Comparison of home-based spirometry and oscillometry measurements in school-age children with bronchopulmonary dysplasia.

INTRODUCTION: This study compares home-based oscillometry and spirometry for characterizing respiratory system disease in school-aged children with bronchopulmonary dysplasia (BPD) in clinical research. We hypothesized higher rates of successful completion and abnormal cases identified through oscillometry, with correlations between device measurements. METHODS: Participants 6-12 years old with BPD in the ongoing Air Quality, Environment and Respiratory Outcomes in BPD (AERO-BPD) study performed oscillometry followed by spirometry at two separate home visits. Parameters measured included airway resistance at 5 Hz(R5), resistance from 5 to 19 Hz(R5-19), resonance frequency(Fres), reactance at 5 Hz(X5), area under the curve between Fres and X5(AX), forced expiratory volume in 1 second(FEV1), forced vital capacity(FVC), and FEV1/FVC. Descriptive statistics identified the proportion of successful tests, correlation in measurements, and rate of lung disease for each device. RESULTS: Among 76 subjects with 120 paired observations, 95% and 71% of participants successfully performed oscillometry and spirometry, respectively, at home visit one. 98% and 77% successfully performed oscillometry and spirometry, respectively, at home visit two. Odds ratios favored oscillometry (range 5.31-10.13, p < 0.01). FEV1 correlated with AX (correlation coefficient r = -0.27, p = 0.03); FEV1/FVC with AX (r = -0.32, p = 0.02); and FEV1/FVC with R5 (r = -0.37, p = 0.01). AX exhibited the highest prevalence of abnormality at 25%; other oscillometry parameters ranged from 5%-22%. Forty-five to sixty-four percent of participants had abnormal spirometry. Oscillometry assessments had significantly lower odds of capturing lung disease (odds ratios 0.07-0.24, p < 0.0001). CONCLUSIONS: School-aged children with BPD demonstrated higher success rates in field-based oscillometry than spirometry. Spirometry exhibited higher rates of abnormality than oscillometry. Moderate correlation exists between device measurements.

Comparison of Pneumotachometer and Portable Digital Turbine Spirometry for Field-Based Assessment: An Air Quality, Environment, and Respiratory Outcomes in Bronchopulmonary Dysplasia Study.

Introduction: Data on the use of remote spirometry are limited in the pediatric population. We sought to assess the feasibility and accuracy of a digital turbine spirometer, Medical International Research (MIR) Spirobank Smart (MIR, New Berlin, WI, USA), compared with a pneumotachography spirometer, Pneumotrac (Vitalograph Inc., Lenexa, KS, USA), in field-based clinical research. Methods: This is a cross-sectional study of a subgroup of school-aged participants enrolled in the Air quality, Environment, and Respiratory Outcomes in Bronchopulmonary Dysplasia (BPD) study, who performed same-day paired coached baseline spirometry measurements from the Pneumotrac and MIR devices. Proportion of successful tests was estimated for each device and compared using McNemar's test. Correlation between devices forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) was analyzed by Lin's concordance correlation, and Bland-Altman plots were generated. Results: Twenty-one participants with history of BPD completed home spirometry maneuvers on both devices. The mean age of participants was 8.7 years. The mean FEV1 and FVC measurement was 81% predicted and 90.4% predicted, respectively. The proportion of acceptable tests appeared higher using Pneumotrac (81%) than when using MIR (67%), although without evidence of discordance (P = 0.317). Among subjects with successful tests on both devices, Lin's concordance correlation demonstrated moderate agreement (FEV1 r = 0.955, 95% confidence interval [CI]: 0.87-0.98; FVC r = 0.971, CI: 0.91-0.99). The mean difference in FEV1 between Pneumotrac and MIR was 0.079 L (95% limits of agreement were -0.141 to 0.298 L) and FVC was 0.075 L (95% limits of agreement were -0.171 to 0.322 L). These were relatively small and without evidence of systematic or volume-dependent bias. Conclusions: Utilizing turbine spirometers may be a promising and feasible way to perform pulmonary function testing for field research in children.

Germline EGFR Mutations and Familial Lung Cancer.

PURPOSE: The genomic underpinnings of inherited lung cancer risk are poorly understood. This prospective study characterized the clinical phenotype of patients and families with germline EGFR pathogenic variants (PVs). METHODS: The Investigating Hereditary Risk from T790M study (ClinicalTrials.gov identifier: NCT01754025) enrolled patients with lung cancer whose tumor profiling harbored possible germline EGFR PVs and their relatives, either in person or remotely, providing germline testing and follow-up. RESULTS: A total of 141 participants were enrolled over a 5-year period, 100 (71%) remotely. Based upon previous genotyping, 116 participants from 59 kindreds were tested for EGFR T790M, demonstrating a pattern of Mendelian inheritance with variable lung cancer penetrance. In confirmed or obligate carriers of a germline EGFR PV from 39 different kindreds, 50/91 (55%) were affected with lung cancer with 34/65 (52%) diagnosed by age 60 years. Somatic testing of lung cancers in carriers revealed that 35 of 37 (95%) had an EGFR driver comutation. Among 36 germline carriers without a cancer diagnosis, 15 had computed tomography (CT) imaging and nine had lung nodules, including a 28-year-old with >10 lung nodules. Given geographic enrichment of germline EGFR T790M in the southeast United States, genome-wide haplotyping of 46 germline carriers was performed and identified a 4.1-Mb haplotype shared by 41 (89%), estimated to originate 223-279 years ago. CONCLUSION: To our knowledge, this is the first prospective description of familial EGFR-mutant lung cancer, identifying a recent founder germline EGFR T790M variant enriched in the Southeast United States. The high prevalence of EGFR-driver lung adenocarcinomas and lung nodules in germline carriers supports effort to identify affected patients and family members for investigation of CT-based screening for these high-risk individuals.

Health-Related Qualities of Life in School-Aged Children with Bronchopulmonary Dysplasia.

OBJECTIVE: To determine health-related quality of life (HRQOL) of school-aged children with bronchopulmonary dysplasia (BPD) using the standardized Patient-Reported Outcomes Measurement Information System (PROMIS) assessment tools. STUDY DESIGN: The Indoor Air Quality and Respiratory Morbidity in Children with BPD Study is an ongoing observational study of school-aged children with BPD. HRQOL is assessed at enrollment by 3 PROMIS questionnaires, Parent Proxy Scale-Global Health 7, Parent Proxy Psychological Stress Experiences-Short Form, and the Parent Proxy Profile-Profile-25. PROMIS data were tested for significant deviation from the standardized T-Score references for normative populations of children. RESULTS: Eighty-nine subjects enrolled in the AERO-BPD study had complete outcome data for HRQOL. The mean age was 9 (±2) years and 43% were female. Mean days on respiratory support totaled 96 (±40). Across all domains, school-aged children with BPD reported similar or slightly better outcomes than the reference sample. Statistically significant findings of lower depression (P < .0001), fatigue (P < .0001), and pain (P < .0001) scores were found; there was no difference in psychological stress experiences (P = .87), global health (P = .06), anxiety (P = .08), relationships (P = .80), and mobility (P = .59) domains. CONCLUSIONS: This study demonstrated that children with BPD may have less depression, fatigue, and pain HRQL than the general population. Once validated, these findings may offer reassurance to parents and providers caring for children with BPD.

Real-world feasibility of short-term, unsupervised home spirometry in CF.

OBJECTIVES: The objective of this study was to study the performance of two available home spirometers used by people with Cystic Fibrosis (PwCF) over a short-term period and to assess user experience. STUDY DESIGN: This was a prospective observational study. Participants age 6 years and older were recruited to participate if they could complete acceptable spirometry in the clinic setting. METHODS: Participants used either the NuvoAir Air Next or the ZEPHYRx MIR Spirobank Smart spirometer. They underwent a one-time virtual training session, then completed 2 weeks of daily spirometry followed by 2 months of weekly spirometry. Participants responded to surveys and completed a debrief interview to understand user experience. Statistical analyses examined feasibility, reliability, and accuracy of each spirometer in an unsupervised, real-world setting. RESULTS: We report high adherence (80% [95% CI 61%-92%]) to our study protocol in all session attempts, but lower rates of adherence after discarding sessions performed with inadequate technique (47% [95% CI 28%-66%] to 63% [95% CI 44%-80%]). We found high reliability of each device by analyzing day-to-day variability and good concordance to recent in-clinic testing (NuvoAir r = 0.91 [0.82-0.93]; ZEPHYRx r = 0.70 [0.45-0.84]). Patient experience in this cohort was favorable with most reporting ease of use and reassurance knowing lung function was being tracked over time. CONCLUSIONS: This real-world study showed good performance of two different available home spirometers used by children and adults with CF. While overall adherence was high, suboptimal technique reduced the total interpretable data, possibly limiting feasibility. Future work should focus on developing sustainable training and coaching programs to support the success of home spirometry in a CF chronic care model.

Eating disorders in adolescents and young adults with cystic fibrosis.

INTRODUCTION: There is evidence for increased risk of eating disorders in individuals with diet-treated chronic illnesses, however, data in patients with cystic fibrosis (CF) is less clear. No studies have evaluated avoidant/restrictive food intake disorder (ARFID) in the CF population. We investigated the prevalence of eating disorders, including ARFID, in adolescents and young adults with CF. METHODS: Patients with CF aged 14-35 years were recruited to complete three validated surveys: (1) Eating Disorder Examination Questionnaire (EDE-Q), (2) Nine-Item Avoidant/Restrictive Food Intake Disorder Scale (NIAS), and (3) Cystic Fibrosis Questionnaire-Revised (CFQ-R). Univariate linear regression analysis identified baseline risk factors associated with these survey scores. Variables with univariate p < 0.20 were considered for inclusion in a multivariable linear regression model. Backwards stepwise linear regression was used to identify the final model. RESULTS: A total of 52 patients enrolled. The prevalence of a positive screen on the EDE-Q was 9.6%, and on the NIAS was 13.5%. The CFQ-R eating and weight subscales were associated with scores on the EDE-Q, and CFQ-R eating subscale and being dF508 homozygous were correlated with the NIAS total score. DISCUSSION: A clinically significant number of participants screened positive for eating disorders on the EDE-Q and NIAS. Scores on the eating and weight scales of the CFQ-R were associated with the scores on these surveys. Further work is needed to better understand the optimal way to use such tools to screen and treat for eating disorders in individuals with CF.

Bone density and bone marrow composition in transgender girls prior to pubertal blockade: A case series.

PURPOSE: To determine bone mineral density (BMD) of transgender girls before pubertal blockade, and correlate with lifestyle and clinical variables. METHODS: Six transfemale peri-pubertal girls had knee magnetic resonance imaging (MRI) with T1-weighted images and single-voxel proton magnetic resonance spectroscopy (MRS). BMD measurements were obtained via dual-energy X-ray absorptiometry. Questionnaires about physical activity, diet, and the Eating Attitudes Test (EAT-26) were completed. The T2 relaxation rate of water (R2 = 1/T2 in s -1) was correlated with scores on surveys. RESULTS: Three participants (50 %) had a low bone mineral density for age based on total body less head Z-score less than -2; two participants (33 %) had a low BMD for age at lumbar spine. All had EAT-26 scores below threshold for clinical concern. All participants self-reported regular exercise. Bone marrow MR variables (T1, fat fraction, unsaturation index and R2 of water) were not correlated with DXA measures. CONCLUSIONS: Participants had low BMD on beginning pubertal blockade. Clinicians should consider monitoring BMD among youth AMAB, a group at potential risk for poor bone health.

Efficacy and Safety of High-dose Cholecalciferol in Patients With Inflammatory Bowel Disease Receiving Infliximab.

OBJECTIVE: Vitamin D deficiency is prevalent in patients with inflammatory bowel disease (IBD). The goal of this study was to assess the efficacy and safety of high-dose, interval cholecalciferol administration in patients with IBD receiving infliximab. METHODS: This prospective, longitudinal, open-label study enrolled pediatric and young adult patients with IBD and vitamin D deficiency. Subjects received 50,000 IU every 4 to 5 weeks (n = 11) or 100,000 IU every 6 to 8 weeks (n = 32) of oral cholecalciferol for 1 year. Dosing was directly observed and administered in conjunction with infliximab infusions. The primary endpoint was vitamin D sufficiency, defined as a 25-hydroxy-vitamin D (25-OHD) level ≥30 ng/mL. RESULTS: Forty-three participants constituted the primary analysis population. 25-OHD levels reached steady-state after the third dose, and mean increases in 25-OHD levels were 8 vs. 4.5 ng/mL in the 100,000 IU vs. 50,000 IU treatment groups, respectively. Only 43.8% of patients receiving 100,000 IU and 18.2% of patients receiving 50,000 IU achieved sufficiency. There was no difference in the 25-OHD level responsiveness in patients with Crohn disease versus those with ulcerative colitis (P = 0.72). There was no correlation between 25-OHD levels and clinical disease activity in patients with Crohn disease (P = 0.85) or ulcerative colitis (P = 0.24). CONCLUSIONS: Supplementation with cholecalciferol was well-tolerated and direct observation is a promising paradigm for ensuring compliance with therapy. Patients with IBD, however, appear to require high doses of cholecalciferol, with less than half of patients (37% overall) achieving vitamin D sufficiency. Additional studies are necessary to determine the optimal treatment regimens.

Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial.

Mesothelioma is a rare and fatal cancer with limited therapeutic options until the recent approval of combination immune checkpoint blockade. Here we report the results of the phase 2 PrE0505 trial ( NCT02899195 ) of the anti-PD-L1 antibody durvalumab plus platinum-pemetrexed chemotherapy for 55 patients with previously untreated, unresectable pleural mesothelioma. The primary endpoint was overall survival compared to historical control with cisplatin and pemetrexed chemotherapy; secondary and exploratory endpoints included safety, progression-free survival and biomarkers of response. The combination of durvalumab with chemotherapy met the pre-specified primary endpoint, reaching a median survival of 20.4 months versus 12.1 months with historical control. Treatment-emergent adverse events were consistent with known side effects of chemotherapy, and all adverse events due to immunotherapy were grade 2 or lower. Integrated genomic and immune cell repertoire analyses revealed that a higher immunogenic mutation burden coupled with a more diverse T cell repertoire was linked to favorable clinical outcome. Structural genome-wide analyses showed a higher degree of genomic instability in responding tumors of epithelioid histology. Patients with germline alterations in cancer predisposing genes, especially those involved in DNA repair, were more likely to achieve long-term survival. Our findings indicate that concurrent durvalumab with platinum-based chemotherapy has promising clinical activity and that responses are driven by the complex genomic background of malignant pleural mesothelioma.

Efficacy and Safety of Glembatumumab Vedotin in Patients With Advanced or Metastatic Squamous Cell Carcinoma of the Lung (PrECOG 0504).

INTRODUCTION: Glycoprotein NMB is a transmembrane protein linked with poor prognosis and is expressed in most squamous lung cancer. Glembatumumab vedotin is an antibody-drug conjugate targeting glycoprotein NMB, administered intravenously every 3 weeks in this phase 1 study to determine the safety, tolerability, and maximum tolerated dose in patients who had progressed on any number of previous therapies. RESULTS: A total of 13 patients were enrolled; adverse events (of any grade) including dyspnea, neutropenia, respiratory failure, anemia, increased aspartate transaminase/alanine transaminase, diarrhea, and hypophosphatemia were seen in 15% of patients. Grade 5 events included two cases of respiratory failure, either completely or partially attributed to cancer progression. The only other grade 5 event was "disease progression." The most common adverse events (23%) were decreased appetite, fatigue, rash, and weight loss.The median overall and progression-free survivals were 5.7 months (90% confidence interval: 2.5-16.8) and 2.5 months (90% confidence interval: 1.6-5.8) respectively. CONCLUSIONS: Glembatumumab vedotin exhibited no serious or unexpected toxicity in this heavily pretreated population, except those caused by disease progression. Modest anticancer activity was observed with a recommendation for a phase 2 dose of 1.9 mg/kg. This portion of the study was not undertaken owing to the company's decision to discontinue drug development.

Smoking Behavior in Patients With Early-Stage NSCLC: A Report From ECOG-ACRIN 1505 Trial.

INTRODUCTION: Smoking cessation has been reported to benefit patients even after a diagnosis of lung cancer. We studied the smoking behavior of patients who participated in a phase 3 trial of adjuvant therapy following resection of stages IB-IIIA NSCLC. METHODS: The ECOG-ACRIN 1505 was conducted to determine whether the addition of bevacizumab to adjuvant chemotherapy would improve overall survival (OS) for patients with early-stage NSCLC. Studying the association between smoking status and OS was a secondary end point. Patients completed a questionnaire on their smoking habits at baseline, 3, 6, 9, and 12 months. RESULTS: A total of 1501 patients were enrolled, and 99.8%, 95%, 94%, 93%, and 93% responded to the questionnaire at baseline, 3, 6, 9, and 12 months, respectively. A total of 90% reported a current or previous history of cigarette smoking. In addition, 60% of nonsmokers at enrollment reported smoking after diagnosis (before randomization); however, 1% of them reported smoking at 12 months. Furthermore, 94% of the respondents smoked none/fewer cigarettes daily at 12 months. The incidence of grades 3-5 toxicity on treatment was 68%, 76%, and 72% in never, former, and current smokers, respectively (p = 0.05). The disease-free survival for never-smokers relative to current and former smokers was (hazard ratio [HR] 0.93, p = 0.64 and HR 1.05, p = 0.72), and OS was (adjusted HR for death 0.54, p = 0.005 and adjusted HR for death 0.68, p = 0.03), respectively. CONCLUSIONS: This is the first comprehensive, prospective report of smoking habits in patients with NSCLC patients from a phase III early-stage trial. There was a high rate of smoking reduction and cessation following study entry. The disease-free survival did not differ significantly between smokers and never smokers, though there were less grade 3-5 toxicities and more favorable OS in never-smokers.

Attitudes towards involving children in decision-making surrounding lung transplantation.

BACKGROUND: Medical care has shifted from a paternalistic model towards one centered around patient autonomy and shared decision-making (SDM), yet the role of the pediatric patient in decision-making is unclear. Studies suggest that many children with chronic disease are capable of making medical decisions at a young age, yet no standardized approaches have been developed for involving children in these decisions. METHODS: This is a single-center survey study investigating the attitudes of pediatric pulmonologists towards involvement of children in decisions regarding lung transplantation, utilizing a hypothetical case scenario with systematic manipulation of age and maturity level. We evaluated physician belief regarding ultimate decision-making authority, reconciliation of parent-child discordance, and utility of ethics and psychiatry consultation services. RESULTS: The majority of pediatric pulmonologists at this center believe decision-making authority rests with the parents. The effects of age and maturity are unclear. In instances of parent-child disagreement, physicians are more likely to try to convince parents to defer to the child if the child is both older and more mature. Physicians are divided on the utility of ethics and psychiatry consultations. CONCLUSION: Involvement of children with cystic fibrosis in SDM is broadly supported but inconsistently implemented. Despite evidence that children with chronic disease may have decisional capacity at a young age, the majority of physicians still grant decisional authority to parents. There are numerous barriers to involving children in decisions, including legal considerations. The role of age and maturity level in influencing these decisions appears small and warrants further investigation.

Tumor volume dynamics and tumor growth rate in ALK-rearranged advanced non-small-cell lung cancer treated with crizotinib.

PURPOSE: The purpose of the study is to investigate volumetric tumor burden dynamics and tumor growth rates in ALK-rearranged advanced NSCLC patients during crizotinib monotherapy. METHODS: The study included 44 ALK-rearranged advanced NSCLC patients treated with crizotinib monotherapy as their initial ALK-directed therapy, who had at least one measurable lung lesion and at least two follow-up CT scans, and experienced tumor volume increase while on crizotinib. The tumor volume (in mm3) of the dominant lung lesion was measured on serial CT scans during therapy for analysis of tumor growth rates after the volume nadir. RESULTS: A total of 231 volume measurements from the nadir to the end of crizotinib therapy or the last follow-up in 44 patients were analyzed in a linear mixed-effects model, fitting time (in months since baseline) as a random effect. When measured from the volume nadir, the tumor growth rate of the logarithm of tumor volume (logeV) was 0.04/month (SE = 0.012, P = 0.0011) in the unadjusted model. When adjusted for the baseline volume (logeV0), the growth rate was again 0.04/month (SE = 0.011, P = 0.0004). When adjusted for clinical variables and logeV0, the growth rate was 0.045/month (SE = 0.012, P = 0.0002), indicating that the tumor growth rate after nadir in this cohort remains very close to 0.04/month regardless of logeV0 or clinical factors. CONCLUSIONS: Tumor volume growth rate after nadir in ALK-rearranged NSCLC patients treated with crizotinib was obtained, providing objective reference values that can inform physicians when deciding to keep their patients on ALK directed therapy with slowly progressing lung cancer.

Patient-reported tolerability of veliparib combined with cisplatin and etoposide for treatment of extensive stage small cell lung cancer: Neurotoxicity and adherence data from the ECOG ACRIN cancer research group E2511 phase II randomized trial.

OBJECTIVES: The ECOG-ACRIN Cancer Research Group trial E2511 recently demonstrated a potential benefit for the addition of veliparib to cisplatin-etoposide (CE) in patients with extensive stage small cell lung cancer (ES-SCLC) in a phase II randomized controlled trial. Secondary trial endpoints included comparison of the incidence and severity of neurotoxicity, hypothesized to be lower in the veliparib arm, and tolerability of the addition of veliparib to CE. Physician-rated and patient-reported neurotoxicity was also compared. MATERIALS AND METHODS: Patients randomized to veliparib plus CE (n = 64) or placebo plus CE (n = 64) completed the 11-item Functional Assessment of Cancer Therapy Gynecologic Oncology Group Neurotoxicity (questionnaire pre-treatment, end of cycle 4 [ie 3 months after randomization] and 3 months post-treatment [ie 6-months]). Adherence analysis was based on treatment forms. RESULTS AND CONCLUSION: No significant differences in mean or magnitude of change in neurotoxicity scores were observed between treatment arms at any time point. However, patients in the placebo arm reported worsening neurotoxicity from baseline to 3-months (M difference = -1.5, P = .045), compared to stable neurotoxicity in the veliparib arm (M difference = -0.2, P = .778). Weakness was the most common treatment-emergent (>50%) and moderate to severe (>16%) symptom reported, but did not differ between treatment arms. The proportion of adherence to oral therapy in the overall sample was 75%. Three percent of patients reported clinically significant neurotoxicity that was not captured by physician assessment. Neurotoxicity scores were not different between treatment arms. The addition of veliparib to CE appeared tolerable, though weakness should be monitored. CLINICALTRIALS. GOV IDENTIFIER: NCT01642251.

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.

Use of Ex Vivo Patient-Derived Tumor Organotypic Spheroids to Identify Combination Therapies for HER2 Mutant Non-Small Cell Lung Cancer.

PURPOSE: Evaluating drug responses using primary patient-derived cells ex vivo represents a potentially rapid and efficient approach to screening for new treatment approaches. Here, we sought to identify neratinib combinations in HER2 mutant non-small cell lung cancer (NSCLC) patient xenograft-derived organotypic spheroids (XDOTS) using a short-term ex vivo system. EXPERIMENTAL DESIGN: We generated two HER2-mutant NSCLC PDX models [DFCI359 (HER2 exon19 755_757LREdelinsRP) and DFCI315 (HER2 exon20 V777_G778insGSP)] and used the PDX tumors to generate XDOTS. Tumor spheroids were grown in a microfluidic device and treated ex vivo with neratinib-based drug combinations. Live/dead quantification was performed by dual-labeling deconvolution fluorescence microscopy. The most efficacious ex vivo combination was subsequently validated in vivo using the DFCI359 and DFCI315 PDXs and a HER2 YVMA genetically engineered mouse model. RESULTS: Both neratinib and afatinib, but not gefitinib, induced cell death in DFCI359 XDOTS. The combinations of neratinib/trastuzumab and neratinib/temsirolimus enhanced the therapeutic benefit of neratinib alone in DFCI315 and DFCI359. The combination of neratinib and trastuzumab in vivo was more effective compared with single-agent neratinib or trastuzumab and was associated with more robust inhibition of HER2 and downstream signaling. CONCLUSIONS: The XDOTS platform can be used to evaluate therapies and therapeutic combinations ex vivo using PDX tumors. This approach may accelerate the identification and clinical development of therapies for targets with no or few existing models and/or therapies.

Tumor Volume Analysis as a Predictive Marker for Prolonged Survival in Anaplastic Lymphoma Kinase-rearranged Advanced Non-Small Cell Lung Cancer Patients Treated With Crizotinib.

PURPOSE: Targeted inhibition of anaplastic lymphoma kinase (ALK) has been widely used for the treatment of advanced non-small cell lung cancer (NSCLC) with ALK rearrangements. We performed tumor volume analysis of ALK-rearranged advanced NSCLC treated with crizotinib to identify an early predictive marker for prolonged survival. MATERIALS AND METHODS: Cases of 42 patients with ALK-rearranged advanced NSCLC (16 men, 26 women; median age: 55.7 y) treated with crizotinib as their first ALK-directed therapy were retrospectively studied. Tumor volume measurements of dominant lung lesions were performed on baseline computed tomography and follow-up computed tomography at 8 weeks of therapy. The relationships between the 8-week volume change (%) and overall survival (OS) were investigated. RESULTS: The 8-week tumor volume change ranged from -99.3% to 117.5% (median: -57.7%). Using the 25th percentile of the 8-week volume change of -74%, 11 patients with >74% volume decrease at 8 weeks had a significantly longer OS compared with 31 patients with ≤74% decrease (median OS: 92.0 vs. 22.8 mo; P=0.0048). In multivariable analyses using Cox proportional hazards models, the 8-week volume decrease of >74% was significantly associated with longer OS (hazard ratio=0.14, 95% confidence interval: 0.03-0.59; Cox P=0.008) after adjusting for tumor stage (stage IV vs. recurrent NSCLC, hazard ratio=5.6, 95% confidence interval: 1.29-24.3; P=0.02). CONCLUSIONS: The 8-week tumor volume decrease of >74% is significantly associated with longer OS in patients with ALK-rearranged NSCLC treated with crizotinib.