First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study.

BACKGROUND Phase-IV, open-label, single-arm study (NCT01203917) to assess efficacy and safety/tolerability of first-line gefitinib in Caucasian patients with stage IIIA/B/IV, epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). METHODS Treatment: gefitinib 250 mg day(-1) until progression. Primary endpoint: objective response rate (ORR). Secondary endpoints: disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety/tolerability. Pre-planned exploratory objective: EGFR mutation analysis in matched tumour and plasma samples. RESULTS Of 1060 screened patients with NSCLC (859 known mutation status; 118 positive, mutation frequency 14%), 106 with EGFR sensitising mutations were enrolled (female 70.8%; adenocarcinoma 97.2%; never-smoker 64.2%). At data cutoff: ORR 69.8% (95% confidence interval (CI) 60.5-77.7), DCR 90.6% (95% CI 83.5-94.8), median PFS 9.7 months (95% CI 8.5-11.0), median OS 19.2 months (95% CI 17.0-NC; 27% maturity). Most common adverse events (AEs; any grade): rash (44.9%), diarrhoea (30.8%); CTC (Common Toxicity Criteria) grade 3/4 AEs: 15%; SAEs: 19%. Baseline plasma 1 samples were available in 803 patients (784 known mutation status; 82 positive; mutation frequency 10%). Plasma 1 EGFR mutation test sensitivity: 65.7% (95% CI 55.8-74.7). CONCLUSION First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC. Plasma samples could be considered for mutation analysis if tumour tissue is unavailable.

First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study.

BACKGROUND: Phase-IV, open-label, single-arm study (NCT01203917) to assess efficacy and safety/tolerability of first-line gefitinib in Caucasian patients with stage IIIA/B/IV, epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). METHODS: TREATMENT: gefitinib 250 mg day(-1) until progression. Primary endpoint: objective response rate (ORR). Secondary endpoints: disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety/tolerability. Pre-planned exploratory objective: EGFR mutation analysis in matched tumour and plasma samples. RESULTS: Of 1060 screened patients with NSCLC (859 known mutation status; 118 positive, mutation frequency 14%), 106 with EGFR sensitising mutations were enrolled (female 70.8%; adenocarcinoma 97.2%; never-smoker 64.2%). At data cutoff: ORR 69.8% (95% confidence interval (CI) 60.5-77.7), DCR 90.6% (95% CI 83.5-94.8), median PFS 9.7 months (95% CI 8.5-11.0), median OS 19.2 months (95% CI 17.0-NC; 27% maturity). Most common adverse events (AEs; any grade): rash (44.9%), diarrhoea (30.8%); CTC (Common Toxicity Criteria) grade 3/4 AEs: 15%; SAEs: 19%. Baseline plasma 1 samples were available in 803 patients (784 known mutation status; 82 positive; mutation frequency 10%). Plasma 1 EGFR mutation test sensitivity: 65.7% (95% CI 55.8-74.7). CONCLUSION: First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC. Plasma samples could be considered for mutation analysis if tumour tissue is unavailable.

Comparison of neoadjuvant cisplatin-based chemotherapy versus radiochemotherapy followed by resection for stage III (N2) NSCLC.

OBJECTIVE: Comparison of prospectively treated patients with neoadjuvant cisplatin-based chemotherapy vs radiochemotherapy followed by resection for mediastinoscopically proven stage III N2 non-small cell lung cancer with respect to postoperative morbidity, pathological nodal downstaging, overall and disease-free survival, and site of recurrence. METHODS: Eighty-two patients were enrolled between January 1994 to June 2003, 36 had cisplatin and doxetacel-based chemotherapy (group I) and 46 cisplatin-based radiochemotherapy up to 44 Gy (group II), either as sequential (25 patients) or concomitant (21 patients) treatment. All patients had evaluation of absence of distant metastases by bone scintigraphy, thoracoabdominal CT scan or PET scan, and brain MRI, and all underwent pre-induction mediastinoscopy, resection and mediastinal lymph node dissection by the same surgeon. RESULTS: Group I and II comprised T1/2 tumors in 47 and 28%, T3 tumors in 45 and 41%, and T4 tumors in 8 and 31% of the patients, respectively (P=0.03). There was a similar distribution of the extent of resection (lobectomy, sleeve lobectomy, left and right pneumonectomy) in both groups (P=0.9). Group I and II revealed a postoperative 90-d mortality of 3 and 4% (P=0.6), a R0-resection rate of 92 and 94% (P=0.9), and a pathological mediastinal downstaging in 61 and 78% of the patients (P<0.01), respectively. 5y-overall survival and disease-free survival of all patients were 40 and 36%, respectively, without significant difference between T1-3 and T4 tumors. There was no significant difference in overall survival rate in either induction regimens, however, radiochemotherapy was associated with a longer disease-free survival than chemotherapy (P=0.04). There was no significant difference between concurrent vs sequential radiochemotherapy with respect to postoperative morbidity, resectability, pathological nodal downstaging, survival and disease-free survival. CONCLUSIONS: Neoadjuvant cisplatin-based radiochemotherapy was associated with a similar postoperative mortality, an increased pathological nodal downstaging and a better disease-free survival as compared to cisplatin doxetacel-based chemotherapy in patients with stage III (N2) NSCLC although a higher number of T4 tumors were admitted to radiochemotherapy.

Lung Cancer That Harbors an HER2 Mutation: Epidemiologic Characteristics and Therapeutic Perspectives.

PURPOSE HER2 mutations are identified in approximately 2%of non-small-cell lung cancers (NSCLC). There are few data available that describe the clinical course of patients with HER2-mutated NSCLC. PATIENTS AND METHODS We retrospectively identified 65 NSCLC, diagnosed with a HER2 in-frame insertion in exon 20. We collected clinicopathologic characteristics, patients' outcomes, and treatments. Results HER2 mutation was identified in 65 (1.7%) of 3,800 patients tested and was almost an exclusive driver, except for one single case with a concomitant KRAS mutation. Our population presented with a median age of 60 years (range, 31 to 86 years), a high proportion of women (45 women v 20 men; 69%), and a high proportion of never-smokers (n= 34; 52.3%). All tumors were adenocarcinomas and 50% were stage IV at diagnosis. For these latter cases, 22 anti-human epidermal growth factor receptor 2 (HER2) treatments were administered after conventional chemotherapy in 16 patients. Subsequently, four patients experienced progressive disease, seven experienced disease stabilizations, and 11 experienced partial responses (overall response rate, 50%; disease control rate [DCR], 82%). Specifically, we observed a DCR of 93% for trastuzumab-based therapies (n = 15) and a DCR of 100% for afatinib (n = 3) but no response to other HER2-targeted drugs (n = 3). Progression-free survival for patients with HER2 therapies was 5.1 months. Median survival was of 89.6 and 22.9 months for early-stage and stage IV patients, respectively. CONCLUSION This study, the largest to date dedicated to HER2-mutated NSCLC, reinforces the importance of screening for HER2 mutations in lung adenocarcinomas and suggests the potential efficacy of HER2-targeted drugs in this population.

Video-assisted thoracoscopic resection of a small pulmonary nodule after computed tomography-guided localization with a hook-wire system. Experience in 45 consecutive patients.

BACKGROUND: This study is a single-institution validation of video-assisted thoracoscopic (VATS) resection of a small solitary pulmonary nodule (SPN) previously localized by a CT-guided hook-wire system in a consecutive series of 45 patients. METHODS: The records of all patients undergoing VATS resection for SPN preoperatively localized by CT-guided a hook-wire system from January 2002 to December 2004 were assessed with respect to failure to localize the lesion by the hook-wire system, conversion thoracotomy rate, duration of operation, postoperative complications, and histology of SPN. RESULTS: Forty-five patients underwent 49 VATS resections, with simultaneous bilateral SPN resection performed in 4. Preoperative CT-guided hook-wire localization failed in two patients (4%). Conversion thoracotomy was necessary in two patients (4%) because it was not possible to resect the lesion by a VATS approach. The average operative time was 50 min. Postoperative complications occurred in 3 patients (6%), one hemothorax and two pneumonia. The mean hospital stay was 5 days (range: 2-18 days). Histological assessment revealed inflammatory disease in 17 patients (38%), metastasis in 17 (38%), non-small-cell lung cancer (NSCLC) in 4 (9%), lymphoma in 3 (6%), interstitial fibrosis in 2 (4%), histiocytoma in one (2%), and hamartoma in one (2%). CONCLUSIONS: Histological analysis of resected SPN revealed unexpected malignant disease in more than 50% of the patients indicating that histological clarification of SPN seems warranted. Video-assisted thoracoscopic resection of SPN previously localized by a CT-guided hook-wire system is related to a low conversion thoracotomy rate, a short operation time, and few postoperative complications, and it is well suited for the clarification of SPN.

Cilengitide: an RGD pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies.

Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology.

Traitements antiangiogéniques des cancers métastatiques du côlon et du rectum, du sein et du poumon: bénéfices et risques [Anti-angiogenic therapies for metastatic colorectal, breast and lung cancer: benefits and risks]

Anti-angiogenic therapies have recently enriched the therapeutic armentarium against the most common cancers. Among these, bevacizumab, a monoclonal antibody against vascular endothelial growth factor, is currently used most frequently. While the addition of bevacizumab to chemotherapy improves overall survival in first and second line treatment of metastatic colorectal cancer, its effect in metastatic breast cancer is limited to improvements in tumor response and progression-free-survival. In non-small-cell lung cancer, the positive results of a first American phase III study have not been confirmed by a second European study and are subject to controversies. A summary of the data concerning anti-angiogenic therapies in these three cancers is presented including safety information.

Mediastinal reinforcement after induction therapy and pneumonectomy: comparison of intercostal muscle versus diaphragm flaps.

OBJECTIVE: Prospective non-randomised comparison of full-thickness pedicled diaphragm flap with intercostal muscle flap in terms of morbidity and efficiency for bronchial stump coverage after induction therapy followed by pneumonectomy for non-small cell lung cancer (NSCLC). METHODS: Between 1996 and 1998, a consecutive series of 26 patients underwent pneumonectomy following induction therapy. Half of the patients underwent mediastinal reinforcement by use of a pedicled intercostal muscle flap (IF) and half of the patients by use of a pedicled full-thickness diaphragm muscle flap (DF). Patients in both groups were matched according to age, gender, side of pneumonectomy and stage of NSCLC. Postoperative morbidity and mortality were recorded. Six months follow-up including physical examination and pulmonary function testing was performed to examine the incidence of bronchial stump fistulae, gastro-esophageal disorders or chest wall complaints. RESULTS: There was no 30-day mortality in both groups. Complications were observed in one of 13 patients after IF and five of 13 after DF including pneumonia in two (one IF and one DF), visceral herniations in three (DF) and bronchopleural fistula in one patient (DF). There were no symptoms of gastro-esophageal reflux disease (GERD). Postoperative pulmonary function testing revealed no significant differences between the two groups. CONCLUSIONS: Pedicled intercostal and diaphragmatic muscle flaps are both valuable and effective tools for prophylactic mediastinal reinforcement following induction therapy and pneumonectomy. In our series of patients, IF seemed to be associated with a smaller operation-related morbidity than DF, although the difference was not significant. Pedicled full-thickness diaphragmatic flaps may be indicated after induction therapy and extended pneumonectomy with pericardial resection in order to cover the stump and close the pericardial defect since they do not adversely influence pulmonary function.

ALK inhibitors in the treatment of advanced NSCLC.

Pharmacologic agents that target protein products of oncogenes in tumors are playing an increasing clinical role in the treatment of cancer. Currently, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. Subsequently other genetic abnormalities with "driver" characteristics - implying transforming and tumor maintenance capabilities have been extensively reported in several small distinct subsets of NSCLC. Among these rare genetic changes, anaplastic lymphoma kinase (ALK) gene rearrangements, most often consisting in a chromosome 2 inversion leading to a fusion with the echinoderm microtubule-associated protein like 4 (EML4) gene, results in the abnormal expression and activation of this tyrosine kinase in the cytoplasm of cancer cells. This rearrangement occurs in 2-5% of NSCLC, predominantly in young (50 years or younger), never- or former-smokers with adenocarcinoma. This aberration most commonly occurs a independently of EGFR and KRAS gene mutations. A fluorescent in situ hybridization assay was approved by the US Food and Drug Administration (FDA) as the standard method for the detection of ALK gene rearrangement in clinical practice and is considered the gold standard. Crizotinib, a first-in-class dual ALK and c-MET inhibitor, has been shown to be particularly effective against ALK positive NSCLC, showing dramatic and prolonged responses with low toxicity, predominantly restricted to the gastro-intestinal and visual systems, and generally self-limiting or easily managed. However, resistance to crizotinib inevitably emerges. The molecular mechanisms of resistance are currently under investigation, as are therapeutic approaches including crizotinib-based combination therapy and novel agents such as Hsp90 inhibitors. This review aims to present the current knowledge on this fusion gene, the clinic-pathological profile of ALK rearranged NSCLC, and to review the existing literature on ALK inhibitors, focusing on their role in the treatment of NSCLC.

Impact of induction therapy on airway complications after sleeve lobectomy for lung cancer.

BACKGROUND: Sleeve lobectomy is a valid alternative to pneumonectomy for the treatment of centrally located operable non-small cell lung cancer (NSCLC), but concern has been evoked regarding a potentially increased risk of bronchial anastomosis complications after induction therapy. This study examined the impact of induction therapy on airway healing after sleeve lobectomy for NSCLC. METHODS: Bronchial anastomosis complications were recorded with respect to the induction regimen applied (neoadjuvant chemotherapy vs chemoradiotherapy) in a consecutive series of patients with sleeve lobectomy for NSCLC. RESULTS: Ninety-nine patients underwent sleeve resection, 28 of them after induction therapy. Twelve patients received chemotherapy alone, and 16 patients had radiochemotherapy. There were no significant differences in postoperative 90-day mortality (3.6% vs 2.8%) and morbidity (54% vs 49%) for patients with and without induction therapy. Bronchial anastomosis complications occurred in 3 patients (10.8%) with neoadjuvant therapy and in 2 (2.8%) without (p = 0.3). In the induction therapy group, two bronchial stenoses occurred after radiochemotherapy and one bronchopleural fistula after chemotherapy alone. In patients without induction therapy, one bronchial stenosis and one bronchopleural fistula were observed. All bronchial stenoses were successfully treated by dilatation, and both bronchopleural fistulas occurring after right lower lobectomy were successfully treated by reoperation and completion sleeve bilobectomy with preservation of the upper lobe. CONCLUSIONS: Sleeve lobectomy for NSCLC can be safely performed after induction chemotherapy and radiochemotherapy with mortality and incidence of airway complications similar to that observed in nonpretreated patients. The treatment of airway complications does not differ for patients with and without induction therapy.

Optimized exosome isolation protocol for cell culture supernatant and human plasma.

Extracellular vesicles represent a rich source of novel biomarkers in the diagnosis and prognosis of disease. However, there is currently limited information elucidating the most efficient methods for obtaining high yields of pure exosomes, a subset of extracellular vesicles, from cell culture supernatant and complex biological fluids such as plasma. To this end, we comprehensively characterize a variety of exosome isolation protocols for their efficiency, yield and purity of isolated exosomes. Repeated ultracentrifugation steps can reduce the quality of exosome preparations leading to lower exosome yield. We show that concentration of cell culture conditioned media using ultrafiltration devices results in increased vesicle isolation when compared to traditional ultracentrifugation protocols. However, our data on using conditioned media isolated from the Non-Small-Cell Lung Cancer (NSCLC) SK-MES-1 cell line demonstrates that the choice of concentrating device can greatly impact the yield of isolated exosomes. We find that centrifuge-based concentrating methods are more appropriate than pressure-driven concentrating devices and allow the rapid isolation of exosomes from both NSCLC cell culture conditioned media and complex biological fluids. In fact to date, no protocol detailing exosome isolation utilizing current commercial methods from both cells and patient samples has been described. Utilizing tunable resistive pulse sensing and protein analysis, we provide a comparative analysis of 4 exosome isolation techniques, indicating their efficacy and preparation purity. Our results demonstrate that current precipitation protocols for the isolation of exosomes from cell culture conditioned media and plasma provide the least pure preparations of exosomes, whereas size exclusion isolation is comparable to density gradient purification of exosomes. We have identified current shortcomings in common extracellular vesicle isolation methods and provide a potential standardized method that is effective, reproducible and can be utilized for various starting materials. We believe this method will have extensive application in the growing field of extracellular vesicle research.

Estimation of lung cancer diagnosis and treatment costs based on a patient-level analysis in Catalonia (Spain)

Background: Assessing of the costs of treating disease is necessary to demonstrate cost-effectiveness and to estimate the budget impact of new interventions and therapeutic innovations. However, there are few comprehensive studies on resource use and costs associated with lung cancer patients in clinical practice in Spain or internationally. The aim of this paper was to assess the hospital cost associated with lung cancer diagnosis and treatment by histology, type of cost and stage at diagnosis in the Spanish National Health Service. Methods: A retrospective, descriptive analysis on resource use and a direct medical cost analysis were performed. Resource utilisation data were collected by means of patient files from nine teaching hospitals. From a hospital budget impact perspective, the aggregate and mean costs per patient were calculated over the first three years following diagnosis or up to death. Both aggregate and mean costs per patient were analysed by histology, stage at diagnosis and cost type. Results: A total of 232 cases of lung cancer were analysed, of which 74.1% corresponded to non-small cell lung cancer (NSCLC) and 11.2% to small cell lung cancer (SCLC); 14.7% had no cytohistologic confirmation. The mean cost per patient in NSCLC ranged from 13,218 Euros in Stage III to 16,120 Euros in Stage II. The main cost components were chemotherapy (29.5%) and surgery (22.8%). Advanced disease stages were associated with a decrease in the relative weight of surgical and inpatient care costs but an increase in chemotherapy costs. In SCLC patients, the mean cost per patient was 15,418 Euros for limited disease and 12,482 Euros for extensive disease. The main cost components were chemotherapy (36.1%) and other inpatient costs (28.7%). In both groups, the Kruskall-Wallis test did not show statistically significant differences in mean cost per patient between stages. Conclusions: This study provides the costs of lung cancer treatment based on patient file reviews, with chemotherapy and surgery accounting for the major components of costs. This cost analysis is a baseline study that will provide a useful source of information for future studies on cost-effectiveness and on the budget impact of different therapeutic innovations in Spain.

Preparation and cytotoxicity of cisplatin-containing liposomes

We encapsulated cisplatin into stealth pH-sensitive liposomes and studied their stability, cytotoxicity and accumulation in a human small-cell lung carcinoma cell line (GLC4) and its resistant subline (GLC4/CDDP). Since reduced cellular drug accumulation has been shown to be the main mechanism responsible for resistance in the GLC4/CDDP subline, we evaluated the ability of this new delivery system to improve cellular uptake. The liposomes were composed of dioleoylphosphatidylethanolamine (DOPE), cholesteryl hemisuccinate (CHEMS), and distearoylphosphatidylethanolamine-polyethyleneglycol 2000 (DSPE-PEG2000) and were characterized by determining the encapsulation percentage as a function of lipid concentration. Among the different formulations, DOPE/CHEMS/DSPE-PEG liposomes (lipid concentration equal to 40 mM) encapsulated cisplatin more efficiently than other concentrations of liposomes (about 20.0%, mean diameter of 174 nm). These liposomes presented good stability in mouse plasma which was obtained using a 0.24-M EDTA solution (70% cisplatin was retained inside the liposomes after 30 min of incubation). Concerning cytotoxic effects, they are more effective (1.34-fold) than free cisplatin for growth inhibition of the human lung cancer cell line A549. The study of cytotoxicity to GLC4 and GLC4/CDDP cell lines showed similar IC50 values (approximately 1.4 µM), i.e., cisplatin-resistant cells were sensitive to this cisplatin formulation. Platinum accumulation in both sensitive and resistant cell lines followed the same pattern, i.e., approximately the same intracellular platinum concentration (4.0 x 10-17 mol/cell) yielded the same cytotoxic effect. These results indicate that long-circulating pH-sensitive liposomes, also termed as stealth pH-sensitive liposomes, may present a promising delivery system for cisplatin-based cancer treatment. This liposome system proved to be able to circumvent the cisplatin resistance, whereas it was not observed when using non-long-circulating liposomes composed of phosphatidylcholine, phosphatidylserine, and cholesterol.

In vitro anti-inflammatory, cytotoxic and antioxidant activities of boesenbergin A, a chalcone isolated from Boesenbergia rotunda (L.) (fingerroot)

The current in vitro study was designed to investigate the anti-inflammatory, cytotoxic and antioxidant activities of boesenbergin A (BA), a chalcone derivative of known structure isolated from Boesenbergia rotunda. Human hepatocellular carcinoma (HepG2), colon adenocarcinoma (HT-29), non-small cell lung cancer (A549), prostate adenocarcinoma (PC3), and normal hepatic cells (WRL-68) were used to evaluate the cytotoxicity of BA using the MTT assay. The antioxidant activity of BA was assessed by the ORAC assay and compared to quercetin as a standard reference antioxidant. ORAC results are reported as the equivalent concentration of Trolox that produces the same level of antioxidant activity as the sample tested at 20 µg/mL. The toxic effect of BA on different cell types, reported as IC50, yielded 20.22 ± 3.15, 10.69 ± 2.64, 20.31 ± 1.34, 94.10 ± 1.19, and 9.324 ± 0.24 µg/mL for A549, PC3, HepG2, HT-29, and WRL-68, respectively. BA displayed considerable antioxidant activity, when the results of ORAC assay were reported as Trolox equivalents. BA (20 µg/mL) and quercetin (5 µg/mL) were equivalent to a Trolox concentration of 11.91 ± 0.23 and 160.32 ± 2.75 µM, respectively. Moreover, the anti-inflammatory activity of BA was significant at 12.5 to 50 µM and without any significant cytotoxicity for the murine macrophage cell line RAW 264.7 at 50 µM. The significant biological activities observed in this study indicated that BA may be one of the agents responsible for the reported biological activities of B. rotunda crude extract.

Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data

Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC.