M1b Disease in the 8th Edition of TNM Staging of Lung Cancer: Pattern of Single Extrathoracic Metastasis and Clinical Outcome.

BACKGROUND: The 8th edition of TNM staging of non-small cell lung cancer (NSCLC) has revised M classification and defined M1b disease with single extrathoracic metastasis, which is distinguished from M1c with multiple extrathoracic metastases. We investigated the prevalence, characteristics, and overall survival (OS) of M1b disease in patients with stage IV NSCLC. METHODS: The study reviewed the medical records and imaging studies of 567 patients with stage IV NSCLC to determine M stage using the 8th edition of TNM staging. Clinical characteristics and OS were compared according to M stages. RESULTS: Among 567 patients, 57 patients (10%) had M1b disease, whereas 119 patients (21%) had M1a disease and 391 patients (69%) had M1c disease. Squamous histology was more common in M1b (16%) than in M1a (6%) and M1c (6%; p = .03). The median OS of patients with M1b disease was 14.8 months, compared with 22.6 months for patients with M1a and 13.4 months for those with M1c disease (p < .0001). Significant OS differences of M1b compared with single-organ M1c and multiorgan M1c groups were noted (single-organ M1c vs. M1b: hazard ratio [HR], 1.49; p = .02; multiorgan M1c vs. M1b: HR, 1.57; p = .01) in multivariable analyses adjusting for smoking and systemic therapy types. Among patients with M1b disease, the brain was the most common site of single metastasis (28/57; 49%), followed by bone (16/57; 28%). Single brain metastasis was more frequently treated with local treatment (p < .0001). CONCLUSION: M1b disease was noted in 10% of patients with stage IV NSCLC. Squamous histology was more common in M1b group than others. The brain was the most common site of single metastasis and was often treated locally. IMPLICATIONS FOR PRACTICE: The newly defined group of M stage consists of a unique subset among patients with stage IV non-small cell lung cancer that can be studied further to optimize treatment approaches.

Algorithm-based decision support for symptom self-management among adults with Cancer: results of usability testing.

BACKGROUND: It is essential that cancer patients understand anticipated symptoms, how to self-manage these symptoms, and when to call their clinicians. However, patients are often ill-prepared to manage symptoms at home. Clinical decision support (CDS) is a potentially innovative way to provide information to patients where and when they need it. The purpose of this project was to design and evaluate a simulated model of an algorithm-based CDS program for self-management of cancer symptoms. METHODS: This study consisted of three phases; development of computable algorithms for self-management of cancer symptoms using a modified ADAPTE process, evaluation of a simulated model of the CDS program, and identification of design objectives and lessons learned from the evaluation of patient-centered CDS. In phase 1, algorithms for pain, constipation and nausea/vomiting were developed by an expert panel. In phase 2, we conducted usability testing of a simulated symptom assessment and management intervention for self-care (SAMI-Self-Care) CDS program involving focus groups, interviews and surveys with cancer patients, their caregivers and clinicians. The Acceptability E-scale measured acceptability of the program. In phase 3, we developed design objectives and identified barriers to uptake of patient-centered CDS based on the data gathered from stakeholders. RESULTS: In phase 1, algorithms were reviewed and approved through a consensus meeting and majority vote. In phase 2, 24 patients & caregivers and 13 clinicians participated in the formative evaluation. Iterative changes were made in a simulated SAMI-Self-Care CDS program. Acceptability scores were high among patients, caregivers and clinicians. In phase 3, we formulated CDS design objectives, which included: 1) ensure patient safety, 2) communicate clinical concepts effectively, 3) promote communication with clinicians, 4) support patient activation, and 5) facilitate navigation and use. We identified patient barriers and clinician concerns to using CDS for symptom self-management, which were consistent with the chronic care model, a theoretical framework used to enhance patient-clinician communication and patient self-management. CONCLUSION: Patient safety and tool navigation were critical features of CDS for patient self-management. Insights gleaned from this study may be used to inform the development of CDS resources for symptom self-management in patients with other chronic conditions.

Clinician perspectives on symptom and quality of life experiences of patients during cancer therapies: Implications for eHealth.

OBJECTIVE: The purpose of this study was to explore clinician experiences with cancer symptom and quality of life (SQL) management from diagnosis throughout therapy in the ambulatory setting, plus identify preferences for a future SQL decision support system. METHODS: Eligible clinicians worked in ambulatory cancer care with responsibility for direct patient care. Focus groups were conducted to discuss symptom management throughout the treatment experience and features desired in a future decision support system. Each group was audio-recorded, transcribed, de-identified, and entered into NVivo 9 for analysis. Open and axial coding was completed, grouping common concepts into nodes; large constructs among the nodes were identified and main messages were synthesized. RESULTS: A total of 118 clinicians were contacted by email resulting in a final sample of 51 attending 1 of 9 focus groups. Clinicians described a standard face-to-face approach to assessment of SQL, before and throughout therapy. Preparing patients for expected symptoms and approaches to management included paper-based patient education materials and referrals. Communicating with patients between visits was covered in detail, notably use of telephone and email. Future system features desired by the clinicians included an electronic, Web-based system with real-time, trended data, reasonable alerts, and tailored information for patients. CONCLUSIONS: Cancer care specialists reported strategies to assess and manage cancer SQL in ambulatory care including patient-reported outcome measures, contact communication modes, face-to-face interviews, and paper-based patient education materials. Future system features desired by clinicians included an electronic, Web-based system with real-time, trended data, reasonable alerts, and tailored information for patients.

Patient and caregiver perspectives on decision support for symptom and quality of life management during cancer treatment: Implications for eHealth.

OBJECTIVES: Adequate symptom and quality-of-life (SQL) management is a priority during cancer treatment. eHealth is a timely way to enhance patient-engagement, facilitate communication, and improve health outcomes. The objectives of this study were to describe patient and caregivers' perspectives for providing, processing, and managing SQL data to enhance communication and identify desired components for decision support. METHODS: Data were collected from 64 participants through questionnaires and focus groups. Analysis was conducted using NVivo. Open and axial coding was completed, grouping commonalities and large constructs into nodes to identify and synthesize themes. RESULTS: Face-to-face meetings with clinicians were the prime time to communicate, and patients strove to understand treatment options and the effect on SQL by bringing caregivers to their visits, taking notes, tracking symptoms, and creating portable health records. Patients/caregivers struggled to self-manage their symptoms and were uncertain when to contact clinicians when experiencing uncontrolled symptoms. Most participants identified eHealth solutions for decision support. However, 38% of participants (n = 24) rarely used computers and identified non-eHealth options for decision support. Core components for both eHealth and non-eHealth systems were access to (1) cancer information, (2) medical records, (3) peer support, and (4) improved support and understanding on when to contact clinicians. CONCLUSIONS: Patients were faced with an overwhelming amount of information and relied on their caregivers to help navigate the complexities of cancer care and self-manage SQL. Health technologies can provide informational support; however, decision support needs to span multiple venues to avoid increasing disparities caused by a digital divide.

Volumetric tumor growth in advanced non-small cell lung cancer patients with EGFR mutations during EGFR-tyrosine kinase inhibitor therapy: developing criteria to continue therapy beyond RECIST progression.

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 (log(e)V). RESULTS: A linear mixed-effects model was fitted to predict the growth of log(e)V, adjusting for time in months from baseline. Log(e)V was estimated as a function of time in months among patients whose tumors started growing after the nadir: log(e)V = 0.12*time + 7.68. In this formula, the regression coefficient for time, 0.12/month, represents the growth rate of log(e)V (standard error, 0.015/month; P < .001). When adjusted for baseline volume, log(e)V0, the growth rate was also 0.12/month (standard error, 0.015/month; P < .001; log(e)V = 0.12*months + 0.72 log(e)V0 + 0.61). CONCLUSIONS: Tumor volume models defined volumetric tumor growth after the nadir in patients with EGFR-mutant, advanced NSCLC who were receiving TKI, providing a reference value for the tumor growth rate in patients who progress after the nadir on TKI therapy. The results can be studied further in additional cohorts to develop practical criteria to help identify patients who are slowly progressing and can safely remain on EGFR-TKIs.

RECIST 1.1 in NSCLC patients with EGFR mutations treated with EGFR tyrosine kinase inhibitors: comparison with RECIST 1.0.

OBJECTIVE: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 has been rapidly accepted in clinical trials as a standard measure to assess tumor response to therapy and is expected to improve response assessment, especially in genomically defined patients. The impact of RECIST 1.1 was compared with RECIST 1.0 in non-small cell lung cancer (NSCLC) patients with sensitizing epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors. MATERIALS AND METHODS: Seventy patients with advanced NSCLC harboring sensitizing EGFR mutations treated with a first-line EGFR tyrosine kinase inhibitor were retrospectively studied. Tumor measurements and response assessment were performed using RECIST 1.0 and RECIST 1.1. The number of target lesions, the percentage change at the initial follow-up, best response, and time to progression were compared between RECIST 1.1 and RECIST 1.0. RESULTS: The number of target lesions identified using RECIST 1.1 was significantly lower compared with that using RECIST 1.0 (mean, 2.7 and 2.0, respectively; p < 0.0001; paired Student t test), with a decrease in 31 patients (44%). The initial proportional changes of the target lesion measurements had high correlation between the two criteria (R(2) = 0.8070), with concordant response assessment in 66 patients (94%). The best response showed almost perfect agreement (κw = 0.970). Time to progression (TTP) did not differ between the two criteria in 52 patients (74%), was longer by RECIST 1.1 in 15 patients (21%), and was shorter by RECIST 1.1 in three patients (4%). CONCLUSION: RECIST 1.1 provided highly concordant response assessment with a decreased number of target lesions compared with RECIST 1.0 in advanced NSCLC patients harboring sensitizing EGFR mutations treated with an EGFR tyrosine kinase inhibitor. RECIST 1.1 altered TTP in 25% of patients compared with RECIST 1.0.

First-line systemic therapy practice patterns and concordance with NCCN guidelines for patients diagnosed with metastatic NSCLC treated at NCCN institutions.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) allow many systemic therapy options for patients with metastatic non-small cell lung cancer (NSCLC). This analysis uses the NCCN NSCLC Outcomes Database to report on first-line therapy practice patterns and concordance with NCCN Guidelines. The analysis was limited to patients diagnosed with metastatic NSCLC between September 2006 and November 2009 at 1 of 8 participating NCCN Member Institutions. Patient characteristics, regimens used, and guidelines concordance were analyzed. Institutional variation and changes in practice over time were also measured. A total of 1717 patients were included in the analysis. Of these, 1375 (80%) were treated with systemic therapy, most often in the form of a carboplatin-based doublet (51%) or carboplatin-based doublet with targeted therapy (17%). Overall, 76% of patients received care that was concordant with NCCN Guidelines. Among patients with good performance status (n = 167), the most common reasons for not receiving first-line therapy were that therapy was not recommended (39%) or death occurred before treatment (33%). The most common reason for receiving nonconcordant drug therapy was the administration of pemetrexed or erlotinib before its incorporation into the NCCN Guidelines for first-line therapy (53%). Most patients in this cohort received care that was concordant with NCCN Guidelines. The NSCLC Outcomes Database is a valuable resource for evaluating practice patterns and concordance with NCCN Guidelines among patients with NSCLC.

Osimertinib-Induced Cutaneous Vasculitis Responsive to Low-Dose Dapsone Without Interruption of Anticancer Therapy: A Case Report and Review of the Literature.

A 45-year-old woman with a history of lung adenocarcinoma treated with osimertinib developed purpuric plaques and vesicles on the lower extremities after 5 months of therapy. Skin biopsy revealed leukocytoclastic vasculitis (LCV). A workup for systemic involvement was unremarkable. The patient was treated with oral dapsone while continuing osimertinib without interruption. Skin lesions cleared within 2 weeks of therapy with no recurrence after titrating off dapsone. To the best of our knowledge, this is the first reported case of LCV induced by a small-molecule EGFR inhibitor in which therapy was not interrupted. This is also the first reported case treated with dapsone rather than systemic corticosteroids. We suggest consideration of dapsone to treat skin-limited LCV induced by EGFR inhibitors in patients with lung cancer without features of systemic vasculitis. In addition, this case highlights that it may not be necessary to stop EGFR inhibitor therapy in the absence of severe features such as ulceration, bullae, necrosis, or severe pain. Dapsone is an effective targeted therapy for cutaneous LCV that does not globally impair the immune system and may allow for uninterrupted treatment of the underlying malignancy.

Phase II Study of Lorlatinib in Patients With Anaplastic Lymphoma Kinase-Positive Lung Cancer and CNS-Specific Relapse.

PURPOSE: The CNS is a recurrent site of progression in anaplastic lymphoma kinase (ALK)-rearranged (ALK+) lung cancer. Lorlatinib is a third-generation ALK inhibitor developed to penetrate the CNS and overcome ALK resistance mutations. We conducted a phase II study to evaluate the intracranial activity of lorlatinib in patients with CNS-only progression on second-generation ALK inhibitors. METHODS: Patients with ALK+ lung cancer who had intracranial progression on ≥ 1 ALK inhibitor without measurable extracranial disease received lorlatinib 100 mg once daily. The primary end point was intracranial disease control rate at 12 weeks per modified RECIST v1.1. Secondary end points included intracranial progression-free survival, intracranial objective response rate, and safety/tolerability. RESULTS: Twenty-three patients were enrolled between November 2016 and January 2019. Fifteen (65%) patients had irradiated CNS metastases, with a median of 20.2 months between radiation and lorlatinib. Control of intracranial disease was observed in 21 (95%) evaluable patients at 12 weeks. The intracranial objective response rate was 59% with six complete and seven partial responses. The median intracranial progression-free survival was 24.6 months (95% CI, 20.2 to not reached). With a median follow-up of 16.8 months, nine patients developed disease progression, including four patients with CNS progression. The most common treatment-related adverse events were hypercholesterolemia (96%), hypertriglyceridemia (87%), edema (65%), cognitive effects (52%), and mood effects (43%). Three patients discontinued treatment because of toxicity, including two patients with fatal respiratory events. CONCLUSION: Lorlatinib induced durable intracranial disease control in patients with CNS-only relapse on second-generation ALK inhibitors, suggesting that tumors with CNS-limited progression on brain-penetrant ALK tyrosine kinase inhibitors remain ALK-dependent.

Clinical Decision Support for Symptom Management in Lung Cancer Patients: A Group RCT.

CONTEXT: Clinical guidelines are available to enhance symptom management during cancer treatment but often are not used in the practice setting. Clinical decision support can facilitate the implementation and adherence to clinical guidelines. and improve the quality of cancer care. OBJECTIVES: Clinical decision support offers an innovative approach to integrate guideline-based symptom management into oncology care. This study evaluated the effect of clinical decision support-based recommendations on clinical management of symptoms and health-related quality of life (HR-QOL) among outpatients with lung cancer. METHODS: Twenty providers and 179 patients were allotted in group randomization to attention control (AC) or Symptom Assessment and Management Intervention (SAMI) arms. SAMI entailed patient-report of symptoms and delivery of recommendations to manage pain, fatigue, dyspnea, depression, and anxiety; AC entailed symptom reporting prior to the visit. Outcomes were collected at baseline, two, four and six-months. Adherence to recommendations was assessed through masked chart review. HR-QOL was measured by the Functional Assessment of Cancer Therapy-Lung questionnaire. Descriptive statistics with linear and logistic regression accounting for the clustering structure of the design and a modified chi-square test were used for analyses. RESULTS: Median age of patients was 63 years, 58% female, 88% white, and 32% ≤high school education. Significant differences in clinical management were evident in SAMI vs. AC for all target symptoms that passed threshold. Patients in SAMI were more likely to receive sustained-release opioids for constant pain, adjuvant medications for neuropathic pain, opioids for dyspnea, stimulants for fatigue and mental health referrals for anxiety. However, there were no statistically significant differences in HR-QOL at any time point. CONCLUSION: SAMI improved clinical management for all target symptoms but did not improve patient outcomes. A larger study is warranted to evaluate effectiveness.

Association between Smoking History and Tumor Mutation Burden in Advanced Non-Small Cell Lung Cancer.

Lung carcinogenesis is a complex and stepwise process involving accumulation of genetic mutations in signaling and oncogenic pathways via interactions with environmental factors and host susceptibility. Tobacco exposure is the leading cause of lung cancer, but its relationship to clinically relevant mutations and the composite tumor mutation burden (TMB) has not been fully elucidated. In this study, we investigated the dose-response relationship in a retrospective observational study of 931 patients treated for advanced-stage non-small cell lung cancer (NSCLC) between April 2013 and February 2020 at the Dana Farber Cancer Institute and Brigham and Women's Hospital. Doubling smoking pack-years was associated with increased KRASG12C and less frequent EGFRdel19 and EGFRL858R mutations, whereas doubling smoking-free months was associated with more frequent EGFRL858R . In advanced lung adenocarcinoma, doubling smoking pack-years was associated with an increase in TMB, whereas doubling smoking-free months was associated with a decrease in TMB, after controlling for age, gender, and stage. There is a significant dose-response association of smoking history with genetic alterations in cancer-related pathways and TMB in advanced lung adenocarcinoma. SIGNIFICANCE: This study clarifies the relationship between smoking history and clinically relevant mutations in non-small cell lung cancer, revealing the potential of smoking history as a surrogate for tumor mutation burden.

High Sensitivity of Plasma Cell-Free DNA Genotyping in Cases With Evidence of Adequate Tumor Content.

Plasma cell-free DNA (cfDNA) sequencing is a compelling diagnostic tool in solid tumors and has been shown to have high positive predictive value. However, limited assay sensitivity means that negative plasma genotyping, or the absence of detection of mutation of interest, still requires reflex tumor biopsy. METHODS: We analyzed two independent cohorts of patients with advanced non-small-cell lung cancer (NSCLC) with known canonical driver and resistance mutations who underwent plasma cfDNA genotyping. We measured quantitative features, such as maximum allelic frequency (mAF), as clinically available measures of cfDNA tumor content, and studied their relationship with assay sensitivity. RESULTS: In patients with EGFR-mutant NSCLC harboring EGFR T790M, detection of driver mutation at > 1% AF conferred a sensitivity of 97% (368/380) for detection of T790M across three cfDNA genotyping platforms. Similarly, in a second cohort of patients with EGFR or KRAS driver mutations, when the mAF of nontarget mutations was > 1%, sensitivity for driver mutation detection was 100% (43/43). Combining the two NSCLC patient cohorts, the presence of nontarget mutations at mAF > 1% predicts for high sensitivity (> 95%) for identifying the presence of the known driver mutation, whereas mAF of ≤ 1% confers sensitivity of only 26%-54% across platforms. Focusing on 21 false-negative cases where the driver mutation was not detected on plasma next-generation sequencing, other mutations (presumably clonal hematopoiesis) were detected at ≤ 1% AF in 14 (67%). CONCLUSION: Plasma cfDNA genotyping is highly sensitive when adequate tumor DNA content is present. The likelihood of a false-negative cfDNA genotyping result is low in a sample with evidence of > 1% tumor content. Bioinformatic approaches are needed to further optimize the assessment of cfDNA tumor content in plasma genotyping assays.

Identification of a RAS-activating TMEM87A-RASGRF1 Fusion in an Exceptional Responder to Sunitinib with Non-Small Cell Lung Cancer.

PURPOSE: We pursued genomic analysis of an exceptional responder with non-small cell lung cancer (NSCLC) through a multi-platform effort to discover novel oncogenic targets. EXPERIMENTAL DESIGN: In this open-label, single-arm phase II study (NCT01829217), an enriched cohort of patients with advanced NSCLC was treated with the multi-kinase inhibitor sunitinib. The primary endpoint was objective response rate. Tissue was collected for multi-platform genomic analysis of responders, and a candidate oncogene was validated using in vitro models edited by CRISPR-Cas9. RESULTS: Of 13 patients enrolled, 1 patient (8%), a never smoker, had a partial response lasting 33 months. Genomic analysis of the responder identified no oncogenic variant using multi-platform DNA analysis including hotspot allelotyping, massively parallel hybrid-capture next-generation sequencing, and whole-exome sequencing. However, bulk RNA-sequencing (RNA-seq) revealed a novel fusion, TMEM87A-RASGRF1, with high overexpression of the fusion partners. RASGRF1 encodes a guanine exchange factor which activates RAS from GDP-RAS to GTP-RAS. Oncogenicity was demonstrated in NIH/3T3 models with intrinsic TMEM87A-RASGRF1 fusion. In addition, activation of MAPK was shown in PC9 models edited to express this fusion, although sensitivity to MAPK inhibition was seen without apparent sensitivity to sunitinib. CONCLUSIONS: Sunitinib exhibited limited activity in this enriched cohort of patients with advanced NSCLC. Nonetheless, we find that RNA-seq of exceptional responders represents a potentially underutilized opportunity to identify novel oncogenic targets including oncogenic activation of RASGRF1.

Turnaround Time of Plasma Next-Generation Sequencing in Thoracic Oncology Patients: A Quality Improvement Analysis.

PURPOSE: Genomic analysis of plasma cell-free DNA has become a widespread tool for advanced non-small-cell lung cancer care. Whereas accuracy has been reported on widely, its usefulness is also tied tightly to its turnaround time (TAT), which is not well studied. METHODS: We studied the TAT of commercial plasma next-generation sequencing (NGS; Guardant360) for 533 results from 461 patients at our center between August 2016 and October 2019. The study received institutional review board approval as a quality improvement study; therefore, the results of the test and clinical setting were not analyzed. RESULTS: TAT from blood draw to result (median of 9 days) was slightly longer than the TAT from laboratory receipt to result, a median of 7 days. Testing volume at our center increased three-fold over the time of the study. During this period, clinical TAT decreased from an initial median of 12 days to a median of 8 days in 2018, but more recently the median increased slightly to 9 days. During the most recent 12 months, 231 (95%) of 247 cases resulted within 14 days from blood draw, with delayed results usually because of billing, whereas 44 cases (18%) resulted within 7 days of blood draw. Studying 92 cases drawn in the most recent 3-month period, the median time of result receipt was 4:01 pm Eastern Time/1:01 pm Pacific Time; 39 results (43%) were returned after 5:00 pm Eastern Time. CONCLUSION: In a large single-institution experience, we find that plasma NGS results can routinely be expected within 2 weeks, but uncommonly result within 1 week, supporting the need for new strategies to incorporate plasma NGS into the initial genotyping of advanced non-small-cell lung cancer.

Interstitial lung abnormality in stage IV non-small cell lung cancer: A validation study for the association with poor clinical outcome.

PURPOSE: The presence of interstitial lung abnormality (ILA) at diagnosis of stage IV non-small cell lung cancer (NSCLC) patients has previously shown to be associated with shorter overall survival (OS). The present study aimed to validate the association between ILA and shorter OS in a larger cohort of treatment-naïve stage IV NSCLC patients. MATERIALS AND METHODS: This study includes 484 patients (205 men and 279 women) with a pathological diagnosis of stage IV NSCLC with pretreatment baseline CT available for review. ILA was visually scored on the baseline chest CT with a 3-point scale (0=no ILA, 1=indeterminate for ILA, 2 = ILA) as published previously. Clinical characteristics and overall survival (OS) were compared in patients with ILA score 2 vs. those with ILA score 0 or 1. RESULTS: ILA was present (score 2) on baseline CT in 19 of 484 patients (3.9%, 95%CI2.4-6.1%). Patients with ILA were significantly older (p = 0.0008) and more commonly male (p = 0.03) compared to those with ILA score 0 or 1. Patients with ILA score 2 showed significantly shorter OS compared to those with ILA score 0 or 1 (median OS 9.95 months vs. 16.95 months; p = 0.0002). In multivariate analyses, baseline ILA score 2 remained significant as a marker for shorter OS (HR = 2.09, p = 0.004) after adjustments for age (HR = 1.48; p = 0.001), gender (HR = 1.22, p = 0.06), and smoking (HR = 0.79; p = 0.051). CONCLUSIONS: ILA on baseline CT at diagnosis of stage IV NSCLC patients was associated with shorter OS (HR = 2.09, p = 0.004), validating ILA as an independent marker for poor clinical outcome.

Outcomes by EGFR, KRAS, and ALK Genotype After Combined Modality Therapy for Locally Advanced Non-Small-Cell Lung Cancer.

PURPOSE: In 699 patients with locally advanced non-small-cell lung cancer (NSCLC) treated with radiation therapy as part of combined modality therapy, we compared outcomes among genotyped and ungenotyped patients and by tumor genotype status (EGFR, KRAS, and ALK). PATIENTS AND METHODS: Genotyping was performed in 250 patients: EGFR+ (19%), KRAS+ (32%), ALK+ (9%), and wild type (WT-/-/-; 40%). Outcomes were analyzed using the Kaplan-Meier method and Cox regression. RESULTS: With a median follow-up of 48.2 months among genotyped patients, median overall survival (OS) was significantly longer for EGFR+ and ALK+ compared with KRAS+ and WT-/-/- (55.8 months v not reached v 28.0 v 33.2 months; P = .02). There was no difference in progression-free survival (median, 15.3 v 13.7 v 13.0 v 14.5 months; P = .47) or in freedom from distant metastases by genotype (3-year estimates: 42% v 49% v 27% v 25%; P = .25). There was higher freedom from locoregional recurrence (LRR) for EGFR+ tumors and lower freedom from LRR in ALK+ tumors, compared with KRAS+ and WT-/-/- tumors (3-year: 77% v 38% v 49% v 46%). In multivariable analysis, ALK+ remained associated with increased OS (HR, 0.32; 95% CI, 0.12 to 0.87; P = .03), and EGFR+ was associated with decreased LRR (HR, 0.47; 95% CI, 0.24 to 0.92; P = .03). Analysis of post-recurrence survival demonstrated that EGFR+/ALK+ patients treated with appropriate tyrosine kinase inhibitors had higher OS compared with other groups. CONCLUSION: In this series of locally advanced NSCLC treated with combined modality therapy, EGFR+ and ALK+ were associated with higher OS, whereas LRR was lower in EGFR+ patients, and the risk of distant metastases was high in all subgroups. The outcomes and patterns of failure in genotypic subgroups of NSCLC from this study can inform the design of future trials integrating targeted therapies.

Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib.

Importance: Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood. Objective: To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior. Design, Setting, and Participants: Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017. Main Outcomes and Measures: Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib. Results: Of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01). Conclusions and Relevance: Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.

Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib.

PURPOSE: Somatic mutations in the epidermal growth factor receptor (EGFR) have been detected in patients with non-small cell lung cancer (NSCLC) and are associated with sensitivity to treatment with gefitinib or erlotinib. Our study explored the relationship between the two most common types of somatic EGFR mutations, exon 19 deletions and the L858R point mutation, and outcomes of patients following treatment with gefitinib or erlotinib. EXPERIMENTAL DESIGN: Tumor specimens obtained before treatment with gefitinib or erlotinib were analyzed for EGFR mutations. Patients with exon 19 deletion or L858R mutations were identified. The response rate, time to progression, and overall survival were determined for the two groups. RESULTS: We identified 36 patients with NSCLC and an EGFR mutation who were treated with gefitinib or erlotinib. Patients with an exon 19 deletion had a significantly longer overall survival compared with patients with an L858R mutation (38 versus 17 months; P = 0.04). There were also trends toward higher response rate (73% versus 50%) and improved time to progression (24 versus 10 months) for the patients with an exon 19 deletion, although these were not independently significant in a multivariate analysis. A difference in response rate for patients treated with gefitinib compared with erlotinib was also noted [18 of 23 (78%) versus 3 of 9 (33%); P = 0.04]. No obvious difference in time to progression or overall survival was noted between gefitinib- and erlotinib-treated patients. CONCLUSIONS: Patients with NSCLC and EGFR exon 19 deletions have a longer survival following treatment with gefitinib or erlotinib compared with those with the L858R mutation. Pooling of greater numbers of patients and completion of prospective trials are needed to further define the predictive and prognostic roles of different EGFR mutations with respect to treatment with gefitinib, erlotinib, and other EGFR inhibitors.