluded. Intracranial progression-free survival (iPFS) was estimated using a competing risks model. Kaplan-Meier analysis was used to analyses iPFS, outcranial PFS (ePFS) and overall survival (OS) and long-rank test was used to compare the data. Among the 93 patients who meet the inclusion criteria, 53 patients received upfront RT while 40 patients received TKI only. The baseline of two groups, including stage at diagnosis, GPA score, symptom from brain metastasis, extracranial metastases, are balanced. The median iPFS for upfront RT and TKI was 27.6 months (95% CI 20.2 to 35.0) and 16.1 months (95%CI 14.6 to17.6), respectively (log-rank p=0.053). Using a competing risks regression model, upfront RT group showed lower intracranial progression after controlling for confounding factors, with adjusted subdistribution hazard ratios of 0.34 (95% CI, 0.17 to 0.67; p = 0.002). There was no difference in the median ePFS time. The number of patients who experience extracranial failure as first site of progression was 26 (49.1%) and 21 (52.5%) in up-front RT and TKI group, respectively. The median OS for upfront RT and TKI was 35.4 months (95% CI 30.3 to 40.6) and 35.8 months (95%CI 27.1 to 44.5), respectively (log-rank p=0.695). After the Cox proportional hazards analysis, only the Osimertinib usage (HR 0.27, 95%CI 0.10 to 0.77) was a protective factor to OS. Upfront RT prolonged the iPFS of the patients but not the OS. Whether upfront RT is the optimal choice for EGFR mutant NSCLC patients with BM still need the evidence from prospect clinical trials.

Osimertinib versus Standard of Care EGFR TKI as First-Line Treatment in Patients with EGFRm Advanced NSCLC: FLAURA Asian Subset

IntroductionHere we report efficacy and safety data of an Asian subset of the phase III FLAURA trial (NCT02296125), which compares osimertinib with standard of care (SoC) EGFR tyrosine kinase inhibitors (TKIs) in patients with previously untreated advanced NSCLC with tumors harboring exon 19 deletion (Ex19del)/L858R EGFR TKI–sensitizing mutations. MethodsEligible Asian patients (enrolled at Asian sites) who were at least 18 years of age (≥20 years in Japan) and had untreated EGFR-mutated advanced NSCLC were randomized 1:1 to receive osimertinib (80 mg, orally once daily) or an SoC EGFR TKI (gefitinib, 250 mg, or erlotinib, 150 mg, orally once daily). The primary end point was investigator-assessed progression-free survival (PFS). The key secondary end points were overall survival, objective response rate, central nervous system efficacy, and safety. ResultsThe median PFS was 16.5 versus 11.0 months for the osimertinib and SoC EGFR TKI groups, respectively (hazard ratio = 0.54, 95% confidence interval: 0.41–0.72, p < 0.0001). The overall survival data were immature (24% maturity). The objective response rates were 80% for osimertinib and 75% for an SoC EGFR TKI. The median central nervous system PFS was not calculable for the osimertinib group and was 13.8 months for the SoC EGFR TKI group (hazard ratio = 0.55, 95% confidence interval: 0.25–1.17, p = 0.118). Fewer adverse events of grade 3 or higher (40% versus 48%) and fewer adverse events leading to treatment discontinuation (15% versus 21%) were reported with osimertinib versus with an SoC EGFR TKI, respectively. ConclusionIn this Asian population, first-line osimertinib demonstrated a clinically meaningful improvement in PFS over an SoC EGFR TKI, with a safety profile consistent with that for the overall FLAURA study population.

The role novel targeted agents in the treatment of previously treated patients with advanced urothelial carcinoma (UC): a meta-analysis.

Second-line treatment options for advanced urothelial carcinoma (UC) patients are limited. We aim to investigate the efficacy and toxicities of novel targeted agents (TAs) as salvage treatment for advanced UC by using a meta-analysis. Relevant trials published from 1994 to 2017 were identified by an electronic search of public databases. Demographic data, treatment regimens, objective response rate (ORR), disease control rate (DCR), median progression-free and overall survival (PFS, OS) and grade 3/4 toxicities were extracted and analyzed using open Meta-Analyst software version 4.16.12 (Tufts University, URL http://tuftscaes.org/open_meta/). Eleven trials with 1,630 previously treated UC patients were included for analysis. The pooled ORR, DCR and 1-year OS for single targeted agent in pre-treated UC patients was 10.7% (95% CI: 10.7-19.6%), 33.2% (95% CI: 25-41.4%), and 31% (95%: 23.6-39.4%), respectively. Sub-group analysis based on specific targeted agents showed that the efficacy of immune checkpoints inhibitors (ICIs) was significantly higher than that of small molecular tyrosine-kinase inhibitors (TKIs) concerning ORR and 1-year OS. Also, a meta-analysis of three randomized controlled trials showed that the use of TAs in advanced UC patients significantly improved ORR, but not for DCR. As for grade 3 and 4 toxicities, more incidences of severe anemia, fatigue, and diarrhea were observed in the TKIs group than in ICIs group, but not for hypertension. Our findings support the use of immune checkpoints inhibitors, but not for tyrosine kinase inhibitors as salvage treatment for previously treated UC patients due to its potential survival benefits.

Abstract 1586: Evaluation of AXL expression on circulating tumor cells from EGFR mutated lung cancer patients who have relapsed after the EGFR TKI treatment

Abstract Background: The EGFR (epidermal growth factor receptor) TKI (tyrosine kinase inhibitor) has become the standard treatment in lung cancer patients with EGFR mutations. When these patients are treated with EGFR TKI, 80~90% of the patients show responses to the drug. However the tumor begins to progress again following the development of resistance about 1 year later on average. About a half of resistance mechanisms are caused by the additional mutation of the EGFR gene (T790M), and the other half of the resistance mechanisms are caused by various mechanisms, with one of them being the overexpression of the AXL protein. Confirming AXL overexpression in circulating tumor cells (CTCs) can be an alternative method for tissue biopsy, but almost no research has been conducted on this so far. Here, we evaluate the AXL expression in CTC in case resistance occurs after the EGFR inhibitor treatment. Materials and Methods: The blood samples (10 ml) were collected from 10 EGFR TKI treated and relapsed lung cancer patients (TKI group) and 10 non-treated patients (control group). The blood samples were processed through Cytogen protocol to enrich CTCs. The enriched cells were immunofluorescent stained for CTC markers (EpCAM or Vimentin), AXL and WBC marker (CD45). The immunofluorescent stained cells were analyzed for each markers using Image Analysis program. Result: CTCs were detected by CTC markers in all patients from TKI group (range 0-210) and control group (range 1-42). AXL positive CTCs were detected in 9 out of 10 cases from TKI group and in all cases from control group. Interestingly, the quantification of AXL staining intensity in CTCs showed that AXL overexpression (3 fold or greater than baseline) was in 50% of TKI group and 20 % of control group. Conclusion: We have tested a new approach to evaluate the AXL overexpression in tumor cells of EGFR TKI resistant patients, and showed the feasibility of the this method. Most of lung cancer patients who undergo biopsy require hospitalization and some degree of complication due to biopsy is inevitable. Here we suggested that the blood-based method as a good alternative to the tissue biopsy in patients with tolerance. Citation Format: Young Hun Kim, Myoung Shin Kim, Jun Sup Lee, Hyun Kyung Lee, Jae Hyuk Lee, Young Woong Sohn, Koichi Tazaki, Kenji Nakamaru, Kenichi Wakita, Byung Hee Jeon, Seokhyung Kim, Se-Hoon Lee. Evaluation of AXL expression on circulating tumor cells from EGFR mutated lung cancer patients who have relapsed after the EGFR TKI treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1586.

Abstract 1675: Design and synthesis of novel tyrosine kinase enzyme inhibitors and evaluating their anti-colorectal cancer activity

Abstract Targeting tyrosine kinases is attracting considerable attention for cancer therapeutics, nonetheless colorectal cancer. Herein we rationally designed and synthesized a group of 4-(3-methoxy-5-methylphenyl)-5-(pyridine-4-yl)pyrimidine-2-amine derivatives as potential inhibitors for tyrosine kinase. Synthesized compounds share a general structure and vary in substituents at position-2 of the terminal pyridine ring. The hydroxy-analogue of each methoxy derivative was also prepared to evaluate the effect of the methoxy group, at the phenyl ring in position-4 of the pyrimidine moiety, on activity. Compounds 1 (2-chloropyridyl and methoxyphenyl), 2 (2-chloropyridyl and hydroxyphenyl), 3 (2-(pyridine-3-yl)pyridyl and methoxyphenyl), 4 (2-(pyridine-3-yl)pyridyl and hydroxyphenyl), 5 (2-phenylpyridyl and hydroxyphenyl), 6 (2-(4-cyanophenyl)pyridyl and hydroxyphenyl) and 7 (2-(4-acetylphenyl)pyridyl and hydroxyphenyl) showed 29% to 79% tyrosine kinase inhibitory activity. Yet, cytotoxicity of all compounds were assessed against colorectal cancer cells (HT29 and HCT116) using SRB assay. Any compound (at 10 μM concentration) induced considerable viability drop was further assessed using detailed dose response curve and its cytotoxic parameters were calculated. Compounds 8 (2-(4-(N,N-dimethylamino)phenyl)pyridyl and hydroxyphenyl), 5, 6 and 7 showed considerable cytotoxic activities against HCT116 cells with IC50's of 9.18, 10.37, 9.47 and 16.60 μM, respectively. In addition, compounds 9 (2-chloropyridyl, methoxyphenyl and free 2-amino), 2, 3, 4, 5 and 6 showed considerable cytotoxicity against HT29 cells with IC50's of 9.31, 7.48, 11.26, 6.37, 9.89 and 7.14 μM, respectively. The mechanisms of cell killing effect of compounds with considerable anti-proliferative/cytotoxic activity were further assessed using cell cycle analysis (DNA content flowcytometry) and Annexin-V/FITC apoptosis assessment. Compound 2 induced antiproliferative effect which might be attributed to induction of cell cycle arrest at the G0/G1 phase; cell population in G0/G1 phase after treatment with compound 2 was 59.7±0.7% compared to 53.4±1.6% for control untreated cells. Compounds 4, 5, 6 and 7 induced significant cell cycle arrest at G2/M phase with cell populations equals 25.1±0.6%, 24.8±0.4%, 24.0±0.7% and 25.9±0.1%, respectively, compared to 19.3±1.6% for control untreated cells. Cell cycle arrest induced by compounds 1, 2, 3, 4, 6 and 7 resulted in significant apoptosis in colorectal cancer cells. In conclusion, this group of tyrosine kinase inhibitors showed promising anti-proliferative/cytotoxic effects in colorectal cancer cell lines attributed to cell cycle arrest. Further studies for the different cell cycle check point proteins and kinases are undergoing to clarify the exact underlying mechanism of cell killing attributed to each one of these compounds. Citation Format: Hanan A. Assiri, Hawazen A. BinMahfouz, Fahad A. Alabbasi, Marc Devocelle, Ibrahim M. El-deeb, Ahmed M. Al-Abd. Design and synthesis of novel tyrosine kinase enzyme inhibitors and evaluating their anti-colorectal cancer activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1675.

Pivotal Role of Liquid Biopsy in Diagnosing, Managing and Monitoring Early and Advanced Stages of Lung Cancer among Asian Population

RATIONALE: Non-small cell lung cancer (NSCLC) remains the leading cause ofcancer-related deaths among Asian population. Liquid biopsy is a new technology thatprovides information on tumor gene profiling through examination of cell-free DNA(CfDNA) in whole blood. This produces data on genetic alterations found in tumortissue that could be used for prompt and effective management of NSCLC. MATERIALS AND METHODS: Between September 2016 and December 2016, weretrospectively collected and reviewed the medical records of thirty-five patients whowere suspected or diagnosed of lung cancer, then underwent serum epidermal growthfactor receptor (EGFR) for further investigation. Liquid biopsy results were comparedwith the subjects’ final diagnosis. RESULTS: The final diagnoses revealed eighteen (51%) benign and seventeen (49%)malignant cases. Fourteen out of seventeen malignant cases were diagnosed asadenocarcinoma. The remaining three out of seventeen subjects’ diagnoses were:anaplastic giant cell, carcinoid tumor and thyroid cancer with lung metastasis. Thesethree were considered as true negative for EGFR liquid biopsy results. The fourteenmalignant cases were divided into two categories which were surgical and chemotherapyor TKI groups. In the surgical group, five were positive for tissue EGFR mutationfollowed by a negative serum EGFR results post-surgery. One out of the five casesreported negative serum EGFR just four days post-operatively.In the chemotherapy or tyrosine kinase inhibitor (TKI) group, four out of nine weretested prior to treatment with three positive results. One was negative serum EGFR buthad positive tissue EGFR. One case out of nine reported positive EGFR followed by anegative EGFR at thirteen days while on treatment. The last four subjects were testedduring prolonged treatment. Two from the four cases reported negative results. Onedetected resistance and the last case was negative EGFR but later deteriorated. CONCLUSION: Liquid biopsy’s roles include lung cancer screening, treatmentevaluation, assessment of recurrence or resistance, an alternative for tissue biopsy anda complementary blood test with radiographic imaging. This test substantially improvespatient care and outcomes at all stages of lung cancer. Keywords: lung cancer diagnosis, Non-small cell lung cancer, liquid biopsy, epidermalgrowth factor receptor

Coexistence of sensitive and resistant epidermal growth factor receptor (EGFR) mutations in pretreatment non-small cell lung cancer (NSCLC) patients: First or third generation tyrosine kinase inhibitors (TKIs)?

ObjectivesOccasionally, primary 20 T790M/insertion plus sensitive mutations can be detected within a single tumor sample by routine molecular testing, but the optimal clinical management for these patients is unclear. Herein, we determined the optimal treatment strategy for these patients. Materials and methodsFrom January 2011 to January 2017, patients diagnosed with epidermal growth factor receptor (EGFR) mutation were screened. For these harboring primary 20 T790M/insertion plus sensitive mutations, the effectiveness of the first or third generation tyrosine kinase inhibitors (TKIs) were retrospectively analyzed. Results16,842 individuals were screened during the study period with 5900 positive patients identified. Sixty-one patients were confirmed to have primary 20 T790M/insertion plus sensitive mutations (1% of all EGFR-mutant patients, 95% CI, 0.8%–1.3%). Among them, 31 eligible patients were included for survival analyses. The median progression–free survival (PFS) of the 15 osimertinib–treated patients was 18.0 months (95% CI, 15.1–20.9 months), which was greatly longer than the 16 patients who were treated with first generation TKIs (1.2 months, 95% CI, 0.9–1.6, P < 0.001). Similar results were also observed in overall survival (OS) with 25.1 months (95% CI, not calculable) in the osimertinib group and 17.3 months (95% CI, 9.3–25.4 months) in the first generation TKI group (P = 0.02). ConclusionsFor patients harboring primary resistant and sensitive mutations detected by routine clinical methods, first generation TKIs are ineffective even with the presence of sensitive mutations. However, osimertinib shows great survival benefit, and thus, should be considered during the whole clinical management.

Efficacy of brain radiotherapy plus EGFR-TKI for EGFR-mutated non-small cell lung cancer patients who develop brain metastasis.

IntroductionTo analyze the appropriate treatment methods or timing to use epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and brain radiation treatment (RT) for symptomatic and asymptomatic brain metastases (BM) in patients with EGFR mutation non-small cell lung cancer (NSCLC).Material and methodsWe retrospectively studied patients diagnosed with EGFR gene mutated NSCLC who developed brain metastasis between June 2006 and December 2015 at Zhejiang Cancer Hospital. Treatment data were assessed in 181 patients with 49 symptomatic BM and 132 asymptomatic BM retrospectively.ResultsIn 49 symptomatic BM patients, the median OS of the stereotactic radiosurgery (SRS)-treated group was longer than in the whole brain radiotherapy (WBRT) group (37.7 vs. 21.1 months) (p = 0.194). In the group of 132 asymptomatic brain metastasis patients, the median overall survival (mOS) was longer in upfront brain radiotherapy compared with the upfront TKI group (24.9 vs. 17.4 months) (p = 0.035). In further analysis regarding the timing of using radiotherapy, out of all 74 patients, 33 underwent concurrent TKI and brain radiation, 13 received TKI after first-line RT treatment and 28 patients received radiotherapy after TKI failure. The intracranial progression free survival (iPFS) of the three groups was 11.1 months, 11.3 months and 8.1 months (p = 0.032), respectively. The mOS of the three groups was 21.9 months, 26.2 months and 17.1 months, respectively (p = 0.085).ConclusionsOur research indicated that delayed brain RT may result in inferior iPFS in EGFR mutated NSCLC patients with asymptomatic brain metastases, but no OS benefit was obtained. In addition, our study revealed that patients treated with SRS had a significantly longer OS for symptomatic BM. Future prospective study of the optimal management strategy with WBRT or SRS and TKI for this patient cohort is urgently needed.

Efficacy of second-line treatment and importance of comorbidity scores and clinical parameters affecting prognosis in elderly patients with non-small cell lung cancer without epidermal growth factor receptor mutations.

The present study investigated the importance of comorbidity scores and clinical parameters in elderly patients with non-small cell lung cancer (NSCLC) not harboring epidermal growth factor receptor (EGFR) mutations who received second-line chemotherapy. The present study also compared the efficacy of tyrosine kinase inhibitor and cytotoxic chemotherapy as second-line treatment in elderly patients. The present study retrospectively reviewed the treatment of elderly patients with NSCLC (≥70 years old) who received second-line chemotherapy at Korea University Guro Hospital. Patients who had an EGFR mutation were excluded from the analysis. Between 2005 and 2013, 126 patients were included in the present study. The median progression-free survival (PFS) and overall survival (OS) for all patients who received second-line treatment were 2.47 months [95% confidence interval (CI), 2.08-2.86] and 8.63 months (95% CI, 5.99-11.28), respectively. A total of 52 patients (41.3%) were treated with tyrosine kinase inhibitor (TKI) and 74 (58.7%) were treated with chemotherapy. No difference was observed in the median PFS and OS between the TKI and chemotherapy groups (P=0.287 for PFS and P=0.374 for OS). The Charlson comorbidity index was not associated with survival, whereas a simplified comorbidity score and clinical factors, including poor performance status, short PFS of first-line chemotherapy, presence of brain metastasis and low serum albumin and sodium levels were significant prognostic factors in these elderly patients. Second-line chemotherapy was not beneficial to patients who had at least 3 of these factors and a median OS of 1.73 months, whereas patients who had less than 2 of these factors had a median OS of 11.50 months. For elderly lung cancer patients without EGFR mutations, clinical parameters were the most important factors affecting survival, rather than the types of drugs.

Upfront treatment with the first and second-generation tyrosine kinase inhibitors in Ph-positive acute lymphoblastic leukemia.

The treatment of Ph-positive acute lymphoblastic leukemia (Ph+ ALL) has entranced tyrosine kinase inhibitors (TKIs) era. Currently both imatinib and dasatinib are registered as the front-line treatment for Ph+ ALL, and the other 2nd-generation TKIs are suggested as an alternative for those who failed the first-line treatment. However, it remains unclear who could benefit from the 2nd-generation TKIs as the first-line treatment for Ph+ ALL. In this study we compared the efficacy and safety of the 1st and 2nd-generation TKIs in the front-line treatment of Ph+ ALL and found a trend toward better disease-free survival (DFS) in the 2nd-generation TKIs group, though no significant difference in early response and long-term survival between the two groups. Furthermore, subgroup analysis showed that if allogeneic hematopoietic stem cell transplantation (allo-HSCT) was incorporated as consolidation, the 2nd-generation TKIs benefited patients with better DFS and overall survival (OS). The two generation TKIs were well tolerated. Higher incidence of acquiring T315I mutation was observed in the patients relapsed on the 2nd-generation TKIs. These findings suggested front-line treatment of Ph+ ALL with the 2nd-generation TKIs might benefit patients with better survival when allo-HSCT was incorporated as consolidation therapy; meanwhile, the higher incidence of T315I mutation in patients relapsed on the 2nd-generation TKIs deserved further attention.

Therapeutic effect and prognostic factors of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Objective To explore the outcome and prognostic factors of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). Methods Forty-nine newly diagnosed adult patients with Ph+ ALL were analyzed retrospectively, and the treatment effect and the impact of different factors on prognosis were explored. Results In 49 patients, there were 24 males and 25 females; the median age was 38 years (range 15-77 years). Hematologic complete remission (CR), major molecular response (MMR) and complete molecular remission (CMR) rate in patients received tyrosine kinase inhibitors (TKI) plus chemotherapy were higher than those in patients received chemotherapy only (96.8% vs. 72.2%, χ2 = 4.308, P = 0.038; 64.5% vs. 16.7%, χ 2 = 10.468, P = 0.001; 25.8% vs. 11.1%, χ 2 = 4.250, P = 0.039). With a median overall survival (OS) of 24 months (3-70 months), the 3-year OS and relapse-free survival (RFS) rates were 32.7% and 21.4%, respectively. The 3-year OS rate and 1-year RFS rate in TKI plus chemotherapy group were 40.3% and 67.8% respectively, which were higher than those in chemotherapy group (11.1% and 11.1%) (χ 2 = 12.725, χ 2 = 17.401, both P < 0.001). The 3-year OS and RFS rates in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) group were higher than those in the group without allo-HSCT (62.5% vs. 25.7%, χ2 = 6.196, P = 0.013; 41.7% vs. 15.0%, χ2 = 8.032, P = 0.005). The 3-year OS and RFS rates in patients achieved MMR after 2 circles treatment were higher than those in the others (45.1% vs. 17.6%, χ2 = 5.446, P = 0.020; 28.9% vs. 11.7%, χ2 = 6.484, P = 0.011). Multivariate analysis showed that received TKI (HR = 0.227, 95% CI 0.094-0.550, P = 0.001) was an independent prognostic factor for OS; received TKI (HR = 0.225, 95% CI 0.082-0.618, P = 0.004) and allo-HSCT (HR = 0.275, 95% CI 0.077-0.983, P = 0.047) were independent prognostic factors for RFS. Conclusions TKI can increase CR, MMR and CMR rates, improve outcome, and give more chance to receive HSCT. In TKI era, allo-HSCT is still the important treatment for Ph+ ALL, especially for patients without MMR. Key words: Leukemia, acute; Philadelphia chromosome; Prognosis; Hematopoietic stem cell transplantation; Imatinib

Hypertension Induced by Tyrosine-Kinase Inhibitors for the Treatment of Renal Cell Carcinoma in Hemodialysis Patients: A Single-Center Experience and Review of the Literature.

Malignancy is a major cause of mortality in dialysis patients. Although molecular-targeted anticancer drugs, including tyrosine-kinase inhibitors, are used for advanced renal cell carcinoma treatment, there are few reports on their effectiveness and safety in dialysis patients. Renal cell carcinoma dialysis patients treated at our hospital from 2010 to 2013 participated in this study. Thirteen patients were treated with tyrosine-kinase inhibitors and 15 patients with surgery only (control group). During treatment, blood pressure changes and dry weight reduction tended to be greater in the tyrosine-kinase inhibitor group than in controls. More intensive management of hypertension was necessary in the tyrosine-kinase inhibitor group than in the controls. Renal cell carcinoma treatment by tyrosine-kinase inhibitors increased blood pressure in hemodialysis patients. We should prevent and manage hypertension carefully by adjusting antihypertensive drugs and dry weight in renal cell carcinoma patients.

Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancer

IntroductionBrain metastases in EGFR/ALK-driven NSCLC frequently pose treatment dilemmas. Tyrosine kinase inhibitors (TKIs) can control extracranial disease, but radiotherapy is often required for intracranial control. We aimed to evaluate the impact of first-line whole brain radiotherapy (WBRT), stereotactic radiotherapy (SRS) or TKI alone on outcomes of patients with brain metastases from EGFR/ALK-driven NSCLC. MethodsThis single center retrospective review included 184 patients with brain metastases from EGFR/ALK-driven NSCLC, and analyzed effect of treatment choice on time to intracranial progression (TTIP) and overall survival (OS). ResultsFirst-line treatment for brain metastases consisted of WBRT in 120 patients, SRS in 37 and TKI alone in 27. WBRT-treated patients had more brain metastases, and more baseline symptoms. Median TTIP was longer in the WBRT group at 50.5months than SRS or TKI groups at 12 and 15months (p=0.0038). No significant difference was seen in median OS: 21.6months in the WBRT group, 23.9months in the SRS group and 22.6months in the TKI group (p=0.67). In multivariable analysis, age>65years (HR 2.2, p=0.0014), greater number of brain metastases (HR 2.48, p=0.0002) and greater number of extracranial metastatic sites (2 vs 0–1 HR=2.05, p=0.014 and 3+ vs 0–1 HR=2.95, p=0.0001 were associated with shorter OS. No independent effect was seen from first-line CNS treatment choice. ConclusionsFirst-line WBRT for brain metastases from EGFR/ALK-driven NSCLC was associated with longer TTIP than SRS or TKI alone, with no difference in OS. These results could support deferral of WBRT until intracranial progression in selected patients who are closely monitored.

New tyrosine kinase inhibitors in the treatment of imatinib resistant GIST: An updated meta-analysis.

110 Background: Primary or secondary resistance to Imatinib, convolutes the control of Gastrointestinal Stromal Tumors (GIST). We aimed to evaluate clinical outcomes of new tyrosine kinase inhibitors (TKIs) in the treatment of Imatinib resistant GIST. Methods: Online database search of PubMed, MEDLINE, EMBASE, SCOPUS, COCHRANE, and GOOGLE SCHOLAR was performed (2000– Present); key bibliographies were reviewed. Studies comparing patients with Imatinib resistant GIST who were treated with placebo versus new generation TKIs (Regorafenib, Sunitinib, Nilotinib). Primary outcomes were overall and progression free survival (OS, PFS), secondary outcomes include the most common side effects described in trials using new TKIs. Meta-analysis was conducted using Statistical Analysis System (SAS) software. Relative risks with the corresponding 95% confidence intervals (CI) by random effects models of pooled data were calculated. Study quality was assessed using JADAD scoring system. Results: Out of 16 studies, 4 studies met our selection criteria including 825 patients in total; 553 treated with new TKIs and 272 were given placebo (control group). Median age was 57.85 years. Meta-analysis of included data showed significantly improved PFS in the new TKIs group (HR = 0.336, 95% CI 0.208-0.542, p &lt; 0.001.) Similar trend but without statistically significant difference was seen in OS (HR = 0.836, 95% CI 0.682-1.026, p = 0.086). Incidence of hypertension was found to be significantly higher in the new TKIs group (RR = 2.903, 95% CI 1.800-4.681, p &lt; 0.001); the same effect was observed in development of hand foot syndrome (RR = 4.818, 95% CI 2.723-8.525, p &lt; 0.001) and diarrhea (RR = 5.341, 95% CI 3.074-9.281, p &lt; 0.001). Conclusions: New generation of TKIs significantly improved PFS compared with placebo in patients with Imatinib resistant GIST. However new TKIs have increased secondary side effects. Randomized controlled trials are needed to evaluate longer term outcomes of these treatments.

A Meta-Analysis and Meta-Regression of the Efficacy of Front-Line Treatment Combinations with Ponatinib Versus 1st- and 2nd-Generation Tyrosine Kinase Inhibitors for Ph+ Acute Lymphoblastic Leukemia

▪Background: The current standard induction therapy for de novo Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is a tyrosine kinase inhibitor (TKI) in combination with chemotherapy or corticosteroids. Three generations of TKIs are currently available for the treatment of Ph+ ALL. Ponatinib, a third generation multi-targeted TKI, is a more potent inhibitor of BCR/ABL than previous generations. It also is effective in cases where there is a threonine-to-isoleucine substitution at position 315 (T315I mutation), which confers resistance to all first- and second-generation TKIs (i.e., imatinib, dasatinib, and nilotinib). However, evidence on the comparative effectiveness of front-line combination therapy with ponatinib relative to other TKIs in de novo Ph+ ALL has not been well-established.Aims: The purpose of this study is to evaluate the effectiveness, as measured by complete molecular response (CMR) and 2- and 3-year overall survival (OS), of front-line treatment combinations with ponatinib versus first- and second-generation TKIs in de novo Ph+ ALL.Methods: Twenty-six studies of front-line Ph+ ALL treatment with TKI in combination with chemotherapy or corticosteroids (18 studies of imatinib, 5 of dasatinib, 2 of nilotinib, and 1 of ponatinib) were identified from published targeted literature reviews and recently published trials. These consisted of 25 phase 2 through 4 trials and 1 retrospective analysis. Study arms in which patients received chemotherapy or corticosteroids only, a single TKI agent, or in which they received autologous stem cell transplant exclusively were excluded. Data on aggregated patient characteristics were extracted and summarized using the median (range). The proportions of patients achieving CMR (following induction or consolidation therapy) and 2- and 3-year OS were also extracted from all study arms and summarized by TKI group (ponatinib versus all other first and second generation TKIs) using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. A binomial distribution was assumed to calculate the 95% CIs for the ponatinib trial. Multivariate logistic meta-regressions were conducted to examine the association between each TKI treatment group and CMR rates, 2-year OS, and 3-year OS, separately, adjusting for age and gender.Results: A total of 32 TKI treatment arms were included in the analysis. The median (range) of age across trial arms was 46 years (36-69 years) and proportion of male patients was 53% (42-67%). The pooled proportion of patients achieving CMR with ponatinib was higher than that with first and second generation TKIs (79% versus 34%). The pooled 2- and 3-year OS with ponatinib were also higher than those with other TKIs (2-year: 83% versus 58%; 3-year: 79% versus 50%). Relative to other TKIs, ponatinib was associated with a statistically significant 6.09-fold increase in the odds of achieving CMR (N=25) [odds ratio=6.09 (95% CI: 1.16-31.90), p=0.034]. While ponatinib was not significantly associated with an increase in the odds of 2-year OS (N=27) [odds ratio=3.70 (95% CI: 0.93-14.73), p=0.062], it was associated with a statistically significant 4.49-fold increase in the odds of 3-year OS (N=19) [odds ratio=4.49 (95% CI: 1.00-20.13), p=0.050] compared to earlier generation TKIs.Conclusion: Frontline treatment with ponatinib in combination with chemotherapy or corticosteroids was associated with significantly better odds of CMR and 3-year OS in patients newly diagnosed with Ph+ ALL than combination therapy with earlier generations of TKIs. In particular, ponatinib was associated with a 6-fold increase in CMR, the most important factor in predicting long-term survival outcomes. The improved efficacy of ponatinib in Ph+ ALL may be particularly important for patients who are ineligible to undergo stem cell transplantation due to lack of suitably matched donors, advanced age, or significant comorbidities. In such cases, combination therapy with TKI may be a suitable alternative. Though the number of studies included was small and few covariates could be used to adjust for heterogeneity across trials, the results suggest that ponatinib in combination with chemotherapy may represent an effective front-line treatment option for patients with Ph+ ALL. Prospective head-to-head clinical trials are needed to confirm these results.Sponsor: ARIAD Pharmaceuticals, Inc. [Display omitted] DisclosuresJabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. DerSarkissian:ARIAD: Research Funding. Duh:Allergan: Consultancy; Abbvie: Consultancy; Novartis: Research Funding; GSK: Research Funding; Bayer: Research Funding; Janssen: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Medtronic: Research Funding; Takeda: Research Funding; Novo Nordisk: Research Funding; Sanofi: Research Funding; Ariad: Research Funding. McCormick:ARIAD: Research Funding. Cheng:ARIAD: Research Funding. McGarry:ARIAD: Employment, Equity Ownership. Souroutzidis:ARIAD: Research Funding. Huang:ARIAD: Employment, Equity Ownership. Kantarjian:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

Tyrosine Kinase Inhibitor (TKI) Switching Patterns during the First 12 Months in Simplicity, an Observational Study of Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Patients (Pts) in Routine Clinical Practice

Introduction:SIMPLICITY (NCT01244750) is an ongoing observational study of CP-CML pts in routine clinical practice receiving first-line (1L) imatinib (IM) prior to 2010 (retrospective) or 1L IM, dasatinib (DAS) or nilotinib (NIL) since 2010 (prospective) in the US and Europe.Methods: This analysis was designed to identify baseline characteristics associated with TKI switching in pts pooled from the prospective and retrospective cohorts. Pts were characterized as ’early switchers’ (who discontinued 1L TKI and switched to a second-line [2L] TKI within 3 months of TKI initiation) or ’late switchers’ (who discontinued 1L TKI and switched to a 2L TKI between 3 and 12 months after TKI initiation). A comparator group of ’non-switcher’ pts did not discontinue 1L TKI within 12 months of TKI initiation; ’early non-switchers’ did not switch 1L TKI within the first 3 months and ’late non-switchers’ did not switch 1L TKI between 3 and 12 months after TKI initiation. Logistic regression analysis was used to identify factors associated with early vs. late switching (gender, age at diagnosis ≥65 years, 1L TKI, region, reason for discontinuation).Results: By March 07 2016, 1494 pts were enrolled at 197 sites in 7 countries. Within 12 months of initiating 1L TKI 238 pts (16%) had switched to 2L TKI. Of switchers, 31% and 69% were early and late, respectively. Of the overall cohort, 1189 pts were early non-switchers and 1146 were late non-switchers. Most early switchers received IM as 1L TKI (49%), followed by NIL (32%) and DAS (19%); most late switchers received IM (56%), followed by DAS (26%) and NIL (18%). Fewer early non-switchers than switchers received IM as 1L TKI (43%), followed by NIL (28%) and DAS (28%); fewer late non-switchers than switchers received IM (44%), followed by DAS (28%) and NIL (28%). Most switchers were female; a higher proportion of female switchers was early vs. late (63% vs. 52%, respectively). In comparison, 43% of pts in both non-switching groups were female. Median ages of early and late switchers were 54 (interquartile range [IQR]: 46-68) and 58 (IQR: 46-69) years, respectively; median ages of early and late non-switchers were 56 (IQR: 46-68) and 56 (IQR: 45-67) years, respectively.Logistic regression analysis showed that pts who switched due to intolerance had greater odds of switching early compared with those who switched due to resistance (odds ratio = 3.49; 95% confidence interval: 1.11-10.98; p=0.0323). Among the 238 pts who switched 1L TKI, the main reason for 1L TKI discontinuation was intolerance (early switchers: 76%; late switchers: 71%; Figure).The most common intolerances leading to changes in early and late switchers varied by 1L TKI. Most common for IM early switchers (n=26) was general disorders/administration site conditions (including fatigue, edema, pain) and skin/subcutaneous disorders; for IM late switchers (n=53), gastrointestinal (GI) disorders, general disorders/administration site conditions and skin/subcutaneous disorders. Most common for DAS early switchers (n=10) was GI disorders; for DAS late switchers (n=36), respiratory/thoracic/ mediastinal disorders. Most common for NIL early switchers (n=19) was GI disorders; for NIL late switchers (n=25), GI disorders, general disorders/administration site conditions and skin/subcutaneous disorders.TKI resistance less commonly contributed to 1L TKI discontinuation. Primary and acquired resistance were seen in higher proportions of late than early switchers (Figure). In late switchers, primary resistance was a more common reason for discontinuation in IM pts vs. DAS pts or NIL pts (22%, 5% and 4%, respectively). Acquired resistance was only reported as a reason for discontinuation in IM-treated pts (early switchers: 0.3%; late switchers: 11%).Conclusions: Of pts switching or discontinuing 1L TKI in the first 12 months of therapy, around one third switched within the first 3 months; compared with late switchers and non-switchers these pts were more likely to be younger and female. TKI intolerance was the main reason for switching and was significantly associated with early switching. Resistance was a less common reason for changing TKI therapy and was seen more frequently after 3 months and among pts treated with IM. More research is necessary to make definitive conclusions about comparisons between TKI groups, given the small numbers of pts in the TKI cohorts and the non-controlled nature of the trial. [Display omitted] DisclosuresGoldberg:COTA Inc: Employment; Novartis: Consultancy; Neostem: Equity Ownership; Pfizer: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Michallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Hehlmann:Bristol-Myers Squibb: Consultancy; Novartis: Research Funding; German CML-Group: Research Funding. Zyczynski:Bristol-Myers Squibb: Employment. Foreman:ICON Clinical Research: Employment. Calimlim:ICON Clinical Research: Employment. Paquette:Incyte: Consultancy, Honoraria; Novartis: Consultancy; Ariad: Consultancy. Gambacorti:Pfizer: Honoraria, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Zagorska:Bristol-Myers Squibb: Employment. Rong:Bristol-Myers Squibb: Employment. Mauro:BMS: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.

PCN5 - A Systematic Review of Tyrosine Kinase Inhibitors as First Line Treatment for Advanced Non Small Cell Lung Cancer

Gefitinib and Erlotinib are two orally active, selective and reversible EGFR-TKIs molecules, which have been extensively used by non small cell lung cancer (NSCLC) patient. The aim of this review is to determine the safety, efficacy/effectiveness and cost-effectiveness of Tyrosine Kinase Inhibitors(TKIs) compared to chemotherapy as first line treatment for advanced non small cell lung cancer. A systematic search was conducted using an electronic database such as MEDLINE, EMBASE, EBM Reviews and EconLit. Selected articles were critically appraised and evidence was graded according to US/Canadian preventive services task force. Sixteen studies were included in this review with the primary outcome was reported as progression free survival (PFS) and secondary outcomes as response rates and overall survival. The pooled meta estimates of hazard ratio for PFS of Erlotinib were 0.25(95%CI: 0.15, 0.42). Similarly, Gefitinib also demonstrated longer PFS with pooled hazard ratio of 0.43 (95%CI: 0.32, 0.58). As for secondary outcome, there was insufficient evidence to demonstrate the difference in the overall survival between TKIs and chemotherapy. Overall response rates were reported to be significantly higher in TKIs group compared with chemotherapy group. The most common reported adverse events with TKIs were rash, diarrhoea, acne, dry skin and pruritis. Liver enzyme elevations and interstitial lung disease has also been seen in TKIs patients. In view of economic analysis, inclusion of Gefitinib as first line was found to be a dominant strategy based on three landmark studies. In contrast, Erlotinib was reported to yield both lower cost and quality adjusted life years (QALY). Moderate to high level of evidence showed that TKIs significantly prolonged the progression free survival of NSCLC patient but not overall survival and increase the overall response rates in chemo-naive patient with positive EGFR gene mutation.