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Background Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is selective for both EGFR-TKI-sensitizing and T790M (threonine-to-methionine substitution at codon 790)-resistance mutations. The authors present long-term follow-up data from a preplanned, pooled analysis of phase 2 studies, the AZD9291 First Time in Patients Ascending Dose Study (AURA) extension trial (clincialtrials.gov identifier NCT01802632) and the AURA2 trial (NCT02094261). Methods Patients with centrally confirmed, T790M mutation-positive, advanced non-small cell lung cancer received osimertinib 80 mg once daily until disease progression or study discontinuation. Response was assessed by a blinded, independent, central review using Response Evaluation Criteria in Solid Tumors, version 1.1. The primary endpoint was the objective response rate. Results In total, 411 patients received osimertinib (second line, 129 patients; third line or later, 282 patients). At the data cutoff date of November 1, 2016, the median treatment exposure was 16.4 months (range, 0-29.7 months), the objective response rate was 66% (95% confidence interval [CI], 61%-70%), the median response duration was 12.3 months (95% CI, 11.1-13.8 months), and the median progression-free survival was 9.9 months (95% CI, 9.5-12.3 months). At the data cutoff date of May 1, 2018, 271 patients (66%) had died, and 140 patients (34%) had discontinued before death. The median overall survival was 26.8 months (95% CI, 24.0-29.1 months); and the 12-month, 24-month, and 36-month survival rates were 80%, 55%, and 37%, respectively. Grade ≥3 possibly causally related (investigator assessed) adverse events were reported in 65 patients (16%), and the most common were rash (grouped terms; 42%; grade ≥3, 1%) and diarrhea (39%; Conclusions This pooled analysis represents the most mature clinical trial data for osimertinib in patients with pretreated, T790M-positive, advanced non-small cell lung cancer, further establishing osimertinib as a standard of care for this patient population.

BACKGROUND Erlotinib is a standard first-line therapy for patients who have metastatic nonsmall cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The recommended dose of 150 mg daily is the maximum tolerated dose (MTD). Few clinical data are available regarding its efficacy at doses less than the MTD. METHODS An institutional database was queried for patients with advanced NSCLC who were positive for EGFR L858R mutations or exon 19 deletions and had received treatment with erlotinib. The treatment course, including the erlotinib dose at initiation of treatment, at 4 months into therapy, and at disease progression, was retrospectively studied. Progression-free survival (PFS) was compared between patients who received the MTD (150 mg) and those who received reduced-dose erlotinib (≤100 mg). RESULTS In total, 198 eligible patients were identified. Thirty-one patients (16%) were initiated on reduced-dose erlotinib; they were older (P = .001) and had lower performance status (P = .01) compared with those who were initiated on erlotinib at the MTD. The response rate to reduced-dose erlotinib was 77%. The median PFS of patients initiated on reduced-dose erlotinib was 9.6 months versus 11.4 months for those initiated at the MTD, a difference that was not statistically significant (hazard ratio, 0.81; 95% confidence interval, 0.54-1.21; P = .30). There was a nonsignificant trend toward higher rates of progression within the central nervous system with reduced-dose erlotinib. CONCLUSIONS At doses below the MTD, erlotinib treatment results in a high response rate and a prolonged median PFS. Review of the literature indicates that 15 of 30 small-molecule inhibitors that are approved or in late-stage development for cancer therapy have recommended doses below the MTD. When the toxicities of MTD dosing are a concern, an investigation of small-molecule inhibitors at doses below the MTD is warranted. Cancer 2016;122:3456–63. © 2016 American Cancer Society.

BACKGROUND Erlotinib is a highly active epidermal growth factor receptor (EGFR) kinase inhibitor that is approved for first-line use in lung cancers harboring EGFR mutations. Anecdotal experience suggests that this drug may provide continued disease control after patients develop objective progression of disease (PD), although this has not been systematically studied to date. METHODS Patients who had Response Evaluation Criteria In Solid Tumors-defined PD who were participating in 3 prospective trials of first-line erlotinib in advanced lung cancer were studied retrospectively, and the progression characteristics were compared between patients with and without EGFR-sensitizing mutations. Factors were studied that influenced the time until treatment change (TTC), defined as the time from PD to the start of a new systemic therapy or death. The rate of tumor progression was assessed by comparing tumor measurements between the computed tomography scan obtained at the time of PD and the preceding scan. RESULTS In total, 92 eligible patients were studied, including 42 with and 50 without an EGFR-sensitizing mutation. The EGFR-mutant cohort had a slower rate of progression (P = .003) and a longer TTC (P 3 months; only 2 patients received local debulking therapy during that period. Multivariate analysis of the patients with EGFR-mutant tumors demonstrated that a longer time to progression, a slower rate of progression, and a lack of new extrathoracic metastases were associated with a longer TTC. CONCLUSIONS A change in systemic therapy commonly can be delayed in patients with EGFR-mutant lung cancer who objectively progress on first-line erlotinib, particularly in those with a longer time to progression, a slow rate of progression, and a lack of new extrathoracic metastases. Cancer 2015;121:2570–2577. © 2015 American Cancer Society.

The widespread adoption of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for the first-line treatment of patients with advanced EGFR-mutated non-small cell lung cancer has resulted in acquired tyrosine kinase inhibitor resistance becoming a ubiquitous clinical problem. The identification of specific mechanisms of acquired resistance has allowed a better understanding of the biology and natural history of resistant disease, but is only now starting to impact treatment decisions. Strategies for managing acquired resistance in patients with advanced non-small cell lung cancer are complex and must be adapted to the individual characteristics of each patient's cancer. Although combination chemotherapy is the presumed standard of care for most patients, prospective trial data are lacking, highlighting the importance of offering patients participation in clinical trials in this setting. Emerging data from trials of third-generation mutant-specific EGFR kinase inhibitors suggests particular promise with this class of agents.

BACKGROUND This phase 2 trial (ClinicalTrials.gov identifier NCT00548093) assessed the efficacy, safety, and impact on health‐related quality of life of dacomitinib (PF‐00299804), an irreversible tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, in patients with KRAS wild‐type non–small cell lung cancer (NSCLC). METHODS Patients with advanced NSCLC, progression on 1 or 2 regimens of chemotherapy and erlotinib, KRAS wild‐type or known EGFR‐sensitizing mutant tumor, and Eastern Cooperative Oncology Group performance status of 0 to 2 received 45 mg of dacomitinib once daily continuously in 21‐day cycles. RESULTS A total of 66 patients enrolled (adenocarcinoma, n = 50; those without adenocarcinoma [nonadenocarcinoma], n = 16). The objective response rate (ORR) for patients with adenocarcinoma (primary endpoint) was 5% (2 partial responses; 1‐sided P = .372 for null hypothesis [H0]: ORR ≤ 5%) and 6% (1 partial response) for patients with nonadenocarcinoma. Responders included: 2 of 25 EGFR mutation‐positive tumors; 1 of 3 EGFR wild‐type with HER2 amplification. Median progression‐free survival was 12 weeks overall (n = 66) and 18 weeks (n = 26) for patients with EGFR mutation‐positive tumors. Common treatment‐related adverse events were of grade 1 or 2 severity, manageable with standard supportive care, and included diarrhea (grade 3 [G3], 12%), acneiform dermatitis (G3, 6%), exfoliative rash (G3, 3%), dry skin (G3, 0%), fatigue (G3, 3%), and stomatitis (G3, 2%). Six patients (9%) discontinued due to treatment‐related adverse events. By patient report, NSCLC symptoms of dyspnea, cough, and pain (chest, arm/shoulder) showed improvement first observed after 3 weeks on therapy. CONCLUSIONS Dacomitinib demonstrated preliminary activity and acceptable tolerability in heavily pretreated patients, and may offer benefit in molecularly defined patient subsets. Cancer 2014;120:1145–1154. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society., This study investigated the efficacy and safety of dacomitinib in advanced, refractory non–small cell lung cancer (NSCLC), selecting for patients with KRAS wild‐type tumors to exclude those least likely, and simultaneously enrich for those most likely, to benefit from therapy. Although the observed response rate was low, a number of patients experienced prolonged disease control accompanied by rapid and durable lung cancer symptom relief, suggesting that dacomitinib has relevant activity against KRAS wild‐type NSCLC.

BACKGROUND The objective of this study was to define the volumetric tumor growth rate in patients who had advanced nonsmall cell lung cancer (NSCLC) with sensitizing epidermal growth factor receptor (EGFR) mutations and had initially received treatment with EGFR-tyrosine kinase inhibitor (TKI) therapy beyond progression. METHODS The study included 58 patients with advanced NSCLC who had sensitizing EGFR mutations treated with first-line gefitinib or erlotinib, had baseline computed tomography (CT) scans available that revealed a measurable lung lesion, had at least 2 follow-up CT scans during TKI therapy, and had experienced volumetric tumor growth. The tumor volume (in mm3) of the dominant lung lesion was measured on baseline and follow-up CT scans during therapy. In total, 405 volume measurements were analyzed in a linear mixed-effects model, fitting time as a random effect, to define the growth rate of the logarithm of tumor volume (logeV). RESULTS A linear mixed-effects model was fitted to predict the growth of logeV, adjusting for time in months from baseline. LogeV was estimated as a function of time in months among patients whose tumors started growing after the nadir: logeV = 0.12*time + 7.68. In this formula, the regression coefficient for time, 0.12/month, represents the growth rate of logeV (standard error, 0.015/month; P

Erlotinib is a standard first-line therapy for patients who have metastatic nonsmall cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The recommended dose of 150 mg daily is the maximum tolerated dose (MTD). Few clinical data are available regarding its efficacy at doses less than the MTD.An institutional database was queried for patients with advanced NSCLC who were positive for EGFR L858R mutations or exon 19 deletions and had received treatment with erlotinib. The treatment course, including the erlotinib dose at initiation of treatment, at 4 months into therapy, and at disease progression, was retrospectively studied. Progression-free survival (PFS) was compared between patients who received the MTD (150 mg) and those who received reduced-dose erlotinib (≤100 mg).In total, 198 eligible patients were identified. Thirty-one patients (16%) were initiated on reduced-dose erlotinib; they were older (P = .001) and had lower performance status (P = .01) compared with those who were initiated on erlotinib at the MTD. The response rate to reduced-dose erlotinib was 77%. The median PFS of patients initiated on reduced-dose erlotinib was 9.6 months versus 11.4 months for those initiated at the MTD, a difference that was not statistically significant (hazard ratio, 0.81; 95% confidence interval, 0.54-1.21; P = .30). There was a nonsignificant trend toward higher rates of progression within the central nervous system with reduced-dose erlotinib.At doses below the MTD, erlotinib treatment results in a high response rate and a prolonged median PFS. Review of the literature indicates that 15 of 30 small-molecule inhibitors that are approved or in late-stage development for cancer therapy have recommended doses below the MTD. When the toxicities of MTD dosing are a concern, an investigation of small-molecule inhibitors at doses below the MTD is warranted. Cancer 2016;122:3456-63. © 2016 American Cancer Society.

Tumor biopsies remain the gold standard for evaluating genetic changes in cancers either at diagnosis or following treatment with targeted therapies. However, this is not always feasible and can seldom be performed more than once. Noninvasive techniques, so-called “liquid biopsies” that measure the allelic burden in blood promise to realize the full potential of genotype-directed cancer therapy. These technologies can be potentially used for non-invasive tumor genotyping and in addition also provide an opportunity for disease monitoring and as a tool for pharmacodynamic assessment of drug efficacy. These features offer the ability to gain real-time dynamic biological insights into the benefits and failures of cancer therapies. Several publications have demonstrated the potential of plasma cell-free DNA (cfDNA) genotyping. While historical studies focused on measuring total cfDNA concentrations for diagnosis and prognosis of disease, recent technologic advances now enable the ability to obtain novel molecular insights non-invasively 1-4. First, monitoring response to treatment, i.e., does one observe a reduction (or increase) in a population of tumor derived mutant alleles from cfDNA that track with treatment response observed by radiographic imaging? Second, monitoring of known, actionable resistance clones that arise, as a result, of selective pressure from targeted therapy. The latter is particularly interesting as there are now several drugs in the clinic that specifically target cancers harboring such resistance mechanisms. In addition one might learn when the resistant clone will become detectable in cases where re-biopsy is difficult or not possible. In a study examining the mechanism of resistance to epidermal growth factor receptor (EGFR) inhibition using monoclonal antibodies in colorectal cancer, investigators performed genotyping on cfDNA specimens from 24 patients and demonstrated that clinical resistance arose through acquisition of KRAS mutations, which were detectable in cfDNA up to 10 months prior to radiographic progression2. Similarly, Oxnard et al. demonstrated the presence of EGFR activating mutations in cfDNA prior to initiation of erlotinib therapy in EGFR mutant lung cancer patients, its reduction or disappearance during therapy and its subsequent re-emergence along with the drug resistance EGFR T790M mutation following continued erlotinib treatment5. The appearance of the EGFR T790M mutation was observed up to 3 months prior to the development of disease progression defined by radiographic (RECIST) criteria. Several different technologies for analyses of cfDNA are currently under evaluation. Allele-Specific Polymerase Chain Reaction (ASPCR) allows for the detection of pre-specified mutations in DNA and exploits the transcription initiation requirements of DNA polymerase. DNA polymerase requires a homology between the 3′ sequence of the primer and the DNA sequence to be transcribed. As such, mutation-specific primers can be designed, fluorescently tagged, and measured and will only be detectable if the correct homology, in this case mutant specific DNA fragment, exists. In cases of a sequence mismatch, extension will not be initiated, and the result would be read as a negative. Advantages of this approach include a low background signal,high sensitivity, and the ability to multiplex the detection of multiple pre-specified mutations at one time. Roche's cobas™ EGFR test is an example of an FDA approved allele-specific tissue based test, which measures 42 EGFR mutations simultaneously. In the current issue of Cancer, Sorensen at al applied a modified version of the cobas™ Tissue EGFR test (cobas™ EGFR blood test) on serially collected plasma from 23 advanced non-small cell lung cancer (NSCLC) patients that were known to have an EGFR sensitizing mutation6. In 22 out of 23 patients a reduction of the original EGFR sensitizing mutation was observed in plasma after 4 weeks of erlotinib treatment. There was considerable variation in the kinetics of the reduction with some patients demonstrating no residual detectable EGFR mutation in cfDNA after 4 weeks of erlotinib treatment. During the course of treatment, the reappearance of the EGFR activating mutation was detected from cfDNA in 17/23 patients. These differences in the kinetics of the mutant alleles may have long term clinical implications and need to be studied in a prospective clinical trial of EGFR mutant NSCLC patients. The current study is a subset of a larger cohort of lung cancer patients, some of whom harbor EGFR mutations, who were treated with erlotinib. In 9 out of 23 patients the known acquired resistance EGFR T790M mutation, which was not detectable in plasma at treatment initiation, was detected in plasma samples at progression. In some cases, the emergence of EGFR T790M was detected months ahead of radiographic progression6. While this study is not the first that investigate plasma genotyping as a way of noninvasively detecting EGFR T790M 7,8, nor to demonstrate that serial assessment of plasma genotype allows detection of resistance weeks (and sometimes months) prior to clinical development of resistance5, it does provide further evidence that plasma genotyping, particularly to monitor acquired resistance, may have clinical utility. It should be noted that the FDA approved version of the cobas™ EGFR test is qualitative and is only approved for using tumor tissue. The present study uses a cobas™ EGFR blood test in a research setting and uses a proprietary and still in development EGFR blood software analysis package. The analytical performance characteristics of this test are not provided. In general, ASPCR tests are best when used qualitative, and at-best are semi-quantitative. The sensitivity and specificity of this test are not provided, and it may be that these parameters vary for each of the alleles being examined. Emulsion PCR is an alternative allele-specific genotyping assays for the detection of mutations in the circulation of cancer patients. It is inherently sensitive, offers improvements in precision of detecting small changes in template DNA, and is highly quantitative. Emulsion PCR, a family of techniques that include droplet digital PCR or BEAMing (beads, emulsion, amplification and magnetics)9,10, involves partitioning input DNA into thousands of oil-aqueous emulsion droplets which can subsequently be evaluated as individual PCR reactions. On average each vessel contains one copy of your DNA template, which are PCR amplified to end-point, and read in a flow cytometer. Each droplet is assigned a positive and negative (1 or 0) value based on their fluorescent intensity, which then is used to calculate the allelic concentration and the 95% Poisson confidence levels. Emulsion PCR is currently being explored for its clinical utility in several diseases, including lung cancer, colon cancer, and melanoma. The quantitative nature of emulsion PCR allows one to define a diagnostically relevant concentration of mutant alleles that will minimize false positives and provides a straightforward path for assay performance characterization (i.e. sensitivity, specificity, reproducibility) across different laboratories. While the assay validation path is the same for ASPCR, and equally achievable, its' semi-quantitative nature may make it more difficult to compare the kinetic characteristics of the assay. The analytic landscape for these technologies is undergoing rapid change. However, platforms, such as ASPCR, emulsion PCR and more recently Next Generation Sequencing (NGS) 11,12 have become sufficiently analytically robust to support hypothesis-based, multi-institutional, and adequately powered prospective evaluation in lung cancer patients. Their true value in replacing or augmenting tissue based genomic analyses, either at diagnosis, or following the development of acquired resistance to targeted therapies needs to be evaluated in prospective clinical trials. For EGFR mutant lung cancer patients, the detection of the emergence of the EGFR T790M drug resistance mutation non-invasively using cfDNA, prior to the development of clinically or radiographically defined EGFR inhibitor resistance, at present time, has limited clinical utility due to the lack of effective treatments. However, this will likely change in the near future with the ongoing clinical development of third generation mutant selective EGFR kinase inhibitors including AZD9291 and CO-168613,14. To date, this class of agents appears to be more effective in patients with EGFR T790M mediated resistance compared to those with non-T790M mediated resistance. The ability to rapidly and non-invasively identify appropriate patients for treatment with new EGFR inhibitors highlights an important clinical application of analyzing cfDNA. However, before implementing such an approach clinically, the ability of cfDNA detected EGFR T790M to predict response to third generation EGFR inhibitor, will first need to be evaluated in a prospective clinical trial.

BACKGROUND: The objective of this study was to identify the factors associated with improved outcome after treatment for stage III nonsmall cell lung cancer (NSCLC). METHODS: A retrospective review of stage III NSCLC patients treated at who were treated at the Dana-Farber Cancer Institute/Brigham and Women's Cancer Center was done with institutional review board approval. Patients were followed for toxicity, local and distant failure, and overall survival. Multivariate Cox logistic regression analysis was used to determine the factors associated with treatment outcome. RESULTS: Between August 2000 and November 2006, 144 patients received concurrent chemoradiation (CRT) for stage III NSCLC. Eighty of 144 patients were men (56%), and the median age was 61 years (range, 33-81 years). Sixty-two patients (43%) had stage IIIA NSCLC, and 82 patients (57%) had stage IIIB NSCLC. Radiotherapy (RT) was given concurrently with chemotherapy to all patients; 100 patients (69%) received CRT without surgery, and 44 patients (31%) received with neoadjuvant CRT followed by surgical resection. The median RT dose was 60 grays (Gy) (range, 46-70 Gy). The median follow-up was 15 months (range, 3-64 months), the median potential follow-up was 37 months (range, 12-84 months), and the median overall survival was 22 months (95% confidence interval, 15-28 months). The 1-year and 2-year survival rates were 68% and 47%, respectively. Among the 44 patients who underwent resection, the median survival was 61 months, and the 2-year survival rate was 73%. On multivariate analysis, stage at the time of treatment (stage IIIA vs stage IIIB) and use of surgery were the only factors associated with improved outcome (P = .01 and P = .001, respectively). CONCLUSIONS: In this retrospective series, those patients who were able to undergo resection appeared to have improved outcome after induction CRT. Cancer 2009. © 2009 American Cancer Society.

BACKGROUND. We conducted a phase 2, multicenter, open-label study of erlotinib plus bevacizumab in patients with malignant pleural mesothelioma who had previously received 1 prior chemotherapy regimen. These agents have activity in non–small cell lung cancer, but their role in mesothelioma is unclear. The primary endpoint is response rate. Secondary endpoints include time to progression, survival, and toxicity. METHODS. Eligible patients with mesothelioma who had previously received 1 chemotherapy regimen were treated with erlotinib 150 mg per os daily and bevacizumab 15 mg/kg administered intravenously on Day 1 of a 21-day cycle. Treatment continued until disease progression or development of significant toxicity. Tumor response was assessed after every 2 cycles using previously established mesothelioma response criteria from Byrne and Nowak. RESULTS. Twenty-four eligible patients initiated therapy with erlotinib and bevacizumab between February 2004 and October 2006. There were no complete or partial responses, although 12 patients achieved stable disease for at least 2 cycles of treatment. The median time to progression was 2.2 months (95% confidence interval [CI], 1.4 months-5.9 months). The median survival was 5.8 months (95% CI, 2.8 months-10.1 months). The most common toxicities were rash and diarrhea. There were no treatment-related deaths, intracranial bleeding, or hemoptysis. CONCLUSIONS. The combination of erlotinib and bevacizumab was tolerated reasonably well, but there was no evidence of radiographic response. This study demonstrates the feasibility of conducting trials in mesothelioma patients who have failed first-line therapy. More therapeutic studies with effective agents are needed for these patients. Cancer 2008. © 2008 American Cancer Society.

BACKGROUND To determine the changes in clinical trials and outcomes of patients with limited-stage small cell lung carcinoma (SCLC) treated on Phase III randomized trials initiated in North America between 1972 and1992. METHODS Phase III trials from 1972 to 1992 for patients with limited-stage SCLC were identified. Patients with limited-stage SCLC treated during a similar time interval were also evaluated in the Surveillance, Epidemiology, and End Results (SEER) database. Trends were tested in the number of trials, in the number and gender of patients entered on trial, and in survival duration over time. RESULTS Thirty trials involving 6564 patients were eligible for analyses. Nineteen trials (61%) involving 3626 patients were initiated within the first half of this time period (1972–1981). The median of median survival times of all patients treated on the control arms of the Phase III trials initiated between 1972 and 1981 and between 1982 and 1992 were 12.0 months (range, 10–16 months) and 17.0 months (range, 11–20 months), respectively (P < 0.001). Of 26 studies available for survival analysis, 5 (19%) showed a statistically significant survival prolongation in the experimental arm compared with the control arm with a median prolongation of 3.4 months (range, 1–5.2 months). All five evaluated some aspect of thoracic radiation therapy. Over a similar time period, there was a 6.4-month increase in the median survival of limited-stage SCLC patients listed in the SEER database (P < 0.0001) and a more than doubling of the 5-year survival from 5.2% to 12.1% (P = 0.0001). CONCLUSIONS Analyses of the patients with limited-stage SCLC treated on Phase III trials in North America initiated between 1972 and 1992 and those listed in the SEER database show significant improvements in median survivals. Furthermore, the 5-year survival of patients with limited-stage SCLC listed in the SEER database has more than doubled over the last 25 years. Further research will be needed to determine the relative contribution of improved therapy, supportive care, and stage migration to this prolongation in survival. Cancer 2002;95:1528–38. © 2002 American Cancer Society. DOI 10.1002/cncr.10841

Background The feasibility of monitoring epidermal growth factor receptor (EGFR) mutations in plasma DNA from patients with advanced non–small cell lung cancer (NSCLC) during treatment with erlotinib and its relation to disease progression was investigated. Methods The amount of EGFR-mutant DNA was tested in plasma DNA from patients with advanced NSCLC with allele-specific polymerase chain reaction assays. Blood samples from 23 patients with adenocarcinoma of NSCLC that carried tyrosine kinase inhibitor-sensitizing EGFR mutations were taken immediately before treatment with erlotinib. Additional blood samples were taken at timed intervals until erlotinib treatment was withdrawn. Results The amount of plasma DNA with sensitizing EGFR mutations was found to be reduced after the first cycle of erlotinib treatment in 22 of 23 patients (96%). No patients presented with the resistant T790M mutation in the pretreatment sample, but at the time of disease progression the mutation was detected in plasma from 9 patients (39%). The quantitative data from the current study demonstrated that when a T790M mutation emerged in the blood it was accompanied by an increase in the original sensitizing EGFR mutation. When T790M was detected, it was found to be present in all subsequent blood samples from that patient. Most interestingly, the results of the current study demonstrated that monitoring the EGFR mutations in the blood allows for the detection of the T790M mutation up to 344 days before disease progression is clinically evident (range, 15-344 days). Conclusions The results of the current study demonstrated that serial monitoring of EGFR mutations in plasma DNA is feasible and may allow for the early detection of resistance mutations. These results warrant further studies to explore the clinical usefulness of such analysis.

BACKGROUND: Somatic mutations in the epidermal growth factor receptor (EGFR) are present in ∼10% of nonsmall cell lung cancers, and higher in never-smokers, women, and Asians. Small in-frame deletions in exon 19 (∼45%) and L858R mutation in exon 21 (∼40%) predict response to treatment with tyrosine kinase inhibitors, whereas some others herald resistance. Direct sequencing of tumor DNA detects all EGFR mutations, but is limited by interference from nonmalignant cells within the samples. Concern over such interference has discouraged testing cytologic samples, but the adequacy of cytologic specimens for EGFR sequencing has not been studied. METHODS: EGFR sequencing of surgical and cytologic specimens at Brigham and Women's Hospital over the past 2 years was reviewed. Of 239 specimens, 227 (95%) were surgical, and 12 (5%) were cytologic (fine needle aspirations, pleural fluids, bronchial washings, and bronchoalveolar lavages). RESULTS: Sixty-three (28%) surgical specimens showed EGFR mutations, whereas 143 (63%) were negative, 8 (3.5%) failed, and 14 (6.2%) were inconclusive (negative result in a heterogeneous sample). Seven (58%) cytologic specimens showed EGFR mutations, whereas 4 (33%) were negative, and 1 (8.3%) was inconclusive. Cytologic specimens were more likely to have a mutation than surgical specimens (P = .02). There was no significant difference in the frequency of inconclusive results. CONCLUSIONS: Cytologic specimens are suitable for EGFR sequencing and show comparable sensitivity for mutation detection as compared with surgical specimens. The suitability of a sample should be determined on a case-by-case basis, and cytologic samples should not be dismissed as inadequate without a thorough review. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.

To determine the changes in clinical trials and outcomes of patients with limited-stage small cell lung carcinoma (SCLC) treated on Phase III randomized trials initiated in North America between 1972 and 1992.Phase III trials from 1972 to 1992 for patients with limited-stage SCLC were identified. Patients with limited-stage SCLC treated during a similar time interval were also evaluated in the Surveillance, Epidemiology, and End Results (SEER) database. Trends were tested in the number of trials, in the number and gender of patients entered on trial, and in survival duration over time.Thirty trials involving 6564 patients were eligible for analyses. Nineteen trials (61%) involving 3626 patients were initiated within the first half of this time period (1972-1981). The median of median survival times of all patients treated on the control arms of the Phase III trials initiated between 1972 and 1981 and between 1982 and 1992 were 12.0 months (range, 10-16 months) and 17.0 months (range, 11-20 months), respectively (P0.001). Of 26 studies available for survival analysis, 5 (19%) showed a statistically significant survival prolongation in the experimental arm compared with the control arm with a median prolongation of 3.4 months (range, 1-5.2 months). All five evaluated some aspect of thoracic radiation therapy. Over a similar time period, there was a 6.4-month increase in the median survival of limited-stage SCLC patients listed in the SEER database (P0.0001) and a more than doubling of the 5-year survival from 5.2% to 12.1% (P = 0.0001).Analyses of the patients with limited-stage SCLC treated on Phase III trials in North America initiated between 1972 and 1992 and those listed in the SEER database show significant improvements in median survivals. Furthermore, the 5-year survival of patients with limited-stage SCLC listed in the SEER database has more than doubled over the last 25 years. Further research will be needed to determine the relative contribution of improved therapy, supportive care, and stage migration to this prolongation in survival.