Kinase Inhibitors In Patients Research Articles

Adverse Events of Tyrosine Kinase Inhibitors in Patients with Advanced Thyroid Cancer

Adverse Events of Tyrosine Kinase Inhibitors in Patients with Advanced Thyroid Cancer

Toward personalized treatment in Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a rare lymphoma with 1000 to 1500 new patients diagnosed per year in the United States. Patients with WM can experience prolonged survival times, which seem to have increased in the last decade, but relapse is inevitable. The identification of recurrent mutations in the MYD88 and CXCR4 genes has opened avenues of research to better understand and treat patients with WM. These developments are giving way to personalized treatment approaches for these patients, focusing on increasing depth and duration of response alongside lower toxicity rates. In the present document, we review the diagnostic differential, the clinical manifestations, and the pathological and genomic features of patients with WM. We also discuss the safety and efficacy data of alkylating agents, proteasome inhibitors, monoclonal antibodies, and Bruton tyrosine kinase inhibitors in patients with WM. Finally, we propose a genomically driven algorithm for the treatment of WM. The future of therapies for WM appears bright and hopeful, but we should be mindful of the cost-effectiveness and long-term toxicity of novel agents.

P1-244 - Discontinuation of BCR-ABL tyrosine kinase inhibitors in patients with chronic myeloid leukemia: a retrospective study

BCR-ABL tyrosine kinase inhibitors (TKIs) have dramatically improved the treatment of chronic myeloid leukemia (CML). In several recent trials, TKIs were successfully discontinued in approximately half of patients who had achieved a deep molecular response. In clinical practice, patients occasionally discontinue TKIs. However, their outcomes are rarely reported. In this study, we analyzed the treatment-free remission (TFR) rate of such patients. We retrospectively evaluated data from patients with CML who were treated with TKIs between January 2001 and December 2016. The TFR rate was estimated using the Kaplan-Meier method. Eight out of 62 patients had discontinued TKI treatment. Their characteristics were as follows: male/female ratio, 5/3; median age, 71 (range, 40-81); median duration of treatment prior to discontinuation, 75 months. The reasons for discontinuation were progression of anemia (2), ischemic heart disease (1), pleural effusion (1), dementia (1), osteomyelitis (1), economic problems (1), and conception (1). Three of the 8 patients who discontinued TKI resumed treatment after a median of 3 months (range, 2-5) because of molecular relapse. The remaining 5 patients maintained MR4 (≥4 log reduction; BCR-ABL1 ≤0.01%) for a median of 16 months (range, 14-26). The TFR rate was 62% at 12 months. Those who maintained TFR tended to have a longer duration of treatment prior to cessation (median, 120 months; range, 37-159) than those who had molecular relapse (median, 36 months; range, 18-63; Mann-Whitney, p = 0.143), with an MR4.5 (≥4.5 log reduction; BCR-ABL1≤0.0032%) duration of 45 and 21 months (Mann-Whitney, p = 0.0714), respectively. All patients with molecular relapse experienced remission after resuming TKI. Patients who had a longer duration of treatment before TKI cessation maintained MR4.5 longer than those who relapsed. The TFR rate after cessation was comparable to results from previous clinical trials.

Hypertension and VEGF (Vascular Endothelial Growth Factor) Receptor Tyrosine Kinase Inhibition: Effects on Renal Function.

VEGF (vascular endothelial growth factor) receptor tyrosine kinase inhibitors have become first-line therapy for metastatic renal cell carcinoma. Their use commonly leads to hypertension, but their effects on long-term renal function are not known. In addition, it has been suggested that the development of hypertension is linked to treatment efficacy. The objective of this study was to determine the effects of these drugs on long-term renal function, especially in those with renal dysfunction at baseline, and to examine the role of hypertension on these effects. Serum creatinine measurements were used to calculate the estimated glomerular filtration rate for 130 renal cell carcinoma patients who were treated with this class of tyrosine kinase inhibitors. New or worsening hypertension was defined by documented start or addition of antihypertensive medications. Overall, the use of tyrosine kinase inhibitors in patients with estimated glomerular filtration <60 or ≥60 mL/min per 1.73 m2 was not associated with a decline in long-term renal function. During follow-up, 41 patients developed new or worsening hypertension within 30 days from first drug administration, and this was not linked to further reductions in glomerular filtration. These patients seemed to survive longer than those who did not develop hypertension within 30 days, although this was not statistically significant (P=0.07). Our findings suggest that the use of VEGF tyrosine kinase inhibitors does not adversely affect long-term renal function even in the setting of new-onset hypertension or reduced renal function at baseline.

Treatment outcome in a population-based, 'real-world' cohort of patients with chronic myeloid leukemia.

Evaluations of the ‘real-world’ efficacy and safety of tyrosine kinase inhibitors in patients with chronic myeloid leukemia are scarce. A nationwide, population-based, chronic myeloid leukemia registry was analyzed to evaluate (deep) response rates to first and subsequent treatment lines and eligibility for a treatment cessation attempt in adults diagnosed between January 2008 and April 2013 in the Netherlands. The registry covered 457 patients; 434 in chronic phase (95%) and 15 (3%) in advanced disease phase. Seventy-five percent of the patients in chronic phase were treated with imatinib and 25% with a second-generation tyrosine kinase inhibitor. At 3 years 44% of patients had discontinued their first-line treatment, mainly due to intolerance (21%) or treatment failure (19%). At 18 months 73% of patients had achieved a complete cytogenetic response and 63% a major molecular response. Deep molecular responses (MR4.0 and MR4.5) were achieved in 69% and 56% of patients, respectively, at 48 months. All response milestones were achieved faster in patients treated upfront with a second-generation tyrosine kinase inhibitor, but ultimately patients initially treated with imatinib also reached similar levels of responses. The 6-year cumulative incidence of eligibility for a tyrosine kinase cessation attempt, according to EURO-SKI criteria, was 31%. Our findings show that in a ‘real-world’ setting the long-term outcome of patients treated with tyrosine kinase inhibitors is excellent and the conditions for an attempt to stop tyrosine kinase inhibitor therapy are met by a third of the patients.

Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies

SummaryAim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC0-inf) and maximum concentrations (Cmax) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90% confidence intervals (CIs). Results The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively. Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib.

Sensitive genotyping of mutations in the EGFR gene from NSCLC patients using PCR-GoldMag lateral flow device

Epidermal growth factor receptor (EGFR) mutations predict better outcomes with EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Most common activating mutations include in-frame deletion in exon 19 and L858R substitution in exon 21, which account for >90% of all EGFR mutations in NSCLC. In this study, a PCR-GoldMag lateral flow assay (PCR-GoldMag LFA) was developed for the visual detection of delE746-A750 and L858R of EGFR mutations. Forty formalin-fixed paraffin-embedded (FFPE) tissue samples of NSCLC patients were analyzed using PCR-GoldMag LFA system and verified by direct sequencing and TaqMan-PCR detection methods. Results showed that EGFR mutations were detected in 34 cases among the 40 samples (85%) by PCR-GoldMag LFA method. Among the 34 cases, 5 cases were simultaneously detected with delE746-A750 in exon 19 and L858R mutation in exon 21. Compared with sequencing, only 4 samples were detected as delE746-A750, which revealed higher sensitivity of PCR-GoldMag LFA detection method than direct sequencing. TaqMan-PCR method verified the L858R mutation and was in 100% agreement with our method. These results indicated that our method has obvious advantages to analyze clinical samples and offers a more sensitive alternative to direct sequencing for the detection of EGFR mutations.

High PHLPP1 expression levels predicts longer time of acquired resistance to EGFR tyrosine kinase inhibitors in patients with lung adenocarcinoma

BackgroundIn spite of an initial good response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in lung adenocarcinoma patients, resistance to treatment eventually occurs. Epidermal growth factor receptor (EGFR) activation stimulates Ras/Raf/Erk/MAPK and influences PI3K/Akt pathways, respectively. PHLPP negatively regulates PI3K/Akt and the RAF/RAS/ERK signaling pathways. Our study aimed to investigate the association between PH domain leucine-rich-repeats protein phosphatase (PHLPP) expression levels and the acquired resistance to EGFR TKIs in lung adenocarcinoma.ResultsHigh expression levels of PHLPP1 and PHLPP2 were detected in 69.3% and 61.3%, respectively, of patients with lung adenocarcinoma. Patients with high expression levels of PHLPP1 showed significantly longer median progression-free survival and overall survival than those with low expression levels of PHLPP1 (29 months versus 11 months, and 36 months versus 19 months respectively) (p = 0.0050 and p = 0.0052). PHLPP1, but not PHLPP2, protein expression levels was negatively correlated with p-Akt (473) and p-Erk1/2. The PHLPP1 expression levels were correlated with Progression-free survival and overall survival (p = 0.001 and p = 0.000).Materials and MethodsWe recruited 75 patients with advanced lung adenocarcinoma receiving EGFR TKIs treatment. The expression levels of PHLPP1, PHLPP2, p-AKT(S473) and p-ERK1/2 were assessed using tissue immunostaining. The association of PHLPP expression levels with clinicopathological parameters and disease prognosis was analyzed.ConclusionsThis study suggests that high expression levels of PHLPP1 predict a better survival from target therapy and a longer time of acquired resistance to EGFR TKIs in patients with lung adenocarcinoma.

Clinical and pathological characterization of HER2 mutations in human breast cancer: a systematic review of the literature.

HER2 gene is a member of the epidermal growth factor receptor (EGFR) family. Across different malignancies, aberrations of HER2 gene commonly correspond to gain-of-function alterations leading to increased receptor signaling. We have reviewed the literature currently available on HER2 mutations in human breast cancer (BC) evaluating type and frequency of such mutations. The primary objective was to determine the frequency and the number of patients with HER2-mut in the series analyzed. The secondary objectives were to assess characteristics of mutated cases (ER and HER2 status and stage of disease, type of mutations, and finally the clinical outcome if reported). We retrieved 31 published papers, and the pooled rate of HER2 mutations across 12,905 BC patients was calculated. Overall, the frequency of HER2 mutations was 2.7% with most involving the intracellular domain. About 4% of patients were finally mutated. The predictive role was not described. Only 30% of these patients were simultaneously HER2 positive and 63% were ER positive. We have found that the prevalence of HER2 mutations is about 3%. These genic alterations are independently associated with HER2 amplification status, occurring in both ER-positive/HER2-negative diseases or HER2-enriched cancers. Ongoing trials are investigating small molecules tyrosine kinase inhibitors in patients harboring these mutations.

Simultaneous determination of six tyrosine kinase inhibitors in human plasma using HPLC-Q-Orbitrap mass spectrometry.

Gefitinib, erlotinib, icotinib, crizotinib, lapatinib and apatinib are targeted cancer therapy agents acting through inhibition of tyrosine kinase. Method for quantifying these six drugs in human plasma of patients was required. An HPLC-Q-Orbitrap method (based on HPLC-MS/MS) was developed and validated for the simultaneous detection and quantitation of six tyrosine kinase inhibitors in human plasma. Sample was extracted by liquid-liquid extraction (ethyl acetate: tert-Butyl methyl ether, 1:1 v/v). The method shows a high level of accuracy and reproducibility. The lower limit of quantification was 0.02 ng/ml for apatinib, 0.1 ng/ml for crizotinib, 2.0 ng/ml for lapatinib and 0.05 ng/ml for erlotinib, gefitinib and icotinib. This method was successfully used for apatinib monitoring in plasma of patients with NSCLC. This simple and reproducible method has potential for monitoring of tyrosine kinase inhibitors in patients' plasma.

Treatment outcomes with tyrosine kinase inhibitors in patients with uncommon EGFR mutations in non-small cell lung cancer: A multi-centre retrospective analysis.

e20678 Background: The clinical significance of common epidermal growth factor receptor (EGFR) mutations (exon 19 deletions and exon 21 L858 mutations) in non-small cell lung cancer is well known1. However, 2-8% of NSCLC patients harbour an uncommon EGFR mutation2. Prognosis and response to tyrosine kinase inhibitors (TKIs) is unclear in this subgroup. The most frequent uncommon EGFR mutations are exon 18 G719 and exon 21 L861. Although not frequently reported, these appear to have favourable outcomes with TKIs3. Methods: We conducted a retrospective review of all patients with uncommon EGFR mutations identified at laboratories in 4 UK centres, between 2012 and 2016. Patient’s not treated with a TKI were excluded. Techniques including cold PCR were in use at contributing laboratories. The T790M resistance mutation was excluded from our study. For patients with uncommon EGFR mutations, patient characteristics and response to TKIs were analysed. Results: 29 patients with uncommon EGFR mutations, with both rare point mutations (86%) and deletions (14%), were identified. All patients were treated with a TKI. Age ranged from 37 to 85 (median 67). The majority (86%) of patients were performance status 1. TKIs used were afatinib (31%), gefitinib (24%) and erlotinib (45%). 19 patients (66%) benefitted from TKI treatment (38% partial response (PR), 28% stable disease (SD). 10 patients (34%) did not respond, including all four with exon 20 mutations. 15 mutations were exon 18 G719 mutations: 40% had a PR and 40% stable disease with TKI therapy. There were two L861 mutations, both responded with a PR. 13 patients remained on TKI treatment at data cut off. The median progression free survival at this time was 8.1months. Tabulated details of response according to mutation will be presented. Conclusions: The majority (66%) of NSCLC patients with uncommon EGFR mutations benefitted from TKI therapy in this series. These high clinical benefit rates, typified by patients with G719 mutation, are in line with the limited previous reports 1,3. Exon 20 mutations were associated with TKI resistance, in line with the literature4.

Feasibility and outcome of repeat biopsy upon progression on tyrosine kinase inhibitors in patients with EGFR mutation positive adenocarcinoma of lung-an Indian tertiary cancer centre experience.

e20628 Background: A repeat biopsy at the time of progression is important to evaluate the mechanism of resistance to tyrosine kinase inhibitors (TKIs) in EGFR mutation positive adenocarcinoma (ADC) of lung and dictates decisions for further therapy. Being an invasive procedure, a rebiopsy is not always possible and presents various hindrances. Methods: Between January 2012 and November 2016, EGFR mutation positive ADC of Lung treated with TKIs were evaluated for and offered a repeat biopsy at the time of progression on TKI. Feasibility of rebiopsy was done by a team of experienced interventional radiologists. Proportion of patients undergoing a rebiopsy, reason for inability to undergo a rebiopsy, histopathology findings including any small cell transformation and adequacy of tissue for further molecular testing were assessed. Results:154 patients were offered a repeat biopsy out of which 119 patients (77.3%) underwent a repeat biopsy. There was no evidence of malignancy in 17.6% (21/119) patients on the rebiopsy specimen and tumor was inadequate for molecular testing in 9 out of 98 patients (9.2%) in whom malignancy was detected on the repeat biopsy specimen. Small cell transformation was seen in 3.3% (4/119) patients who underwent a repeat biopsy. Amongst the 34 patients who could not undergo rebiopsy, patient unwillingness for the procedure was the most common reason, accounting for 47% cases (16/34) followed by a technically difficult biopsy as per judgement of the interventional radiology team in 32.3% (11/34). 5 out of 34 patients were not subjected to a rebiopsy a poor performance status and 3 patients were not subjected to rebiopsy as per treating clinician’s discretion. Thus, out of 154 patients, adequate tissue was not available for molecular testing in 41.5% patients who progressed on TKI due to various reason as elaborated above. Molecular testing is planned on the remaining biopsy specimens. Conclusions: Conventional invasive rebiopsy upon progression on TKIs fails to collect adequate tissue for molecular testing in almost 40% cases due to various reasons making liquid biopsy a very important tool in this setting.

The enhanced tumor inhibitory effects of gefitinib and L-ascorbic acid combination therapy in non-small cell lung cancer cells

Despite documentation of successful therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with lung cancer, the response rate of patients treated with this therapy remains low. The present study investigated whether L-ascorbic acid serves an adjuvant role in vitro when combined with the EGFR tyrosine kinase inhibitor gefitinib (Iressa®) in lung cancer cell lines. A total of three human lung cancer cell lines were used. The antiproliferative effects and changes in the cell cycle and expression of intracellular signaling molecules, including extracellular signal-regulated kinases (Erk), signal transducer and activator of transcription 3 (Stat3) and protein kinase B (Akt), were measured in cells treated with gefitinib and/or L-ascorbic acid at various concentrations. When combined with gefitinib, L-ascorbic acid exhibited an additive effect on cell proliferation in all gefitinib-sensitive and gefitinib-resistant cell lines. A decrement of ~40% was observed with a low dose 0.5 mM L-ascorbic acid and gefitinib in the relatively gefitinib-resistant A549 cell line (85.6±5.4% with gefitinib alone vs. 52.7±7.3% with combination therapy; P=0.046). The downregulation of intracellular signaling cascades, including EGFR, Akt, Erk and Stat3, was also observed. L-Ascorbic acid serves an adjuvant role when administered in combination with gefitinib; however, the degree of inhibition of cell proliferation differs between lung cancer cell lines.

Impact of age on efficacy and toxicity of nilotinib in patients with chronic myeloid leukemia in chronic phase: ENEST1st subanalysis

PurposeAchievement of deep molecular response with a tyrosine kinase inhibitor in patients with chronic myeloid leukemia (CML) is required to attempt discontinuation of therapy in these patients. The current subanalysis from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study evaluated whether age has an impact on the achievement of deeper molecular responses or safety with frontline nilotinib in patients with CML.MethodsENEST1st is an open-label, multicenter, single-arm, prospective study of nilotinib 300 mg twice daily in patients with newly diagnosed CML in chronic phase. The patients were stratified into the following 4 groups based on age: young (18–39 years), middle age (40–59 years), elderly (60–74 years), and old (≥75 years). The primary end point was the rate of molecular response 4 ([MR4] BCR–ABL1 ≤0.01% on the international scale) at 18 months from the initiation of nilotinib.ResultsOf the 1091 patients enrolled, 1089 were considered in the analysis, of whom, 23% (n = 243), 45% (n = 494), 27% (n = 300), and 5% (n = 52) were categorized as young, middle age, elderly, and old, respectively. At 18 months, the rates of MR4 were 33.9% (95% confidence interval [CI], 27.8–40.0%) in the young, 39.6% (95% CI, 35.3–44.0%) in the middle-aged, 40.5% (95% CI, 34.8–46.1%) in the elderly, and 35.4% (95% CI, 21.9–48.9%) in the old patients. Although the incidence of adverse events was slightly different, no new specific safety signals were observed across the 4 age groups.ConclusionsThis subanalysis of the ENEST1st study showed that age did not have a relevant impact on the deep molecular response rates associated with nilotinib therapy in newly diagnosed patients with CML and eventually on the eligibility of the patients to attempt treatment discontinuation.

The Use of the Second-Generation Protein Kinase Inhibitors in Patients with Gastrointestinal Stromal Tumor with Failure to the Treatment with Imatinib

The Use of the Second-Generation Protein Kinase Inhibitors in Patients with Gastrointestinal Stromal Tumor with Failure to the Treatment with Imatinib

Clinical features of Bim deletion polymorphism and its relation with crizotinib primary resistance in Chinese patients with ALK/ROS1 fusion-positive non-small cell lung cancer.

The authors' previous study demonstrated that the B-cell chronic lymphocytic leukemia/lymphoma (Bcl-2)-like 11 (BCL2L11) (Bim) deletion polymorphism was associated with poor clinical response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC) with EGFR mutations. The objective of the current study was to investigate the impact of the Bim deletion polymorphism among patients with anaplastic lymphoma kinase (ALK)-positive or ROS proto-oncogene 1, receptor tyrosine kinase (ROS1)-positive NSCLC who were treated with crizotinib. A total of 55 patients with ALK-positive NSCLC and 14 patients with ROS1-positive NSCLC who were treated with crizotinib were enrolled into the current study. The Bim deletion polymorphism was analyzed by polymerase chain reaction. The clinical features of the Bim deletion polymorphism and its impact on the effect of crizotinib were investigated. The Bim deletion polymorphism was present in 9 of 69 patients with ALK-positive or ROS1-positive NSCLC (13.0%). There were no differences noted with regard to clinicopathological features between patients with and without the Bim deletion polymorphism. Patients with the Bim deletion polymorphism had a significantly shorter progression-free survival (PFS) and lower objective response rate compared with those without (median PFS, 182 days vs 377 days [P = .008]) (objective response rate, 44.4% vs 81.7% [P =.041]) in all populations. The significant difference in PFS was observed in patients with ALK-positive NSCLC (83 days vs 305 days [P =.0304]) compared with those with ROS1-positive NSCLC (218 days vs not reached [P =.082]). Multivariate analysis indicated that the Bim deletion polymorphism was an independent predictive factor for patients with ALK-positive NSCLC who were treated with crizotinib (hazard ratio, 4.786 [P =.006]). The Bim deletion polymorphism was found to be associated with poor clinical response to crizotinib in patients with ALK fusion-positive NSCLC. Cancer 2017;123:2927-35. © 2017 American Cancer Society.

Patterns of care among patients receiving sequential targeted therapies for advanced renal cell carcinoma: A retrospective chart review in the USA

To assess real-world treatment patterns of targeted therapies after failure of first-line tyrosine kinase inhibitors in patients with advanced renal cell carcinoma. A large, retrospective review of medical charts of patients with advanced renal cell carcinoma in the USA was carried out. Descriptive statistics were used to summarize physicians' and patients' characteristics, treatment sequences, and reasons for treatment choices. P-values were calculated using χ2 -tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. A descriptive comparison was carried out between current results and those of a previous treatment pattern study conducted in 2012 to identify changes in treatment patterns over time. Sunitinib and everolimus remained the most commonly-used first and second targeted therapies, respectively. Among patients who continued to a third targeted therapy, everolimus and axitinib were the most commonly-used treatments after second targeted therapy with a tyrosine kinase inhibitor and a mammalian target of rapamycin inhibitor, respectively. The use of pazopanib as first targeted therapy, and of axitinib and sorafenib as second targeted therapies, increased over time. Efficacy, treatment guidelines and a different mechanism of action were the main reasons given by physicians for choosing among second targeted therapies after failure of a first tyrosine kinase inhibitor. The results of the present study document patterns of care during a period of rapid and ongoing therapeutic advancement in advanced renal cell carcinoma. Sequencing of therapies warrants ongoing analysis in light of new agents entering the advanced renal cell carcinoma treatment landscape.

Exon 14 Deleted MET Receptor as a New Biomarker and Target in Cancers.

Inhibitors of the receptor tyrosine kinase (RTK) MET have been ineffective at treating cancer, possibly because of lack of knowledge that would allow selection of tumors likely to respond to this treatment. In contrast, specific epidermal growth factor receptor (EGFR) inhibitors have been used successfully against lung tumors displaying activating mutations in the kinase domain of EGFR. Recent publications describe a set of mutations causing MET exon 14 skipping, and importantly, several case reports describe objective responses to MET-targeting tyrosine kinase inhibitors in patients with such mutations. These observations suggest a novel therapeutic strategy for fighting cancer, especially in the lung. Exon 14 encodes the MET juxtamembrane domain targeted by mechanisms that negatively regulate receptor stability and activity. In this review, we describe the molecular mechanisms leading first to exon 14 skipping and then to activation of the MET receptor and how this process differs from that triggered by classical RTK-activating mutations in the kinase domain. We detail the clinical characteristics of patients carrying these mutations and the sensitivity of their tumors to MET inhibitors. Lastly, we discuss future challenges related to MET mutations in cancers, including patient screening and anticipating resistance to MET inhibitors.

Epidermal growth factor receptor (EGFR) mutation status before and after acquired resistance to EGFR tyrosine kinase inhibitors in patients with lung adenocarcinoma

Objective: To investigate epidermal growth factor receptor (EGFR) mutation status in lung adenocarcinomas before and after acquiring resistance to EGFR tyrosine kinase inhibitors (TKIs) using ARMS method followed by further verification using droplet digital PCR technique. Methods: Twenty qualified patients were included, among them 13 were male and 7 were female patients. Before EGFR-TKIs treatment, 5 patients were EGFR wild-type by ARMS, and the other 15 patients had L858R or 19-del point mutations. The time to progression varied from 4 to 18 months. Mutation of exons 18, 19, 20 and 21 were detected by ARMS, and were verified by droplet digital PCR system method. Results: EGFR wild-type status was unchanged before and after acquired resistance to EGFR-TKIs in 5 lung adenocarcinoma patients. Alteration of EGFR mutation status occurred in 10 of the 15 patients with pre-treatment L858R or 19-del mutations. Among them, T790M mutation was found in 8 patients, L858R became G719X plus S768I mutation in one patient, and 19-del converted into wild-type in one other patient. Conclusions: T790M mutation is the primary type of EGFR mutation in lung adenocarcinomas with acquired resistance to EGFR-TKIs therapy. Acquired resistance to EGFR-TKIs dose not lead to the alteration of EGFR status in pre-treatment EGFR wild-type patients, but can alter EGFR mutation status in pre-treatment EGFR mutant patients.

P1.06-007 Radical Treatment of Synchronous Oligometastatic Non-Small Cell Lung Cancer (NSCLC)

Cancer represents a large biological spectrum of disease ranging from localized to multisystem involvement with multiple intermediate stages. Oligometastatic NSCLC is thought to carry a better overall survival (OS) but there are few prospective studies that evaluate it. Prospective cohort study with NSCLC patients treated at the Instituto Nacional de Cancerologia of Mexico, with stage IV and oligometastatic disease (≤ 5 metastatic lesions). Patients were enrolled to receive, after 4 cycles of systemic treatment with platinum-doublet chemotherapy or 4 months of tyrosine kinase inhibitors in patients with driver mutations, local consolidative treatment for the primary lesion and their metastases with chemoradiotherapy, surgery, radiotherapy, stereotactic radiosurgery or radiofrequency ablation based on the decision of the Multidisciplinary Thoracic Committee of the institution. The primary outcome was overall survival. The study was approved by de Institutional Ethics Committee and registered in clinical trials NCT02805530. Up to this moment, we have evaluated 29 patients with NSCLC and oligometastatic disease. Of these, 62% males with a median age of 58 years (IQR 52.5-64.5), median CEA 10.2 (IQR 3.25-55), 59% former or currently smokers (median 37.5 package/year), wood-smoke exposure 28%. Overall 90% of the patients presented adenocarcinomas, 28% EGFR mutation (50% deletion of exon 19, 38% mutation on exon 21). At diagnosis 93% of the patients had symptoms mainly cough (48%), dyspnea (30%), neurologic symptoms (26%), weight loss (18%) and dysphonia (15%). We evaluated the oligometastatic disease status with PET-CT and MRI in 66% of the patients and the remaining with CT scan plus MRI. At diagnosis 66% had one or two metastases, 14% three to four metastases and 20% five metastases. For metastatic sites CNS was the main site of metastases in 52% of patients, 28% contralateral lung, 17% bone metastases and 7% at suprarenal. For radical treatment to the primary tumor, 59% chemoradiotherapy, 21% radiotherapy, 28% surgery and 3% radiofrequency. For definite treatment for the metastases, 45% received radiotherapy, 14% chemoradiotherapy and 17% surgery. The mean dose of radiotherapy received for the control of the primary tumor was 56.3 Gy (SD 11.28 Gy) and 29.5 Gy (SD 3.84Gy) for metastases. After multimodal treatment 24% had radiologic complete response. The median OS were 18.26 months (95%CI:10.89-25.64), the median OS for those with and without radiologic complete response were 28.58 months (95%CI:12.98-44.18) and 14.45 months (95%CI:10.40-18.51) respectively. Patients with oligometastatic NSCLC with agressive treatment have a large OS regardless their mutational status.