Multilevel Opportunities to Address Lung Cancer Stigma across the Cancer Control Continuum J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-05-23 Heidi A. Hamann, Elizabeth S. Ver Hoeve, Lisa Carter-Harris, Jamie L. Studts, Jamie S. Ostroff
Introduction The public health imperative to reduce the burden of lung cancer has seen unprecedented progress in recent years. Realizing fully the advances in lung cancer treatment and control requires attention to potential barriers in their momentum and implementation. In this analysis, we present and evaluate the argument that stigma is a highly significant barrier to fulfilling the clinical promise of advanced care and reduced lung cancer burden. Methods This evaluation of lung cancer stigma is based on a multilevel perspective that incorporates the individual, persons in their immediate environment, the healthcare system, and the larger societal structure which shapes perceptions and decisions. We also consider current interventions and interventional needs within and across aspects of the lung cancer continuum, including prevention, screening, diagnosis, treatment, and survivorship. Results Current evidence suggests that stigma detrimentally impacts psychosocial, communication, and behavioral outcomes over the entire lung cancer control continuum and across multiple levels. Interventional efforts to alleviate stigma in the context of lung cancer show promise, yet more work is needed to evaluate their impact. Conclusions Understanding and addressing the multi-level role of stigma is a crucial area for future study in order to realize the full benefits offered by lung cancer prevention, control, and treatment. Coordinated, interdisciplinary, and well-conceptualized efforts have the potential to reduce the barrier of stigma in the context of lung cancer and facilitate demonstrable improvements in clinical care and quality of life.
Nivolumab Plus Erlotinib in Patients with Epidermal Growth Factor Receptor-Mutant Advanced Non-Squamous Non-Small Cell Lung Cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-05-23 Scott Gettinger, Matthew D. Hellmann, Laura Q.M. Chow, Hossein Borghaei, Scott Antonia, Julie R. Brahmer, Jonathan W. Goldman, David E. Gerber, Rosalyn A. Juergens, Frances A. Shepherd, Scott A. Laurie, Tina C. Young, Xuemei Li, William J. Geese, Naiyer Rizvi
Introduction This phase I study evaluated nivolumab combined with erlotinib in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). Methods Patients with advanced EGFR-mutant NSCLC who were EGFR tyrosine kinase inhibitor (TKI)-naive or TKI-treated but had not received chemotherapy were treated with nivolumab 3 mg/kg every 2 weeks and erlotinib 150 mg/day until disease progression or unacceptable toxicity. The primary objective was safety and tolerability. Results Twenty patients with TKI-treated and one with TKI-naive EGFR-mutant NSCLC were treated with nivolumab plus erlotinib. Treatment-related grade 3 toxicities occurred in five patients (liver enzyme elevations, n = 2; diarrhea, n = 2; weight loss, n = 1), with no grade ≥4 toxicities. In the TKI-treated population, the objective response rate was 15% (3/20, including one complete response), and the 24-week progression-free survival rate was 48%. Responses lasted 13.8, 17.6, and 38.2 months per investigator records. A fourth patient had a non-conventional immune-related response lasting 12.5 months. Among these four patients, two were never-smokers and one each had 35– and <1–pack-year histories. Post-EGFR TKI pre-trial tumor biopsies from these patients detected EGFR T790M mutations in two patients and MET amplification in a third; two patients each had primary EGFR exon 19 deletions or L858R mutations. The TKI-naive patient, who had compound EGFR mutations (L858R and S768I) and ultimately achieved a complete response, had an ongoing response lasting more than 5 years based on investigator records. Conclusion Nivolumab plus erlotinib was tolerable, with durable responses in patients with EGFR-mutant, TKI-treated NSCLC.
Updated efficacy analysis including secondary population results for OAK: a randomized phase III study of atezolizumab vs docetaxel in patients with previously treated advanced non-small cell lung cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-05-17 L. Fehrenbacher, J. von Pawel, K. Park, A. Rittmeyer, D.R. Gandara, S. Ponce Aix, J.-Y. Han, S.M. Gadgeel, T. Hida, D.L. Cortinovis, M. Cobo, D.M. Kowalski, F. De Marinis, M. Gandhi, B. Danner, C. Matheny, M. Kowanetz, P. He, F. Felizzi, H. Patel, A. Sandler, M. Ballinger, F. Barlesi
Introduction The efficacy and safety of atezolizumab vs docetaxel as second- or third-line treatment in patients with advanced non-small cell lung cancer in the primary (n=850; ITT850) and secondary (n=1225; ITT1225) efficacy populations of the randomized phase III OAK study at an updated data cutoff were assessed. Methods Patients received atezolizumab 1200mg or docetaxel 75mg/m2 intravenously every 3 weeks until loss of clinical benefit or disease progression, respectively. The primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population and programmed death-ligand 1 (PD-L1)-expressing subgroup. A sensitivity analysis was conducted to evaluate the impact of subsequent immunotherapy use in the docetaxel arm on observed survival benefit with atezolizumab. Results Atezolizumab demonstrated OS benefit vs docetaxel in the updated ITT850 (hazard ratio [HR] 0.75; 95% CI 0.64–0.89; P = .0006) and the ITT1225 (HR 0.80; 0.70–0.92; P = .0012) after minimum follow-up of 26 and 21 months, respectively. Improved survival with atezolizumab was observed across PD-L1 and histology subgroups. The relative OS benefit with atezolizumab was slightly greater in the immunotherapy sensitivity analysis in the ITT850 (HR 0.69) and ITT1225 (HR 0.74) compared to conventional OS estimation. Fewer patients receiving atezolizumab experienced grade 3/4 treatment-related adverse events (14.9%) than those receiving docetaxel (42.4%); no grade 5 events related to atezolizumab were observed. Conclusions The updated ITT850 and initial ITT1225 analyses were consistent with the primary efficacy analysis demonstrating survival benefit with atezolizumab vs docetaxel. Atezolizumab continued to demonstrate a favorable safety profile after longer treatment exposure and follow-up.
Racial-Ethnic Disparities in End-of-Life Care Quality among Lung Cancer Patients: A SEER-Medicare–Based Study J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-05-10 Siddharth Karanth, Suja S. Rajan, Gulshan Sharma, Jose-Miguel Yamal, Robert O. Morgan
Introduction Cancer end-of-life care and associated racial-ethnic disparities have been in focus during the last few years due to concerns regarding subjective care variations and poor quality of care. Given the high mortality rate and disease burden of lung cancer, end-of-life care quality is particularly crucial for this disease. This study uses previously validated measures and examines racial-ethnic disparities in lung cancer end-of-life care quality. Methods This study involves retrospective analysis of patients ≥66 years, who were diagnosed with stage I–IV lung cancer, and who died on or before December 31, 2013, using the Surveillance Epidemiology and End Result-Medicare data from 1991–2013. Poor quality of care was measured using three themes: (1) potentially preventable medical encounters, (2) delayed hospice referral, and (3) aggressive chemotherapy provision during end-of-life. The patients were analyzed as two separate cohorts of NSCLC and SCLC patients. Logistic regression analyses were performed to estimate racial-ethnic disparities in the adjusted odds of receiving poor quality end-of-life care. Results The study found considerable racial-ethnic disparities in end-of-life care quality. The racial-ethnic minorities had higher odds of experiencing potentially preventable medical encounters in the last month of life as compared with non-Hispanic whites. Odds of delayed hospice referral and aggressive chemotherapy provision during end-of-life were lower in non-Hispanic blacks as compared with non-Hispanic whites. Conclusions The study findings highlight the continued lack of access and care disparity among the minorities, which could precipitate potentially preventable utilizations, and limit access to hospice care during end-of-life. The study suggests the need to develop educational, patient navigational and other interventions that could potentially reduce aggressive utilizations and improve appropriate hospice care provision during end-of-life.
Revised Modified RECIST Criteria for Assessment of Response in Malignant Pleural Mesothelioma (Version 1.1) J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-05-09 Samuel G. Armato III, Anna K. Nowak
Malignant pleural mesothelioma poses unique difficulties in tumor measurement and response assessment; however, robust and reproducible assessment of response is critically important in the conduct, interpretation, and reporting of clinical trials. The current de-facto standard for the assessment of mesothelioma tumor response, “modified RECIST” (Response Evaluation Criteria in Solid Tumors), was published in 2004 as a research paper. Practical application of the modified RECIST guidelines has suffered from varied interpretations, resulting in inaccuracies and inconsistencies in tumor response assessment across and within mesothelioma clinical trials. The presented “modified RECIST 1.1 for mesothelioma” response assessment guidelines provide a much-needed update that incorporates recommendations from RECIST 1.1 and approaches to other practical issues, including: (1) definition of minimally measurable disease; (2) definition of measurable lesions; (3) acceptable measurement location; (4) non-pleural disease considerations; (5) characterization of non-measurable pleural disease; (6) assessment of pathological lymph nodes; (7) establishing progressive disease; and (8) accommodations for bilateral pleural disease. These modified RECIST 1.1 guidelines for mesothelioma tumor response collate and apply research published since the development of modified RECIST, align modified RECIST with RECIST 1.1, address those aspects of tumor measurement that were neglected or not well characterized in the modified RECIST paper, and clarify ambiguous or difficult measurement issues that have been highlighted through the subsequent decade of clinical trials research. Adoption of the modified RECIST 1.1 guidelines for mesothelioma is recommended to harmonize the application of tumor measurement and response assessment across the next generation of clinical trials in this disease.
Anti-Epidermal Growth Factor Vaccine Antibodies Enhance the Efficacy of Tyrosine Kinase Inhibitors and Delay the Emergence of Resistance in EGFR Mutant Lung Cancer Cells J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-05-08 Jordi Codony-Servat, Silvia García-Roman, Miguel Ángel Molina-Vila, Jordi Bertran-Alamillo, Ana Giménez-Capitán, Santiago Viteri, Andrés F. Cardona, Erik d’Hondt, Niki Karachaliou, Rafael Rosell
Introduction Mutations in EGFR correlate with impaired response to immune checkpoint inhibitors and the development of novel immunotherapeutic approaches for EGFR mutant non-small cell lung cancer (NSCLC) is of particular interest. Immunization against EGF has demonstrated efficacy in a phase III trial including unselected NSCLC patients, but little was known about the mechanisms involved in the effects of the anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) or their activity in tumor cells with EGFR mutations. Methods The EGFR-mutant, NSCLC cell lines H1975 and PC9, together with several gefitinib and osimertinib-resistant cells derived from PC9, were treated with anti-EGF VacAbs and/or EGFR tyrosine kinase inhibitors (TKIs). Cell viability was analyzed by proliferation assays, cell cycle by fluorescence-activated cell sorting analysis and levels of RNA and proteins by quantitative retro-transcription PCR and Western blotting. Results Anti-EGF VacAbs generated in rabbits suppressed EGF-induced cell proliferation and cycle progression and inhibited downstream EGFR signaling in EGFR-mutant cells. Sera from patients immunized with an EGF vaccine were also able to block activation of EGFR effectors. In combination, the anti-EGF VacAbs significantly enhanced the antitumor activity of all TKIs tested, suppressed Erk1/2 phosphorylation, blocked the activation of signal transducer and activator of transcription 3 (STAT3) and downregulated the expression of AXL. Finally, anti-EGF VacAbs significantly delayed the emergence in vitro of EGFR TKI resistant clones. Conclusions EGFR-mutant patients can derive benefit from immunization against EGF, particularly if combined with EGFR TKIs. A Phase I trial of an EGF vaccine in combination with afatinib has been initiated.
Sarcopenia in resected non-small cell lung cancer: Effect on postoperative outcomes J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-05-08 Ryota Nakamura, Yoshihisa Inage, Rika Tobita, Satoshi Yoneyama, Takeshi Numata, Kyoko Ota, Hidetoshi Yanai, Takeo Endo, Yukinori Inadome, Shingo Sakashita, Hiroaki Satoh, Kenji Yuzawa, Toru Terashima
Background Skeletal muscle depletion, referred to as sarcopenia, has recently been identified as a risk factor for poor outcomes in various malignancies. However, the prognostic significance of sarcopenia in patients with non-small cell lung cancer (NSCLC) following surgery has not been adequately determined. This study investigated the impact of sarcopenia in patients undergoing pulmonary resection for lung cancer. Methods This retrospective study consisted of 328 patients with pathologically confirmed NSCLC who underwent curative resection between January 2005 and April 2017. Preoperative computed tomography (CT) imaging at the third lumbar vertebrae level was assessed to measure the psoas muscle mass index (PMI, cm2/m2). Sarcopenia was defined as a cutoff value of PMI less than 6.36 cm2/m2 for males and 3.92 cm2/m2 for females, based on PMI values from “healthy” subjects. Results The median patient age was 71 years and 59% were male. Sarcopenia was present in 183 (55.8%) and was significantly related with increasing age (p<0.001), being male (p<0.001), smoking habit (p<0.001), lower body mass index (p<0.001), and postoperative major complication (Clavien Dindo grade ≥3, p=0.036). The prevalence of sarcopenia was higher in men than in women, and the prevalence increased with age in men, whereas the prevalence did not increase in females above 70 years. The five-year survival rate was 61% in patients with sarcopenia and 91% in those without. Multivariate analysis revealed that sarcopenia was an independent unfavorable prognostic factor (p=0.019). Conclusion Sarcopenia as determined using preoperative CT could be used to predict postoperative major complication and prognosis in patients with resected NSCLC. Our results may provide some important information for preoperative management.
Brief report on the detection of the EGFR-T790M mutation in exhaled breath condensate from lung cancer patients J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-05-08 Robert J. Smyth, Sinead M. Toomey, Alexander Sartori, Emer O. Hanrahan, Sinead D. Cuffe, Oscar S. Breathnach, Ross K. Morgan, Bryan T. Hennessy
The EGFR-T790M somatic mutation is the most common mechanism of resistance to Tyrosine Kinase Inhibitors (TKI) in non-small cell lung cancer. Patients with advanced disease are not always amenable to repeat biopsy for further molecular analysis. Developing non-invasive methods to detect T790M in cell-free DNA (cfDNA), in the absence of tissue is being actively investigated. Unfortunately the low sensitivity of plasma for T790M detection has limited its clinical use. Exhaled breath condensate (EBC) is an easily collected sample, known to harbour cfDNA, including lung cancer mutations. This report details the potential utility of EBC in the detection of the EGFR-T790M mutation.
The Impact of Staging by Positron Emission Tomography on Overall Survival and Progression-free Survival in Patients with Locally Advanced Non-Small Cell Lung Cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-05-05 Everett E. Vokes, Ramaswamy Govindan, Neill Iscoe, Anwar M. Hossain, Belen San Antonio, Nadia Chouaki, Marianna Koczywas, Suresh Senan
Objective We investigated the potential impact of stage migration because of positron emission tomography (PET) scan staging on survival in the locally advanced (Stage IIIA/B) non-small cell lung cancer (NSCLC) setting. Methods In PROCLAIM, 598 patients with stage IIIA/B nonsquamous NSCLC (intent-to-treat [ITT] population) were randomized to either pemetrexed plus cisplatin and concurrent thoracic radiotherapy (TRT) for 3 cycles followed by 4 cycles of pemetrexed consolidation or etoposide plus cisplatin and concurrent TRT for 2 cycles followed by a consolidation platinum-based doublet regimen for up to 2 cycles. Baseline PET scan (PET Yes vs. No) was one of the stratification factors. Subgroup analyses (PET Yes vs. No) of overall survival (OS) and progression-free survival (PFS) were conducted on the ITT population regardless of treatment, as the study did not demonstrate superior efficacy for either arm. Results Majority (491/598; 82.1%) of patients had baseline PET scan staging performed. A longer median OS (PET Yes vs. No: 27.2 vs. 20.8; hazard ratio=0.81, p=0.130) and an improved median PFS (PET Yes vs. No: 11.3 vs. 9.2; hazard ratio=0.73, p=0.012) were observed for patients with PET scans compared to those with conventional staging in both treatment arms. Conclusions Both a significantly improved PFS and a numerically longer OS in the PET Yes subgroup, compared to patients with conventional staging, are consistent with improved survival due to stage migration. The magnitude of differences in OS and PFS based on PET scan is a reminder of the potential for factors other than the therapeutic intervention to affect outcomes.
Radiosensitivity of lung metastases by primary histology and implications for stereotactic body radiation therapy using the genomically adjusted radiation dose J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-05-05 Kamran A. Ahmed, Jacob G. Scott, John A. Arrington, Arash O. Naghavi, G. Daniel Grass, Bradford A. Perez, Jimmy J. Caudell, Anders E. Berglund, Eric A. Welsh, Steven A. Eschrich, Thomas J. Dilling, Javier F. Torres-Roca
Introduction We assessed the radiosensitivity of lung metastases based on primary histology using a validated gene signature and model lung metastases for the genomically adjusted radiation dose (GARD). Methods Tissue samples were identified from our prospective observational protocol. The radiosensitivity index (RSI) 10 gene assay was run on samples and calculated alongside GARD using the previously published algorithms. A cohort of 105 patients with 137 lung metastases treated with SBRT at our institution was used for clinical correlation. Results A total of 138 unique metastatic lung lesions were identified for inclusion from our institution’s tissue biorepository. There were significant differences in the RSI of lung metastases based on histology. In order of decreasing radioresistance, the median RSIs were endometrial adenocarcinoma (0.49), soft tissue sarcoma (0.47), melanoma (0.44), rectal adenocarcinoma (0.43), renal cell carcinoma (0.33), head and neck squamous cell cancer (0.33), colon adenocarcinoma (0.32), and breast adenocarcinoma (0.29), p=0.002. We modeled GARD for these samples and identified the BED necessary to optimize local control. The 12 and 24 month Kaplan-Meier rates of local control for radioresistant vs radiosensitive histologies from our clinical correlation cohort following lung SBRT were 92%/87% and 100%, respectively (p=0.02). Conclusions In this analysis, we note significant differences in radiosensitivity based on primary histology of lung metastases and model the BED necessary to optimize local control. This study suggests primary histology may be an additional factor to consider in lung SBRT dose selection and dose personalization may be feasible.
Italian nivolumab expanded access program in nonsquamous non–small-cell lung cancer patients: results in never-smokers and EGFR-mutant patients J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-05-03 M.C. Garassino, A.J. Gelibter, F. Grossi, R. Chiari, H. Soto Parra, S. Cascinu, F. Cognetti, D. Turci, L. Blasi, C. Bengala, E. Mini, E.E. Baldini, S. Quadrini, G.L. Ceresoli, P. Antonelli, E. Vasile, C. Pinto, G. Fasola, D. Galetta, M. Macerelli, D. Giannarelli, G. Lo Russo, F. de Marinis
Background Nivolumab is the first checkpoint inhibitor approved for the treatment of nonsquamous non–small-cell lung cancer (nonsq–NSCLC). We report results from the nivolumab Italian expanded access program (EAP), focusing on never-smokers and EGFR-mutant patients with nonsq–NSCLC. Patients and Methods Nivolumab (3 mg/kg intravenously every 2 weeks) was administered upon physicians’ request for patients who had relapsed after ≥1 prior systemic treatment for stage IIIB/IV nonsq–NSCLC. Efficacy and safety were evaluated in patients who received ≥1 nivolumab dose. Results Of 1,588 patients with nonsq–NSCLC, 305 (19.2%) were never-smokers. EGFR status was available for 1,395 patients. Of 102 (6.4%) patients with EGFR-mutation–positive tumors, 51 (50%) were never-smokers. Objective response rate (ORR) was significantly higher in EGFR wild-type than EGFR-mutant patients (19.6% vs 8.8%; P=0.007), in former/current smokers than never-smokers (21.5% vs 9.2%; P=0.0001), and in EGFR wild-type than EGFR-mutant never-smokers (11.0% vs 1.9%; P=0.04). There was no significant difference in ORR between EGFR wild-type and EGFR-mutant smokers (22.0% vs 20.6%). There was no statistically significant difference in median progression-free survival (PFS) and in median overall survival (OS). Specifically median OS was 11.0 vs 8.3 months in patients with EGFR wild-type vs EGFR-mutant tumors, 11.6 vs 10.0 months in smokers vs never-smokers, 11.0 vs 5.6 months in never-smokers with EGFR wild-type vs mutant tumors, and 14.1 vs 11.3 months in smokers with EGFR-mutant vs wild-type tumors. Conclusions Italian EAP data in nonsq–NSCLC populations suggest that subgroups of patients could benefit differently from nivolumab according to EGFR mutational status and smoking habits. These results warrant further investigation.
BRAF mutant lung cancer: PD-L1 expression, tumor mutational burden, microsatellite instability status and response to immune check-point inhibitors J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-30 Elizabeth Dudnik, Nir Peled, Hovav Nechushtan, Mira Wollner, Amir Onn, Abed Agbarya, Mor Moskovitz, Shoshana Keren, Noa Popovits-Hadari, Damien Urban, Moshe Mishaeli, Alona Zer, Aaron M. Allen, Natalie Maimon Rabinovich, Ofer Rotem, Teodor Kuznetsov, Tzippy Shochat, Laila C. Roisman, Jair Bar
Introduction The efficacy of immune check-point inhibitors (ICPi) in BRAF mutant NSCLC is unknown. Methods Multi-institutional retrospective chart review identified 39 patients with BRAF mutant NSCLC. The patients were divided into two groups: V600E (Group A, n=21) and non-V600E (Group B, n=18). PD-L1 expression, tumor mutational burden (TMB) and microsatellite instability status (MSI) were assessed in 29 (74%), 11 (28%) and 12 (31%) patients, respectively. ORR, PFS with ICPi and OS were analyzed. Results High (≥50%), intermediate (1-49%), and no (<1%) PD-L1 expression was observed in 8/19 (42%), 6/19 (32%), 5/19 (26%), and 5/10 (50%), 1/10 (10%), and 4/10 (40%) cases in Groups A and B, respectively. Two tumors in Group A demonstrated high TMB (25%); none were MSI-High. Twenty two patients (Group A, n-12; Group B, n-10) received ICPi. ORR with ICPi was 25% and 33% in Groups A and B, respectively (p-1.0). Median PFS with ICPi was 3.7 months (95% CI, 1.6-6.6), and 4.1 months (95% CI, 0.1-19.6) in Groups A and B, respectively (log-rank test - 0.81, p-0.37). Neither BRAF mutation type nor PD-L1 expression affected the response probability/PFS. Median OS was not reached (95% CI, 13-NR) and comprised 21.1 months (95% CI, 1.8-NR) for patients who were and were not exposed to ICPi, respectively (log-rank test - 5.58, p-0.018). Conclusions BRAF mutant NSCLC is associated with high level of PD-L1 expression, low/intermediate TMB and MS-Stable status. ICPi have favorable activity both in BRAF V600E and BRAF non-V600E mutant NSCLC.
The Care and Outcomes of Older Persons with Lung Cancer in England and the United States, 2008-2012 J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-05-01 Anita Andreano, Michael D. Peake, Samuel M. Janes, Maria Grazia Valsecchi, Kathy Pritchard-Jones, Jessica R. Hoag, Cary P. Gross
Introduction Although prior research has demonstrated lower lung cancer survival in England compared to the United States, more detailed comparisons are needed. We conducted a population-based analysis to compare diagnostic, treatment, and survival patterns. Methods Data from cancer registries and administrative databases were linked for older patients diagnosed with non-small cell lung cancer (NSCLC) in England and the United States (2008-2012). We compared patient and clinical characteristics, as well as the distribution of age-standardized receipt of treatment by stage. We compared relative survival overall, by stage and treatment. Finally, we assessed the degree to which stage distribution and stage-specific survival contributed to survival differences. Results Among patients aged 66 years or older diagnosed with NSCLC in England (n=86,978) and the United States (n=84,415), the pathological confirmation rate was 63% in England compared to 85% in the United States (difference 22·2%, 99% confidence interval [CI], 22·8-21·7%). Receipt of active treatment was lower in England (46% vs 60%; difference, 14·0%; 99% CI, 13·3-14·7%). In England, we identified 98 excess deaths per 1,000 patients with pathologically confirmed NSCLC; these additional deaths could be partially mitigated by adjusting stage at diagnosis (reduction to 54 excess deaths) or stage-specific survival (reduction to 36 excess deaths). Conclusions Compared to the United States, patients with NSCLC in England are less likely to present with early stage disease and receive treatment, and more likely to die. Future work should explore whether the intensity of resources directed to diagnostic and therapeutic activity may help mitigate disparities in outcomes.
PD-L1 expression heterogeneity in non-small cell lung cancer: defining criteria for harmonization between biopsies and whole sections J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-25 E. Munari, G. Zamboni, G. Lunardi, L. Marchionni, M. Marconi, M. Sommaggio, M. Brunelli, G. Martignoni, G.J. Netto, M.O. Hoque, F. Moretta, M.C. Mingari, M.C. Pegoraro, A. Inno, S. Paiano, A. Terzi, A. Cavazza, G. Rossi, F.R. Mariotti, P. Vacca, L. Moretta, G. Bogina
Background PD-L1 expression determination defines eligibility for treatment with pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC). This study was designed to better define which value across core biopsies from the same case more closely reflects the PD-L1 expression status on whole sections and how many biopsies are needed for confident classification of tumors in terms of PD-L1 expression. Materials and Methods We built tissue microarrays as surrogate of biopsies collecting 5 cores per case from 268 cases and compared PD-L1 staining results using validated clone SP263 with tumor whole sections. Results We found an overall positivity in 39% of cases at 1% cutoff and 10% of cases at 50% cutoff. The maximum value across cores was associated with high concordance between cores and whole sections and the lowest number of false negative cases overall. In order to reach high concordance with whole sections, 4 and 3 cores are necessary at 1% and 50% cutoff, respectively. Importantly, with 20% as cutoff on biopsies, less than 3 cores showed high sensitivity and specificity in identifying cases with ≥50% of tumor cells positive for PD-L1 on whole sections. Specifically, for PD-L1 values of 20-49% on cores, the probability of tumor specimen expressing PD-L1 in ≥ 50% of cells on whole section is 46% and 24% with 1 and 2 biopsies, respectively. Conclusions An accurate definition of the criteria to determine the PD-L1 status of a given tumor may greatly help to select those patients who could benefit from anti-PD1/PD-L1 treatment.
Efficacy of Crizotinib Among Different Types of ROS1 Fusion Partners in Patients with ROS1-Rearranged Non–small-cell Lung Cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-25 Ziming Li, Lan Shen, Ding Ding, Jia Huang, Jie Zhang, Zhiwei Chen, Shun Lu
Introduction ROS1 rearrangement-positive non–small-cell lung cancer (NSCLC) can be treated effectively, with an anaplastic lymphoma kinase (ALK)/ROS1/mesenchymal-epithelial transition factor inhibitor such as crizotinib. However the rate of response remains variable. Although several ROS1 fusion partners have been identified, the efficacy of crizotinib in patients with different types of ROS1 fusion partners is poorly understood. Methods We reviewed clinicopathological data of patients with ROS1-rearrangement who received crizotinib therapy at our institution between April 2014 and December 2016. ROS1 fusion partners were evaluated using Sanger sequencing for tumor tissue available. Results During the study duration, 49 patients were found to have ROS1-rearrangement and were subsequently treated with crizotinib. Tumor was available on 36 patients; 19 were found to have CD74-ROS1 fusion partners. Prior to therapy CD74-ROS1 group was found to have a higher rate of brain metastases (6 vs 0, p=0.020). The objective response rate (ORR) of crizotinib was 83.3% for all patients, whereas it was 94.11% and 73.68% in the non-CD74-ROS1 and CD74-ROS1 group respectively. As compared to the CD74-ROS1 group, the non-CD74-ROS1 group had both a significantly longer PFS (17.63 months vs 12.63 months; p = 0.048) as well as overall survival (OS) (44.50 months vs 24.33 months; p = 0.036). On multivariable analysis the only factor associated with OS was presence of brain metastases prior to therapy (p = 0.010). There were no significant factors associated with PFS in the multivariable analysis. Conclusions These findings suggests that patients with CD74-ROS1 fusion partners are more likely to present with brain metastases. While not independently significant, a trend in improved survival was observed in patients in the non-CD74-ROS1 group when treated with crizotinib.
Brief report: Afatinib and cetuximab in four patients with EGFR exon 20 insertion positive advanced non-small-cell lung cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-24 Bianca van Veggel, Adrianus J. de Langen, Sayed Hashemi, Kim Monkhorst, Daniëlle A.M. Heideman, Erik Thunnissen, Egbert F. Smit
Introduction Epidermal growth factor receptor (EGFR) exon 20 insertions comprise 4-9% of EGFR mutated non-small-cell lung cancer (NSCLC). Despite being an oncogenic driver, they are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). We hypothesized that dual EGFR blockade with afatinib, an irreversible EGFR TKI, and cetuximab, a monoclonal antibody against EGFR, could induce tumor responses. Methods Four patients with EGFR exon 20 insertion positive NSCLC were treated with afatinib 40 mg once daily and cetuximab 250-500 mg/m2 every two weeks. Results All patients had stage IV adenocarcinoma of the lung harboring an EGFR exon 20 insertion mutation. Previous lines of treatment consisted of platinum doublet chemotherapy (n=4) and EGFR TKI (n=2). Three out of four patients showed a partial response according to RECIST 1.1. Median progression-free survival was 5.4 months (95% confidence interval 0.0 – 14.2 months; range 2.7 – 17.6 months). Toxicity was manageable with appropriate skin management and dose reduction being required in two patients. Conclusions Dual EGFR blockade with afatinib and cetuximab may induce tumor responses in patients with EGFR exon 20 insertion positive NSCLC.
Identification of mutation accumulation as resistance mechanism emerging in first-line osimertinib treatment J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-24 Ken Uchibori, Naohiko Inase, Makoto Nishio, Naoya Fujita, Ryohei Katayama
Introduction The survival of patients with epidermal growth factor receptor (EGFR) mutation-positive lung cancer has dramatically improved since the introduction of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Recently, osimertinib demonstrated significantly prolonged progression-free survival than 1st-generation EGFR-TKI in first-line treatment, suggesting that a paradigm change that would move osimetinib to first-line treatment is indicated. We performed N-ethyl-N-nitrosourea (ENU) mutagenesis screening to uncover the resistant mechanism in first- and second-line osimertinib treatment. Materials and Methods Ba/F3 cells harbouring EGFR activating-mutation with or without secondary resistant mutation were exposed to ENU for 24 h to introduce random mutations and selected with gefitinib, afatinib or osimertinib. Mutations of emerging resistant cells were assessed. Results The resistance of T790M and C797S to gefitinib and osimertinib, respectively, was prevalent in the mutagenesis screening with the Ba/F3 cells harbouring activating-mutation alone. From C797S/activating-mutation expressing Ba/F3, the additional T790M was a major resistant mechanism in gefitinib and afatinib selection and the additional T854A and L792H were minor resistance mechanisms only in afatinib selection. However, the additional T854A or L792H mediated resistance to all classes of EGFR-TKI. Surprisingly, no resistant clone due to secondary mutation emerged from activating-mutation alone in the gefitinib + osimertinib selection. Conclusions We demonstrated the resistance mechanism to EGFR-TKI focusing on first- and second-line osimertinib using ENU mutagenesis screening. Additional T854A and L792H on C797S/activating-mutation were found as afatinib resistance and not as gefitinib resistance. Thus, compared to afatinib, the first-generation EGFR-TKI might be preferable as second-line treatment to C797S/activating-mutation emerging after first-line osimertinib treatment.
Expression patterns, prognostic value, and intratumoral heterogeneity of PD-L1 and PD-1 in thymoma and thymic carcinoma J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-24 Dwight Owen, Benjamin Chu, Amy M. Lehman, Lakshmanan Annamalai, Jennifer H. Yearley, Konstantin Shilo, Gregory A. Otterson
Introduction Thymic epithelial tumors (TET) including thymoma and thymic carcinoma are rare tumors with little data available to guide treatment. Immunotherapy with checkpoint blockade has shown promising activity, but data regarding the expression patterns and prognostic implications of programmed death 1 (PD-1) and its ligand (PD-L1) in TET have yielded conflicting results. Intratumoral heterogeneity of PD-1/L1 expression has been demonstrated in other cancers but has not been described in the TET literature. Methods We performed a retrospective single-center review of 35 patients with resected TET. PD-1/L1 expression was assessed by immunohistochemistry utilizing PD-1 clone: NAT105 and PD-L1 clone: 22C3. Tumor samples from 35 patients were evaluated including 32 patients with thymoma and 3 patients with thymic carcinoma. Results PD-L1 expression was detected in 83% (29/35) tumor samples, including 100% (3/3) of thymic carcinoma patients and 81% (26/32) of thymoma patients. PD-1 expression was detected in 77% (27/35), including 33% (1/3) of thymic carcinoma patients and 81% (26/32) thymoma patients. High PD-1 expression was associated with lower grade tumors. Unlike prior studies, PD-L1 expression was not associated with higher grade tumors or higher stage. Neither PD-L1 nor PD-1 expression was significantly associated with survival. Three patients with thymoma had multiple tumor sections evaluated for expression of PD-1/L1, with differing expression patterns of both PD-L1 and PD-1 observed in two patients. Conclusions This study confirms high expression of PD-L1 and PD-1 in TET and demonstrates for the first time intra-tumoral heterogeneity of PD-L1 and PD-1 in thymoma patients.
Estimating the cost-effectiveness of lung cancer screening with low dose computed tomography for high risk smokers in Australia J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-22 Stephen Wade, Marianne Weber, Michael Caruana, Yoon-Jung Kang, Henry Marshall, Renee Manser, Shalini Vinod, Nicole Rankin, Kwun Fong, Karen Canfell
Background Health economic evaluations of lung cancer screening with low dose computerised tomography (LDCT) that are underpinned by clinical outcomes are few. Methods We assessed the cost-effectiveness of LDCT lung screening in Australia by applying Australian cost and survival data to the outcomes observed in the U.S. National Lung Screening Trial (NLST), in which a 20% lung cancer mortality benefit was demonstrated for three rounds of annual screening among high-risk smokers aged 55-74 years. Screening-related costs were estimated from Medicare Benefits Schedule reimbursement rates (2015); lung cancer diagnosis and treatment costs from a 2012 Australian, hospital-based study; lung cancer survival rates from the New South Wales Cancer Registry (2005-2009); and other-cause mortality from Australian life tables, weighted by smoking status. Health utility outcomes, screening participation and lung cancer rates were those observed in the NLST. Incremental cost effectiveness ratios (ICERs) were calculated for a ten-year time horizon. Results LDCT lung screening was estimated at AU$138,000 (80% CI, AU$84,700-$353,000)/life-year gained and AU$233,000 (80% CI, AU$128,000-$1,110,000)/quality-adjusted life year (QALY) gained. The ICER was more favourable when all-cause mortality and the costs of incidental findings were estimated in sensitivity analyses: AU$157,000/QALY gained This can be compared to an indicative willingness-to-pay threshold in Australia of AU$30,000-$50,000/QALY. Conclusions LDCT lung screening using NLST selection and implementation criteria is unlikely to be cost-effective in Australia. Future economic evaluations should consider alternate screening eligibility criteria, intervals, nodule management, the impact and costs of new therapies, investigations of incidental findings, and incorporating smoking cessation interventions.
Exploring Radiotherapy Targeting Strategy and Dose: A Pooled Analysis of Cooperative Group Trials of Combined Modality Therapy for Stage III Non-Small Cell Lung Cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-22 Steven E. Schild, Wen Fan, Thomas E. Stinchcombe, Everett E. Vokes, Suresh S. Ramalingam, Jeffrey D. Bradley, Karen Kelly, Herbert H. Pang, Xiaofei Wang
Introduction Concurrent chemoradiotherapy(CRT) is standard therapy for locally-advanced non–small-cell lung cancer(LA-NSCLC)patients. This study was performed to examine thoracic radiotherapy(TRT) parameters and their impact on patient survival. Methods We collected Individual patient data(IPD) from 3600LA-NSCLC patients participating in 16 cooperative group trials of concurrent CRT. The primary TRT parameters examined included field design strategy(elective nodal irradiation(ENI) compared to involved field TRT(IF-TRT)), total dose, and biologically effective dose(BED). Hazard ratios(HRs) for overall survival were calculated with univariable and multivariable Cox models. Results TRT doses ranged from 60 to 74 Gy with most treatments administered once-daily. ENI was associated with poorer survival than IF-TRT(univariable HR,1.37;95%CI,1.24-1.51,p<0.0001;multivariable HR,1.31;95%CI,1.08-1.59,p=0.002). The median survival of the IF and ENI patients were 24 and 16 months, respectively. Patients were divided into 3 dose groups: low total dose(60 Gy), medium total dose(>60Gy-66Gy) and high total dose(>66Gy-74 Gy). With reference to the low dose group, the multivariable HR’s were 1.08 for the medium dose group(95%CI=0.93-1.25) and 1.12 for the high dose group(CI=0.97-1.30).The univariate p=0.054 and multivariable p=0.17. BED was grouped as follows: low(<55.5Gy10), medium(=55.5 Gy10), or high(>55.5 Gy10). With reference to the low BED group, the HR was 1.00(95%CI=0.85-1.18) for the medium BED group and 1.10(95%CI=0.93-1.31) for the high BED group. The univariable p=0.076 and multivariable p=0.16. Conclusions For LA-NSCLC patients treated with concurrent CRT, IF-TRT was associated with significantly better survival than ENI-TRT. TRT total and BED dose levels were not significantly associated with patient survival. Future progress will require research focusing on better systemic therapy and TRT.
Bevacizumab Reduces S100A9+ MDSC Linked to Intracranial Control in Patients with EGFR Mutant Lung Adenocarcinoma J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-21 Po-Hao Feng, Kuan-Yuan Chen, Yu-Chen Huang, Ching-Shan Luo, Shen Ming Wu, Tzu-Tao Chen, Chun-Nin Lee, Chi-Tai Yeh, Hsiao-Chi Chuang, Chia-Li Han, Chiou-Feng Lin, Wei-Hwa Lee, Chih-Hsi Kuo, Kang-Yun Lee
Background In vitro models have demonstrated immune-modulating effects of bevacizumab. Combinations of EGFR tyrosine kinase inhibitor (TKI) with bevacizumab improve progression free survival (PFS) in patients with EGFR mutated lung adenocarcinoma. How bevacizumab confers this clinical effect and underlying mechanisms are not clear. Patient and methods Fifty-five patients with stage 4 EGFR mutated lung adenocarcinoma were enrolled. Myeloid derived suppressor cells (MDSCs), T helper cells (Th1/Th2) and cytotoxic T lymphocytes (CTLs) were analyzed by flow cytometry. Clinical data were collected for analysis. Result Twenty-five patients received EGFR-TKI and BEV combination therapy (BEV/TKI group) and thirty patients received EGFR-TKI (TKI group) monotherapy. BEV/TKI group had longer PFS (23.0 vs. 8.6 months, p=0.001) and, particularly, better intracranial control rates (80.0% vs. 43.0%, p=0.03), longer time to intracranial progression (49.1 vs. 12.9 months, p=0.002) and fewer new brain metastases (38.0% vs. 71.0%, p=0.03) than TKI group. BEV/TKI group had lower circulating MDSCs (20.4±6.5% vs. 12.8±6.6%, pre- vs. post-treatment, respectively, p=0.02) and higher Th1 (22.9±15.3% vs. 33.2±15.6%, p<0.01) and CTLs (15.5±7.2% vs. 21.2±5.6%, p<0.01) after treatment, changes which were not seen in the TKI only group. Pretreatment MDSC was correlated with PFS, which correlation was attenuated after Bev/TKI treatment. MDSC was also associated with shorter time to intracranial progression. Conclusion Combining EGFR-TKI with bevacizumab extended PFS and protected from brain metastasis. Those effects were probably due to bevacizumab reduction of circulating S100A9+ MDSCs, leading to restoration of effective anti-tumor immunity. Our data also support the rationale for BEV-immune checkpoint inhibitors combination.
Progress in the management of Early Stage Non-Small Cell Lung Cancer in 2017 J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-12 Jessica S. Donington, Young Tae Kim, Betty Tong, Andre L. Moreira, Jame Bessich, Kathleen D. Weiss, Yolonda L. Colson, Dennis Wigle, Raymond U. Osarogiagbon, Jeffrey Zweig, Heather Wakelee, Justin Blasberg, Megan Daly, Leah Backhus, Paul Van Schil
The landscape of care for early stage non-small cell lung cancer continues to evolve. While some of the developments do not seem as dramatic as what has occurred in advanced disease in recent years, there is a continuous improvement in our ability to diagnose disease earlier and more accurately. We have an increased understanding of the diversity of early stage disease and how to better tailor treatments to make them more tolerable without impacting efficacy. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publishes this annual update to help readers keep pace with these important developments. Experts in the care of early stage lung cancer patients have provided focused updates across multiple areas including screening, pathology, staging, surgical techniques and novel technologies, adjuvant therapy, radiotherapy, surveillance, disparities, and quality of life. The source for information includes large academic meetings, the published literature, or novel unpublished data from other international oncology assemblies.
Prognostic Impact of Tumor Mutation Burden in Patients with Completely Resected Non-Small Cell Lung Cancer: Brief Report J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-12 Yuki Owada-Ozaki, Satoshi Muto, Hironori Takagi, Takuya Inoue, Yuzuru Watanabe, Mitsuro Fukuhara, Takumi Yamaura, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Jun Ohsugi, Mika Hoshino, Yutaka Shio, Hideaki Nanamiya, Jun-ichi Imai, Takao Isogai, Shinya Watanabe, Hiroyuki Suzuki
Introduction Tumor mutation burden (TMB), is thought to be associated with the amount of neoantigen in the tumor and to have an important role in predicting the effect of immune checkpoint inhibitors. However, the relevance of TMB to prognosis is not yet fully understood. In this study, we investigated the clinical significance of TMB in patients with non-small cell lung cancer (NSCLC) and examined the relationship between TMB and prognosis. Methods We calculated TMB within individual tumors by whole exome sequencing analysis using next-generation sequencing. We included 90 patients with NSCLC who underwent surgery in the Hospital of Fukushima Medical University from 2013 to 2016. No patients received chemotherapy or immunotherapy before surgery. We assessed the correlation between TMB and prognosis. Results TMB >62 was associated with worse overall survival (OS) of patients with NSCLC (hazard ratio [HR] = 6.633, P = 0.0003). Multivariate analysis showed poor prognosis with high TMB (HR = 12.31, P = 0.019). In patients with stage I NSCLC, higher TMB was associated with worse prognosis for both OS (HR = 7.582, P = 0.0018) and disease-free survival (HR = 6.07, P = 0.0072). Conclusion High TMB in NSCLC is a poor prognostic factor. If high TMB is a predictor of the efficacy of immune checkpoint inhibitors, postoperative adjuvant therapy with immune checkpoint inhibitors may contribute to improvement of recurrence and OS.
Safety and Efficacy of PD-1 Inhibitors Among HIV-Positive Patients with Non-Small-Cell Lung Cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-06 Lorena Ostios-Garcia, Jennifer Faig, Giulia C. Leonardi, Anika E. Adeni, Safiya J. Subegdjo, Christine A. Lydon, Deepa Rangachari, Mark S. Huberman, Kartik Sehgal, Meghan Shea, Paul A. VanderLaan, Matthew P. Cheng, Francisco M. Marty, Sarah P. Hammond, Daniel B. Costa, Mark M. Awad
Introduction Despite widespread administration of programmed death receptor 1 (PD-1) pathway inhibitors among individuals with non-small-cell lung cancer (NSCLC), little is known about the safety and activity of these agents among human immunodeficiency virus (HIV) infected patients since this population has largely been excluded from immunotherapy clinical trials. Methods Here, we describe seven patients with metastatic NSCLC and HIV infection who were treated with PD-1 inhibitors nivolumab (two cases) or pembrolizumab (five cases with three in the first-line setting). Results Partial responses to immune checkpoint inhibitors were observed in three of seven cases. Among four patients with a PD-L1 tumor proportion score ≥50%, three partial responses were observed. All patients received antiretroviral therapy while on anti-PD-1 treatment. None of the patients experienced grade 3 or 4 immune-related adverse events or immune reconstitution inflammatory syndrome, and none required PD-1 inhibitor dose interruption or discontinuation due to toxicity. Conclusions Nivolumab and pembrolizumab can be safe and effective among patients with NSCLC and HIV. Larger studies will be needed to determine the overall safety and efficacy of immune checkpoint inhibitors among cancer patients with HIV.
A Brief Report: Localization of Pulmonary Ground-Glass Opacities with Folate Receptor-Targeted Intraoperative Molecular Imaging J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-04 Jarrod D. Predina, Andrew Newton, Christopher Corbett, Leilei Xia, Lydia Frenzel Sulyok, Michael Shin, Charuhas Deshpande, Leslie Litzky, Eduardo Barbosa, Philip S. Low, John C. Kucharczuk, Sunil Singhal
Purpose Intraoperative localization and resection of ill-defined pulmonary ground-glass opacities (GGOs) during minimally invasive pulmonary resection is technically challenging. Current preoperative techniques to facilitate GGO localization include microcoil and hook-wire placement, but have logistic limitations, carry safety concerns, and do not help with margin assessment. In this clinical trial, we explore an alternative method involving near-infrared molecular imaging using a folate receptor-targeted agent, OTL38, to improve localization and margin confirmation of GGOs. Methods In a human trial, twenty subjects with pulmonary GGOs eligible for VATS resection received 0.025mg/kg of OTL38 prior resection. Primary objectives were to (1) determine if OTL38 safely localizes GGOs and assesses margins during VATS, and (2) determine patient, radiographic and histopathologic variables that predict the amount of fluorescence during near-infrared imaging. Results We observed no toxicity. Twenty of 21 GGOs accumulated OTL38 and displayed fluorescence upon in situ or back-table. Intraoperatively, near-infrared imaging localized 15 of 21 lesions while VATS alone localized 10 of 21 (p=0.05). The addition of molecular imaging impacted care of 9 of 21 subjects by improving intraoperative localization (n=6) and identifying close margins (n=3). This approach was most effective for subpleural lesions measuring less than 2cm. For lesions deeper than 1.5cm from the pleural surface, intraoperative localization using fluorescent feedback was limited. Conclusions This approach provides a safe alternative for intraoperative localization of small, peripherally located pulmonary lesions. In contrast to alternative localization techniques, this OTL38 also allows confirmation of adequate margins. Future studies will compare this approach to alternative localization techniques in a clinical trial.
First-in-Human Phase I Study of AC0010, a Mutant-Selective EGFR Inhibitor in Non–Small Cell Lung Cancer: Safety, Efficacy, and Potential Mechanism of Resistance J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-04 Yuxiang Ma, Xin Zheng, Hongyun Zhao, Wenfeng Fang, Yang Zhang, Jieying Ge, Lu Wang, Weicong Wang, Ji Jiang, Shaokun Chuai, Zhou Zhang, Wanhong Xu, Xiao Xu, Pei Hu, Li Zhang
Introduction AC0010 is a mutation-selective, third-generation EGFR tyrosine kinase inhibitor (TKI). This first-in-human phase I trial determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D), schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AC0010 in patients with advanced or recurrent NSCLC and acquired resistance to the first-generation EGFR-TKI. Methods Patients received escalating daily doses of AC0010 (50 to 600 mg) throughout 28-day cycles. A modified 3+3 design was applied. Patients with EGFR T790M mutation were selected in dose expansion. Next generation sequencing of plasma cell-free DNA (cf-DNA) was performed pre- and post-treatment to determine mechanisms of anticancer activity and underlying acquired resistance. Results Data from 52 patients were reported. Common treatment emergent adverse events (TEAEs) were diarrhea (75%), skin rash (48%), and alanine aminotransferase elevation (44%); AEs of grade ≥3 were seen for aminotransaminase elevation (12%) and skin rash (4%). MTD was not reached. Including all evaluated doses and T790M negative patients, the overall response rate (ORR) was 36.5%. At daily doses ≥350mg, the ORR was 50.0%, and the median PFS estimated by Kaplan-Meier method ranged from 14.0 to 35.6 weeks, across daily dose level from 350mg to 600mg. Based on PK data analysis, BID administration is recommended and 300 mg BID is suggested to be RP2D. Cf-DNA sequencing results from 17 patients indicate T790M allele frequency significantly decreased after AC0010 treatment (from 2.24 at baseline to 0 with partial response/stable disease; P<.001). In patients who developed resistance to AC0010, BRAF-V600E mutation, ROS1 fusion, c-Met and ERBB2 amplification were detected, but EGFR-C797S mutation was not detected. Conclusions AC0010 had a well-tolerated safety profile, and promising antitumor activity in NSCLC patients with acquired resistance to first generation EGFR-TKI, supporting its continued development.
Genetic Contribution to Non-Squamous, Non-Small Cell Lung Cancer in Non-Smokers J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-04-04 Shamus R. Carr, Wallace Akerley, Lisa Cannon-Albright
Introduction Lung carcinogenesis is strongly influenced by environmental and heritable factors. The genetic contribution to the different histologies is unknown. Methods A population-based computerized genealogy resource linked to a statewide cancer registry of lung cancer cases (n=5408) was analyzed to evaluate the heritable contribution to lung cancer histology in smoking (n=1751) and non-smoking cases (n=818). Statistical methods were used to test for significant excess relatedness of lung cancer cases. Results Significant excess distant relatedness was observed for all lung cancer histology subgroups analyzed except the small cell lung cancer subset (p=0.213). When smoking and non-smoking histologic subsets of lung cancer were considered, excess relatedness was observed only in non-smoking NSCLC (n=653; p=0.026) and, particularly, in those non-smokers with non-squamous histology (n=561; p=0.036). Sixty one pedigrees were identified which demonstrated a significant excess risk of non-smoking, non-squamous lung cancer cases; and an excess of female cases was observed among the cases in these high-risk pedigrees. Conclusions This analysis supports a genetic predisposition to lung cancer carcinogenesis in non-smoking, non-squamous NSCLC cases.
Time-to-Treatment-Failure and Related Outcomes among 1000+ Advanced Non-Small Cell Lung Cancer Patients: Comparisons Between Older Versus Younger Patients J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-30 Ajeet Gajra, Tyler J. Zemla, Aminah Jatoi, Josephine L. Feliciano, Melisa L. Wong, Hongbin Chen, Ronald Maggiore, Ryan P. McMurray, Arti Hurria, Hyman B. Muss, Harvey J. Cohen, Jacqueline Lafky, Martin J. Edelman, Rogerio Lilenbaum, Jennifer G. Le-Rademacher
Background Time-to-treatment-failure (TTF) is the interval from chemotherapy initiation to premature discontinuation. We evaluated TTF based on age. Methods Pooled analyses were conducted with, first-line chemotherapy trials for advanced non-small cell lung cancer (CALGB 9730, 30203, and 30801). Comparisons -- with age 65+ and 70+ years -- were performed for TTF (primary endpoint), reasons for early chemotherapy cessation, grade 3+ adverse events, and overall survival. Results Among 1006 patients, 460 (46%) were 65+ years of age. 145 older patients (32% of this age cohort) completed all six, planned chemotherapy cycles, as did 170 (32%) younger patients. Median TTF was 2.9 months (95% confidence interval (CI) = (2.7, 3.2)) in older and 3 months (95% CI= (2.9, 3.5)) in younger patients; adjustment for performance status and stratification by chemotherapy by trial yielded no statistically significant age-based difference in TTF. However, reasons for early chemotherapy cessation differed between age groups (multivariate p = 0.004). Older patients were less likely to discontinue from cancer progression (41% versus 55%) and more likely from toxicity or patient choice (16% and 15%, respectively) compared to younger patients (13% and 6%, respectively). Older patients were more likely to experience grade 3+ adverse events (86% versus 79%) with no statistically significant difference in survival. An age cut point of 70+ showed no difference in TTF, a lower trend of early cessation due to cancer progression, and somewhat shorter older patient survival. Conclusion TTF was comparable between older and younger patients; but different, age-based, and potentially modifiable reasons account for it.
Next generation sequencing assisted in establishing the diagnosis and treatment for a Chinese patient with breast and lung multiple primary malignancies J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-30 Chunqing Song, Zhengxing Gao, Jiabao Zong, Junping Shi, Ming Yao, Guilong Lu, Xiaoliang Liu, Kai Wang, Lei Han
Introduction A case of primary lung cancer was reported, which was misdiagnosed as breast cancer metastasis to the lung based on pathology in combination with a history of breast cancer. Methods The common driver gene mutation was detected in different lesions by next generation sequencing (NGS), and it was shown that the genomic profiling of lung lesion and breast lesion were inconsistent. Results The typical driver mutation of EGFR L858R in lung cancer was found in lung lesion, and the patient received the first-generation EGFR-TKI, icotinib, as treatment and achieved a partial response. Conclusions With NGS detection in this case, the specific driver gene in the tumor site was identified, which facilitated the diagnosis of a double primary cancer, and resulted in a change in treatment.
Brief Report: Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-29 Yingmei Li, Boxiang Liu, Ian David Connolly, Bina Wasunga Kakusa, Wenying Pan, Seema Nagpal, Stephen B. Montgomery, Melanie Hayden Gephart
When compared to solid brain metastases from NSCLC, leptomeningeal disease (LMD) has unique growth patterns and is rapidly fatal. LMD does not undergo surgical resection, limiting the tissue available for scientific research. Here we performed whole-exome sequencing (WES) on 8 LMD samples to identify somatic mutations and compared the results with 26 solid brain metastases. We found that TAS2R31 and PDE4DIP were recurrently mutated among LMD samples, suggesting involvement in LMD progression. Together with retrospective chart review of an additional 44 NSCLC LMD patients, we discovered a surprisingly low number of KRAS mutations (n=4, 7.7%), but a high number of EGFR mutations (n=33, 63.5%). The median interval for developing LMD from NSCLC was shorter in EGFR-mutant (16.3 mo) than wild-type (23.9 mo) patients (p = 0.017). Targeted analysis of recurrent mutations thus presents a useful complement to the existing diagnostic toolkit, and correlations of EGFR in LMD and KRAS in solid metastases suggest molecular distinctions or systemic treatment pressure underpinning differences in growth patterns within the brain.
Intrinsic and Extrinsic Regulation of PD-L2 Expression in Oncogene-Driven Non–Small Cell Lung Cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-27 Daisuke Shibahara, Kentaro Tanaka, Eiji Iwama, Naoki Kubo, Keiichi Ota, Koichi Azuma, Taishi Harada, Jiro Fujita, Yoichi Nakanishi, Isamu Okamoto
Introduction The interaction of programmed cell death–ligand 2 (PD-L2) with programmed cell death–1 (PD-1) is implicated in tumor immune escape. The regulation of PD-L2 expression in tumor cells has remained unclear, however. We here examined intrinsic and extrinsic regulation of PD-L2 expression in non–small cell lung cancer (NSCLC). Methods PD-L2 expression was evaluated by reverse transcription and real-time polymerase chain reaction analysis and by flow cytometry. Results BEAS-2B cells stably expressing an activated mutant form of the epidermal growth factor receptor (EGFR) or the EML4-ALK fusion oncoprotein manifested increased expression of PD-L2 at both mRNA and protein levels. Furthermore, treatment of NSCLC cell lines that harbor such driver oncogenes with corresponding EGFR or ALK tyrosine kinase inhibitors or depletion of EGFR or ALK by siRNA transfection suppressed expression of PD-L2, demonstrating that activating EGFR mutations or EML4-ALK fusion intrinsically induce PD-L2 expression. We also found that interferon-γ extrinsically induced expression of PD-L2 via STAT1 signaling in NSCLC cells. Oncogene-driven expression of PD-L2 in NSCLC cells was inhibited by knockdown of the transcription factors STAT3 or c-FOS. Interferon-γ also activated STAT3 and c-FOS, suggesting that these proteins may also contribute to the extrinsic induction of PD-L2 expression. Conclusions Expression of PD-L2 is induced intrinsically by activating EGFR mutations or EML4-ALK fusion as well as extrinsically by interferon-γ, with STAT3 and c-FOS possibly contributing to both intrinsic and extrinsic pathways. Our results thus provide insight into the complexity of tumor immune escape in NSCLC.
Initiative for Early Lung Cancer Research on Treatment: Development of Study Design and Pilot Implementation J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-23 Raja Flores, Emanuela Taioli, David F. Yankelevitz, Betsy Jane Becker, Artit Jirapatnakul, Anthony Reeves, Rebecca Schwartz, Rowena Yip, Esther Fevrier, Kathleen Tam, Benjamin Steiger, Claudia I. Henschke, Raja Flores, Andrew Kaufman, Dong-Seok Lee, Daniel Nicastri, Andrea Wolf, Kenneth Rosenzweig, Jorge Gomez, Mary Beth Beasley, Maureen Zakowski, Michael Chung, David Yankelevitz, Claudia Henschke, Rita Futamura, Sydney Kantor, Carly Wallace, Faiz Bhora, Wissam Raad, Andrew Evans, Walter Choi, Zrzu Buyuk, Adie Friedman, Ronald Dreifuss, Stacey Verzosa, Mariya Yakubox, Karina Aloferdova, Patricia Stacey, Simone De Nobrega, Rita Futamura, Sydney Kantor, Carly Wallace, Ardeshir Hakami, Kathleen Tam, Carly Wallace, Harvey Pass, Berne Crawford, Jessica Donnington, Benjamin Cooper
Purpose To maximize the benefits of CT screening for lung cancer, optimal treatment is for small, early lung cancers is needed. Limiting the extent of surgery spares lung tissue, preserves pulmonary function, and decreases operative time, complications, and morbidities. It also increases the likelihood of resecting future new primary lung cancers. The goal is to assess alternative treatments in a timely manner. Methods The focus sessions with patients and physicians separately highlighted the need to consider their perceptions. Literature reviews and analyses of treatment results using large databases were performed to formulate critical questions about long-term treatment outcomes, recurrence, and quality of life (QoL) of alternative treatments. Based on these analyses, the investigators developed a prospective multi-institutional cohort study, the Initiative for Early Lung Cancer Research for Treatment (IELCART), to compare treatments for Stage I non-small-cell lung cancer (NSCLC). HIPAA compliant IRB approval was obtained and we performed a feasibility study of the first 200 surgical patients. Results Lobectomy was performed in 89 (44.5%) patients and sublobar resection in 111 (55.5%). Mediastinal lymph node resection was performed in 162 (81.0%) patients, 8 had N1 and 2 N2 lymph node metastases. Patients stated that both the surgeon’s opinion (93%) and the patient’s own opinion (93%) were extremely important, followed by the patients’ view that the chosen procedure would provide the best QoL (90%). Conclusions It was feasible to obtain pre- and post-surgical information from patients and surgeons. We anticipate statistically meaningful results about treatment alternatives in 3 to 5 years.
The value of early depth of response in predicting long-term outcome in EGFR-mutant lung cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-23 Chee Khoon Lee, Sally Lord, Ian Marschner, Yi Long Wu, Lecia Sequist, Rafael Rosell, Masahiro Fukuoka, Tetsuya Mitsudomi, Rebecca Asher, Lucy Davies, Val Gebski, Richard Gralla, Tony Mok, James Chih-Hsin Yang
Introduction Traditionally, marked tumor shrinkage has been assumed to portend better outcome. We investigated whether depth of tumor response was associated with improved survival outcomes in advanced EGFR-mutant non-small cell lung cancer (NSCLC). Methods Individual patient data from randomized trials (EURTAC, IPASS, ENSURE, LUX-Lung 3, and LUX-Lung 6) were used. The association of depth of response with progression-free survival (PFS) and overall survival (OS) was examined using landmark analyses. Depth of response, based on radiologic assessments at 6-week and 12-week, was calculated as the relative changes in the sum of the longest diameters of the target lesions from baseline. Results Of 1081 evaluable patients at 6-week with no disease progression, 71.2% achieved RECIST response. Using a landmark analysis, EGFR-TKI was more effective than chemotherapy (PFS hazard ratio [HR] 0.36, P<.0001); and was associated with greater mean tumor shrinkage than chemotherapy (35.1% versus 18.5%, P<.0001). However, there was no significant difference in the relative PFS benefit between treatment groups across the entire spectrum of tumor shrinkage (P=.18 for test of interaction between treatment and continuously measured depth of response). Depth of response at 6 weeks was not associated with PFS when adjusted for treatment effect (HR 0.96, P=.78). Similar results were obtained for 12-week landmark analysis and for OS outcome. Conclusions The PFS advantage of EGFR-TKI over chemotherapy in advanced EGFR mutant NSCLC is not explained by depth of response at 6 or 12 weeks. It should not be used as a surrogate of benefit in future trials or routine clinical decision making.
Inflammatory Gene Polymorphisms in Lung Cancer Susceptibility J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-23 Keith D. Eaton, Perrin E. Romine, Gary E. Goodman, Mark D. Thornquist, Matt J. Barnett, Effie W. Petersdorf
Introduction Chronic inflammation has been implicated in carcinogenesis, with increasing evidence of its role in lung cancer. We aimed to evaluate the role of genetic polymorphisms in inflammation-related genes in the risk for development of lung cancer. Methods A nested case-control study design was used, and 625 cases and 625 well-matched controls were selected from participants in the β-Carotene and Retinol Efficacy Trial, which is a large, prospective lung cancer chemoprevention trial. The association between lung cancer incidence and survival and 23 polymorphisms descriptive of 11 inflammation-related genes (interferon gamma gene [IFNG], interleukin 10 gene [IL10], interleukin 1 alpha gene [IL1A], interleukin 1 beta gene [IL1B], interleukin 2 gene [IL2], interleukin 4 receptor gene [IL4R], interleukin 4 gene [IL4], interleukin 6 gene [IL6], prostaglandin-endoperoxide synthase 2 gene [PTGS2] (also known as COX2), transforming growth factor beta 1 gene [TGFB1], and tumor necrosis factor alpha gene [TNFA]) was evaluated. Results Of the 23 polymorphisms, two were associated with risk for lung cancer. Compared with individuals with the wild-type (CC) variant, individuals carrying the minor allele variants of the IL-1β-511C>T promoter polymorphism (rs16944) (CT and TT) had decreased odds of lung cancer (OR = 0.74, [95% confidence interval (CI): 0.58–0.94] and OR = 0.71 [95% CI: 0.50–1.01], respectively, p = 0.03). Similar results were observed for the IL-1β-1464 C>G promoter polymorphism (rs1143623), with presence of the minor variants CG and CC having decreased odds of lung cancer (OR = 0.75 [95% CI: 0.59–0.95] and OR = 0.69 [95% CI: 0.46–1.03], respectively, p = 0.03). Survival was not influenced by genotype. Conclusions This study provides further evidence that IL1B promoter polymorphisms may modulate the risk for development of lung cancer.
Clinical Features and Management of Acquired Resistance to PD-1 Axis Inhibitors in Twenty-Six Patients with Advanced Non-Small Cell Lung Cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-22 Scott N. Gettinger, Anna Wurtz, Sarah B. Goldberg, David Rimm, Kurt Schalper, Susan Kaech, Paula Kavathas, Anne Chiang, Rogerio Lilenbaum, Daniel Zelterman, Katerina Politi, Roy Herbst
Introduction With expanding indications for PD-1 axis inhibitors in non-small cell lung cancer (NSCLC), acquired resistance (AR) to these therapies is increasingly being encountered. We sought to characterize clinical patterns of AR to PD-1 axis inhibitors in patients with advanced NSCLC, and evaluate subsequent outcome and management strategies for such patients. Methods Patients with NSCLC who developed AR to PD-1 axis inhibitor therapy initiated between December 2009 and February 2016 at one institution were identified and examined by clinical and radiographic features. AR was defined as progressive disease after initial response by either RECIST v1.1 or immune-related response criteria. Results Twenty-six patients with AR to PD-1 axis inhibitor therapy were identified and evaluated. Median time to AR was 313 days; 2-year survival rate from AR was 70% (95%CI, 0.53-0.92). Twenty patients (77%) experienced AR in LNs, including eleven patients with LN-only progression. Twenty-three (88%) patients had recurrence limited to one (54%) or two (35%) sites of disease. Fourteen patients (54%) continued PD-1 axis inhibitor therapy beyond progression. Three patients were re-challenged with same PD-1 axis inhibitor after holiday from and progression off therapy, two again responded. Fifteen patients (58%) received local therapy to site(s) of AR, eleven continued respective PD-1 axis inhibitor after local therapy. Two-year survival rate from AR among these 15 patients was 92% (95%CI, 0.77-1). Conclusion Acquired resistance to PD-1 axis inhibitors is often limited to one or two sites, when local therapy and continuation of PD-1 axis inhibitor therapy can result in prolonged benefit. Lymph node metastases appear to be particularly susceptible sites to AR. When progression of disease following response occurs after holiday from PD-1 axis inhibitor, re-challenge can again lead to tumor regression.
Translation of knowledge to practice - Improving awareness in NSCLC molecular testing J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-11 Alona Zer, Jean Claude Cutz, Harman Sekhon, David M. Hwang, Christina Sit, Manjula Maganti, Mike Sung, Matthew Binnie, Anthony Brade, Tae Bong Chung, Suzanne Kamel-Reid, Paul Narinder, Ming S. Tsao, Tom Waddell, Gilda da Cunha Santos, Milan Patel, Ron F. Carter, Natasha B. Leighl
Background Molecular testing in advanced lung cancer is standard in guiding treatment selection. However, population-wide implementation of testing remains a challenge. We developed a knowledge translation intervention to improve understanding among diagnostic specialists about molecular testing and appropriate diagnostic sampling in lung cancer. Methods Specialty-specific education programs were developed from existing literature and input from Canadian leaders in lung pathology, respirology, interventional radiology, thoracic surgery, radiation and medical oncology. The programs, including key messages, review of current data, existing guidelines, group discussion and participant feedback, were administered at provincial and national specialty meetings. Participant knowledge was assessed before and after the intervention using anonymous questionnaires. Molecular testing rates (EGFR) in Ontario were also evaluated before and after the intervention period. Results Ten programs were administered to diagnostic specialists including respirologists, pathologists, thoracic surgeons, radiologists, radiation and medical oncologists, with completion of 255 pre- and 219 post-intervention surveys. At baseline, 30% were unsure of tissue handling methods for molecular testing, 20% chose an incorrect technique and half were unfamiliar with how to initiate testing. Post-intervention, specialist knowledge improved regarding tissue handling, appropriate fixation techniques, and uncertainty decreased from 30% to 2% (p<0.001). A 12% increase (relative 57%) in molecular testing requests (EGFR) in Ontario was observed over the intervention period (p=0.0032). Conclusions Significant knowledge gaps exist among diagnostic specialists regarding molecular testing and targeted therapy in lung cancer. This initiative significantly improved understanding of the importance and methods of successful molecular testing, and correlated with increased testing rates.
Immunohistochemical and Image Analysis-based Study Demonstrate that Several Immune Checkpoints are Co-expressed in Non-Small Cell Lung Carcinoma Tumors J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-08 Edwin Roger Parra, Pamela Villalobos, Jiexin Zhang, Carmen Behrens, Barbara Mino, Stephen Swisher, Boris Sepesi, Annika Weissferdt, Neda Kalhor, John Victor Heymach, Cesar Moran, Jianjun Zhang, Jack Lee, Jaime Rodriguez-Canales, Don Gibbons, Ignacio Ivan Wistuba
Background The understanding of immune checkpoint molecules’ co-expression in non-small cell lung carcinoma (NSCLC) is important to potentially design combinatorial immunotherapy approaches. Material and Methods We studied 225 formalin-fixed, paraffin-embedded tumor tissues from stage I-III NSCLCs—142 adenocarcinomas (ADCs) and 83 squamous cell carcinomas (SCCs)—placed in tissue microarrays. Nine immune checkpoint markers were evaluated; 4 (PD-L1, B7-H3, B7-H4, and IDO-1) expressed predominantly in malignant cells (MCs) and 5 (ICOS, VISTA, TIM3, LAG3, and OX40) expressed mostly in stromal tumor-associated inflammatory cells (TAICs). All markers were examined using a quantitative image analysis and correlated with clinicopathological features, TAICs, and molecular characteristics. Results Using above the median value as positive expression in MCs and high density of TAICs expressing those markers, we identified higher expression of immune checkpoints in SCC than ADC. Common simultaneous expression by MCs was PD-L1 + B7-H3 + IDO-1 in ADC and PD-L1 + B7-H3, or B7-H3 + B7-H4, in SCC. TAICs expressing checkpoint were significantly higher in current-smokers than in never-smokers. Almost all the immune checkpoint markers showed positive correlation with TAICs expressing inflammatory cell markers. KRAS-mutant ADC specimens showed higher expression of PD-L1 in MCs and of B7-H3, TIM3, and IDO-1 in TAICs than WT. Kaplan-Meier survival curves showed worse prognosis in ADC patients with higher B7-H4 expression by MCs. Conclusions We found frequent immunohistochemical co-expression of immune checkpoints in surgically resected NSCLC tumors and correlated with tumor histology, smoking history, tumor size, and the density of inflammatory cells and tumor mutational status.
Breathprinting and early diagnosis of lung cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-08 Gaetano Rocco, Giorgio Pennazza, Marco Santonico, Filippo Longo, Raffaele Rocco, Pierfilippo Crucitti, Raffaele Antonelli Incalzi
The electronic nose (e-nose) is a promising technology to be used as a useful addition to the currently available modalities to achieve lung cancer diagnosis. The e-nose can assess the volatile organic compounds (VOCs) detected in the breath and derived from the cellular metabolism. VOCs can be analyzed to identify either the individual chemical elements as well as their pattern of expression to reproduce a sensorial combination similar to a fingerprint (breathprint). The e-nose can be used alone, mimicking the combinatorial selectivity of the human olfactory system, or as part of a multisensorial platform. This review analyzes the progress made by investigators interested in this technology as well as the perspectives for its future utilization.
Antitumor efficacy of dual blockade of EGFR signaling by osimertinib in combination with selumetinib or cetuximab in activated EGFR human NSCLC tumor models J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-08 Carminia Maria Della Corte, Vincenza Ciaramella, Claudia Cardone, Silvia La Monica, Roberta Alfieri, Pier Giorgio Petronini, Umberto Malapelle, Elena Vigliar, Francesco Pepe, Giancarlo Troncone, Maria Domenica Castellone, Teresa Troiani, Erika Martinelli, Fortunato Ciardiello, Floriana Morgillo
Hypothesis Osimertinib showed great clinical efficacy for activated-EGFR-NSCLC patients treatment. The aim of this work was to test the efficacy of a complete EGFR-inhibition by osimertinib plus the monoclonal antibody, cetuximab, or the MEK1/2-inhibitor, selumetinib, in EGFR-mutated-NSCLC in vivo models. Methods We evaluated combinations of osimertinib plus selumetinib/cetuximab in HCC827 (E746-A759del/T790M-), H1975 (L858R/T790M+) and PC9-T790M (E746-A759del /T790M+) xenografts, in second-line after the developing of resistance to osimertinib and in first-line, and we explored mechanisms of resistance to these treatments. Results The addition of selumetinib or cetuximab to osimertinib in second-line reverted the sensibility to osimertinib in the majority of mice, with a response rate (RR) of 50-80%, and a median PFS (mPFS) of first plus second-line of therapy of 28 weeks. The early use of combinations in first-line increased the RR to 90%, with a mPFS not reached in all combination arms in the three xenografts models, with a statistically significant superiority (p<0,005) as compared to osimertinib, achieving in first-line a mPFS of 17-18 weeks. Moreover, in ex vivo primary cell cultures obtained from osimertinib plus selumetinib-resistant tumors, we found hedgehog pathway activation and we demonstrated that therapy with a Smo inhibitor plus osimertinib and selumetinib inhibited proliferation and migratory and invasive properties of resistant cells. Conclusions we demonstrated that a dual vertical EGFR blockade with osimertinib plus selumetinib/cetuximab is a novel effective therapeutic option in EGFR-mutated-NSCLC and that Hedgehog pathway activation and its interplay with MAPK is involved in resistance to these combination treatments.
The Role of Prophylactic Cranial Irradiation in Patients with Extensive Stage Small Cell Lung Cancer: A Systematic Review and Meta-Analysis J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-08 Chi Hoon Maeng, Jae-Uk Song, Sung Ryul Shim, Jonghoo Lee
Introduction The role of prophylactic cranial irradiation (PCI) is controversial in patients with extensive stage small cell lung cancer (ES-SCLC). The aim of this study was to determine the impact of PCI in these patients. Methods We performed a systematic review and meta-analysis in accordance with PRISMA guidelines. A systematic literature search was conducted in MEDLINE, EMBASE, and the Cochrane Central Register. The primary outcome was overall survival (OS). Results We identified five studies comprising 984 patients, of whom 448 received PCI and 536 did not receive PCI. In pooled estimates, PCI did not statistically improve OS compared with controls (hazard ratio [HR] 0.82; 95% CI 0.60 to 1.11; I2 = 77%; p = 0.19). However, the PCI group had a significant advantage in one-year survival compared to the no-PCI group (37.1% vs. 27.1%; risk ratio [RR] 0.87; 95% CI 0.80 to 0.95; I2 = 47%; p = 0.002), and the pooled estimates indicated that progression-free survival (PFS) and the risk of brain metastasis were associated with significant benefit in the PCI group (HR 0.83; 95% CI 0.70 to 0.98; I2 = 22%; p = 0.03 and HR 0.34; 95% CI 0.23 to 0.50; I2 = 0%; p < 0.001, respectively). Conclusion Our findings suggest that PCI in patients with ES-SCLC may lead to a significant benefit in one-year survival, PFS, and the risk of brain metastasis, despite the lack of a significant advantage in OS.
State of the Art: Advances in Malignant Pleural Mesothelioma in 2017 J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-08 Amanda J. McCambridge, Andrea Napolitano, Aaron S. Mansfield, Dean A. Fennell, Yoshitaka Sekido, Anna K. Nowak, Thanyanan Reungwetwattana, Weimin Mao, Harvey I. Pass, Michele Carbone, Haining Yang, Tobias Peikert
Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication and treatment are urgently needed. Herein we review the advances in MPM achieved in 2017. While recent epidemiological data demonstrated that the incidence of MPM-related death continued to increase in United States between 2009 and 2015, new insight into the molecular pathogenesis and the immunological tumor microenvironment of MPM, for example, regarding the role of BRCA1 associated protein 1 (BAP1) and the expression programmed death receptor ligand 1 (PD-L1), are highlighting new potential therapeutic strategies. Furthermore, there continues to be an ever-expanding number of clinical studies investigating systemic therapies for MPM. These trials are primarily focused on immunotherapy using immune checkpoint inhibitors alone or in combination with other immuno- andnon-immuno therapies. In addition, other promising targeted therapies including ADI-PEG20 focusing on argininosuccinate synthase 1 deficient tumors and Tazemetostat, an EZH2 inhibitor of BAP1 deficient tumors are currently being explored.
Phase 1/2 Study of the Safety and Tolerability of Nivolumab Plus Crizotinib for the First-line Treatment of ALK Translocation–Positive Advanced Non-Small Cell Lung Cancer (CheckMate 370) J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-06 David R. Spigel, Craig Reynolds, David Waterhouse, Edward B. Garon, Jason Chandler, Sunil Babu, Paul Thurmes, Alexander Spira, Robert Jotte, Jin Zhu, Wen Hong Lin, George Blumenschein Jr.
Introduction Crizotinib, an anaplastic lymphoma kinase inhibitor, is a first-line treatment for ALK translocation–positive advanced non-small cell lung cancer (NSCLC); however, patients eventually progress. Immunotherapies, including the programmed death-1 inhibitor nivolumab, have resulted in durable responses and long-term overall survival in patients with NSCLC. We hypothesized that combining targeted therapy with immunotherapy could result in more patients with responses and/or more durable responses. Herein we report data from a study assessing nivolumab plus crizotinib in patients with previously untreated advanced ALK translocation–positive NSCLC. Patients and Methods Group E in CheckMate 370 was a single-arm cohort designed to evaluate the safety of first-line nivolumab (240 mg every 2 weeks) plus crizotinib (250 mg twice daily) in patients with ALK translocation–positive NSCLC. The primary endpoint of safety would be met if ≤20% of patients discontinued treatment due to treatment-related adverse events by week 17. Objective response rate was a secondary endpoint. A planned safety review occurred in November 2016; the data cutoff was May 26, 2017. Results Of the first 13 patients treated with nivolumab plus crizotinib, five (38%) developed severe hepatic toxicities leading to the discontinuation of the combination. Of these, two patients died and the presence of severe hepatic toxicities may have contributed to death. Enrollment was closed and combination treatment discontinued due to observed grade ≥3 hepatic toxicities. Five patients (38%) had a partial response. Conclusions These findings do not support further evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily.
Brief report on radiological changes following stereotactic ablative radiotherapy (SABR) for early-stage lung tumors: a pictorial essay J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-06 Merle I. Ronden, David Palma, Ben J. Slotman, Suresh Senan
Distinctive patterns of early and late benign fibrosis are commonly observed after stereotactic ablative radiotherapy (SABR) for lung malignancies. These changes on computed tomographic scans need to be distinguished from so-called ‘high-risk’ radiological features, which can be associated with a higher risk for tumor recurrence. This pictorial report illustrates the different radiological changes seen following SABR delivered using the volumetric modulated radiotherapy, a technique which is increasingly used in clinical care.
A multi-center randomized controlled study of paclitaxel plus carboplatin versus oral uracil-tegafur as the adjuvant chemotherapy in resected non-small cell lung cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-02 Shinichi Toyooka, Norihito Okumura, Hiroshige Nakamura, Masao Nakata, Motohiro Yamashita, Hirohito Tada, Shinsuke Kajiwara, Naoki Watanabe, Morihito Okada, Junichi Sakamoto, Motoi Aoe, Junichi Soh, Shinichiro Miyoshi, Katsuyuki Hotta, Keitaro Matsuo, Hiroshi Date
Introduction We conducted a randomized controlled study to compare the survival benefit of paclitaxel plus carboplatin and oral uracil-tegafur (UFT) as adjuvant chemotherapy in resected NSCLC Methods In an open-label multicenter trial, patients with pathological stage IB–IIIA NSCLC were randomized into a group receiving paclitaxel (175 mg/m2) / carboplatin (AUC 5) every 3 weeks for 4 cycles (Arm A) or a group receiving oral administration of UFT (250 mg/m2) daily for 2 years (Arm B). The primary and secondary endpoints were overall survival (OS), and relapse-free survival (RFS) and toxicity. Results Between November 2004 and November 2010, 402 patients from 40 institutions were included (201 in both arms). The median follow-up period was 6.5 years. The 5-year OS rate was 70% [95% confidential interval (CI), 63 – 76] in the Arm A versus 73% (95%CI, 66 – 78) in the Arm B [Hazard ratio (HR), 0.92 (95%CI, 0.55 – 1.41); P = 0.69]. There was no significant difference of the 5-year RFS rates between the Arms A and B (56% versus 57%) [HR, 0.92 (95%CI, 0.63 – 1.34); P = 0.50). Toxicities were well tolerated and there was no treatment-related death. Toxicities of any grade or grade 4 were significantly more frequent in the paclitaxel plus carboplatin group (95.7% and 22.1%, respectively) than the UFT group (76.5% and 1.0%, respectively; P < 0.0001 in both). Conclusions As adjuvant chemotherapy, paclitaxel plus carboplatin was not better than UFT in terms of survival among patients with stage IB–IIIA NSCLC tumors that underwent complete resection. (UMIN000000810)
Cell-free plasma DNA-guided treatment with osimertinib in patients with advanced EGFR-mutated NSCLC J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-03-02 Anna Buder, Maximilian J. Hochmair, Sophia Schwab, Tatjana Bundalo, Peter Schenk, Peter Errhalt, Romana E. Mikes, Gudrun Absenger, Kurt Patocka, Bernhard Baumgartner, Ulrike Setinek, Otto C. Burghuber, Helmut Prosch, Robert Pirker, Martin Filipits
Introduction Osimertinib is standard treatment for patients with advanced EGFR T790M-mutated NSCLC who have been pre-treated with EGFR-TKIs. We studied whether cell-free plasma DNA for T790M detection can be used to select patients for osimertinib treatment in clinical routine. Methods From April 2015 to November 2016, we included 119 patients with advanced EGFR-mutated NSCLC who had progressed under treatment with an EGFR-TKI. The T790M mutation status was assessed in cell-free plasma DNA by droplet digital PCR (ddPCR) in all patients and by tissue analyses in selected patients. Results T790M mutations were detected in 85 (93%) patients by analyses of cell-free plasma DNA and in 6 (7%) plasma-negative patients by tumor re-biopsy. Eighty-nine out of the 91 T790M-positive patients received osimertinib. Median progression-free survival (PFS) was 10.1 months (95% CI 8.1–12.1). Median survival was not reached and the 1-year survival was 64%. The response rate (RR) was 70% in T790M-positive patients (n=91) in the intention-to-treat population. PFS trended to be longer in patients with low T790M copy number (<10 copies/mL) compared to those with high T790M copy number (≥10 copies/mL) (hazard ratio [HR] for PFS 1.72, 95% confidence interval [CI] 0.92–3.2, p=0.09). A comparable trend was observed for overall survival (HR for OS 2.16, 95% CI 0.89–5.25, p=0.09). No difference in RR was observed based on T790M copy numbers. Conclusions Plasma genotyping using ddPCR is clinically useful for the selection of patients who had progressed during first-line EGFR-TKI therapy for treatment with osimertinib.
The IASLC Lung Cancer Staging Project: A Renewed Call to Participation J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-02-22 Dorothy J. Giroux, Paul Van Schil, Hisao Asamura, Ramón Rami-Porta, Kari Chansky, John J. Crowley, Valerie W. Rusch, Kemp Kernstine
Over the past two decades, the International Association for the Study of Lung Cancer (IASLC) Staging Project has been a steady source of evidence-based recommendations for the tumor, node, metastasis (TNM) classification for lung cancer published by the Union for International Cancer Control (UICC) and by the American Joint Committee on Cancer (AJCC). The Staging and Prognostic Factors Committee (SPFC) of the IASLC is now issuing a call for participation in the next phase of the project, designed to inform the ninth edition of the TNM classification for lung cancer. Following the case recruitment model for the eighth edition database, volunteer site participants are asked to submit data on patients diagnosed between January 1, 2011 and December 31, 2019 to the project by means of a secure, electronic data capture (EDC) system provided by Cancer Research And Biostatistics (CRAB) in Seattle, WA, USA. Alternatively, participants may transfer existing data sets. The continued success of the IASLC Staging Project in achieving its objectives will depend on the extent of international participation, the degree to which cases are entered directly into the EDC system, and how closely externally submitted cases conform to the data elements for the project.
Potentially Functional variants of ATG16L2 predict radiation pneumonitis and outcomes in patients with non-small cell lung cancer after definitive radiotherapy J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-02-15 Juyi Wen, Hongliang Liu, Lili Wang, Xiaomeng Wang, Ning Gu, Zhensheng Liu, Ting Xu, Daniel R. Gomez, Ritsuko Komaki, Zhongxing Liao, Qingyi Wei
Introduction Autophagy not only plays an important role in the progression of cancer but also is involved in tissue inflammatory response. However, few published studies have investigated associations between functional genetic variants of autophagy-related genes and radiation pneumonitis (RP) as well as clinical outcomes in patients with non-small cell lung cancer (NSCLC) after definitive radiotherapy. Methods We genotyped nine potentially functional single nucleotide polymorphisms (SNPs) in four autophagy-related genes (ATG2B, ATG10, ATG12 and ATG16L2) in 393 North American NSCLC patients treated by definitive radiotherapy and assessed their associations with RP, local recurrence-free survival (LRFS), progression-free survival (PFS) and overall survival (OS) in multivariable Cox proportional hazards regression analyses. Results We found that the ATG16L2 rs10898880 CC variant genotype had a better LRFS, PFS and OS [adjusted hazards ratio (adjHR) = 0.59, 0.64 and 0.64; 95% confidence interval (95% CI = 0.45-0.79, 0.48-0.84 and 0.48-0.86); and P = 0.0004, 0.002 and 0.003, respectively], but a greater risk of developing severe RP (adjHR = 1.80, 96% CI = 1.04-3.12, P = 0.037), than patients with CC/CT genotypes. Further functional analyses suggested that the ATG16L2 rs10898880 C variant allele modulated the expression of the ATG16L2 gene. Conclusion This is the first report that functional ATG16L2 C variant homozygous genotype may be a predictor of RP, LRFS, PFS, and OS in NSCLC patients after definitive radiotherapy. Additional larger, prospective studies are needed to confirm these findings.
New insights into the molecular characteristics of pulmonary carcinoids and large-cell neuroendocrine carcinomas, and the impact on their clinical management J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-02-14 J.L. Derks, N. Leblay, S. Lantuejoul, A.M. Dingemans, E.J.M. Speel, L. Fernandez-Cuesta
Carcinoids and large-cell neuroendocrine carcinomas (LCNEC) are rare neuroendocrine lung tumors. Here we provide an overview of the most updated data on the molecular characteristics of these diseases. Recent genomic studies showed that carcinoids generally contain a low mutational burden and few recurrently mutated genes. Most of the reported mutations occur in chromatin-remodeling genes (e.g. MEN1), and few affect genes of the PI3K-AKT-mTOR pathway. Aggressive disease has been related to chromothripsis, DNA-repair gene mutations, loss of OTP/CD44, and upregulation of RET gene expression. In the case of LCNECs, which present with a high mutation burden, two major molecular subtypes have been identified: one with bi-allelic inactivation of TP53 and RB1, a hallmark of small-cell lung cancer (SCLC); and the other one with bi-allelic inactivation of TP53 and STK11/KEAP1, genes that are frequently mutated in non-small cell lung cancer (NSCLC). These data, together with the identification of common mutations in the different components of combined LCNEC-NSCLC tumors, provides further evidence of the close molecular relation of LCNEC with other lung tumor types. In terms of therapeutic options, future studies should explore the association between mTOR pathway mutations and response to mTOR inhibitors in carcinoids. For LCNEC, preliminary data suggest that the two molecular subtypes might have a predictive value for chemotherapy response, but this observation needs to be validated in randomized prospective clinical trials. Finally, DLL3 inhibitors and immunotherapy may provide alternative options for patient-tailored therapy in LCNEC.
Progress in Radiotherapy for Regional and Oligometastatic Disease in 2017 J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-02-13 Suresh Senan, Chad G. Rusthoven, Ben J. Slotman, Shankar Siva
This review highlights key publications and abstracts in the field of radiation oncology for lung cancer in 2017, and attempts to place these in the context of developments for the broader thoracic oncology community.
Training and validating a portable electronic nose for lung cancer screening J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-02-06 Rens van de Goor, Michel van Hooren, Anne-Marie Dingemans, Bernd Kremer, Kenneth Kross
Introduction Profiling volatile organic compounds in exhaled breath enables the diagnosis of several types of cancer. In this study we investigated if a portable point-of-care version of an electronic nose (Aeonose™) is able to discriminate between lung-cancer patients and healthy controls, based on their volatile organic compound pattern. Methods In this study, we used five e-nose devices to collect breath samples from lung-cancer patients and healthy controls. Sixty lung-cancer patients and 107 controls exhaled through an e-nose for five minutes. Patients were assigned either to a training group for building an artificial neural network model, or to a blinded control group for validating this model. Results For differentiating lung-cancer patients from healthy controls, the results showed a diagnostic accuracy of 83% with a sensitivity of 83%, specificity of 84% and area under the curve of 0.84. Results for the blinded group showed comparable results with sensitivity of 88%, specificity of 86% and diagnostic accuracy of 86%. Conclusion This feasibility study showed that this portable e-nose can properly differentiate between lung-cancer patients and healthy controls. This result could have important implications for future lung cancer screening. Further studies with larger cohorts, including also more early-stage tumor participants, should be performed to increase the robustness of this non-invasive diagnostic tool, and to determine its added value in the diagnostic chain for lung cancer.
EGFR T790M and C797S mutations as mechanisms of acquired resistance to dacomitinib J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-02-02 Yoshihisa Kobayashi, Toshio Fujino, Masaya Nishino, Takamasa Koga, Masato Chiba, Yuichi Sesumi, Shuta Ohara, Masaki Shimoji, Kenji Tomizawa, Toshiki Takemoto, Tetsuya Mitsudomi
Introduction Dacomitinib is superior to gefitinib in terms of progression-free survival in patients with EGFR-mutant lung cancer in a recent ARCHER 1050 trial. However, despite a marked initial response, lung cancers eventually acquire resistance to these inhibitors. This study aimed to elucidate the mechanisms of acquired resistance to dacomitinib in vitro. Methods Dacomitinib-resistant clones were established by exposure to fixed concentrations of dacomitinib using N-ethyl-N-nitrosurea (ENU) mutagenesis or by chronic exposure to increasing concentrations of dacomitinib without ENU. EGFR secondary mutations were analyzed by Sanger sequencing. Time to resistance in each clone was compared according to the mutational status. EGFR Del19, L858R, and G719A mutations were introduced into Ba/F3 cells using retroviral vectors. Results Chronic exposure to dacomitinib without ENU induced T790M in Ba/F3 cells expressing Del19. ENU mutagenesis resulted in 171 dacomitinib-resistant clones. Among these clones, 90% acquired T790M. However, C797S occurred in 11% (4/35) of L858R-mutant clones and in 24% (12/38) of G719A-mutant clones established using low-dose dacomitinib. Time to resistance was not significantly different between T790M- and C797S-mutant clones in both of L858R clones (p = 0.93) and G719A clones (p = 0.86). Cells expressing Del19 that acquired T790M were sensitive to osimertinib, whereas cells with L858R+C797S mutations were sensitive to gefitinib or erlotinib. Conclusions These in vitro data demonstrate that dacomitinib can directly induce T790M or C797S secondary mutations. Our data suggest the importance of analyzing these secondary mutations because appropriate selection of EGFR inhibitors could overcome acquired resistance to dacomitinib in a subset of lung cancers.
Early mortality in patients undergoing adjuvant chemotherapy for non-small-cell lung cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-02-02 Daniel Morgensztern, Pamela Samson, Saiama N. Waqar, Siddhartha Devarakonda, Clifford Robinson, Ramaswamy Govindan, Varun Puri
Background Although adjuvant chemotherapy improves survival in patients with completely resected non-small-cell lung cancer (NSCLC), it is also associated with potentially disabling or lethal adverse events. Since there is limited information on the early mortality among patients undergoing adjuvant chemotherapy, we used the National Cancer Data Base (NCDB) to calculate the percentage of deaths within the first 6 months from starting chemotherapy. Methods The NCDB was queried for patients aged 18 or older who were diagnosed with stage IB to IIIA NSCLC between 2004 and 2012 and received multi-agent adjuvant chemotherapy starting within 120 days from the surgical resection with negative surgical margins. Age groups were divided into less than 50, 51-60, 61-70, 71-80 and more than 80 years. Results A total of 19,691 patients met the eligibility criteria, of which 19,398 had a known 6-month mortality status. The median age was 65 years (range 19-89). The 1, 2, 3, 4, 5 and 6-month cumulative mortality rates from initiation of chemotherapy were 0.7%, 1.3%, 1.9%, 2.6%, 3.3% and 4.2% respectively. The 6-month mortality rates for each age group (≤ 50 years, 51-60, 61-70, 71-80, and >80) was 2.6%, 3.1%, 4.1%, 5.3% and 7.6% respectively (p<0.001). Independent factors associated with increased 6-month mortality included age (age 71-80 vs < 50: odds ratio (OR) 1.72, 95% CI 1.16-2.55, p = 0.007, age > 80 vs < 50: OR 2.43; 1.40-4.20, p = 0.002), male gender (OR 1.42; 1.21-1.67, p <0.001), Charlson-Deyo comorbidity score (score 2 vs 0: OR 1.52; CI 1.22-1.89, p < 0.001), type of surgery (pneumonectomy OR 1.38, 1.11-1.73, p=0.004), length of stay after surgery > 6 days (OR 1.21; 1.03-1.41, p = 0.02) and readmission within 30 days from surgery (OR 1.48; 1.15-1.90, p = 0.02). Conclusion Early mortality with the use of adjuvant chemotherapy following complete resection of NSCLC is a clinical concern. The risk is higher in patients older than 70 years, with higher co-morbidity scores and a prolonged length of stay post-operatively.
Immunological Aspects of Cryoablation of Non-Small Cell Lung Cancer: A Comprehensive Review J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31 Daniel Katzman, Shirley Wu, Daniel H. Sterman
In cryo-immunotherapy, target tumors are treated with cryoablation to generate anti-tumor immune responses. Since immune checkpoint inhibitors have demonstrated that lung cancer can be an immunotherapy responsive disease, there has been renewed interest in the immunological aspects of cryoablation of lung cancer. Herein, we review pre-clinical and clinical trials of cryoablation of primary lung tumors. We examine the magnitude of cryoablation induced anti-tumor immune responses and the synergy between cryoablation and either other immunotherapies or molecular targeted therapies to improve treatment responses in advanced lung cancer. We further discuss a rationale for the addition of cryoablation to immune checkpoint inhibitors for the treatment of advanced lung cancer, which is currently under clinical investigation.
Cannabis Use, Lung Cancer, and Related Issues J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31 Emily Stone, James Jett, Graham Warren, K Michael Cummings
The cannabis plant and its derivatives have been exploited for centuries for recreational and medicinal purposes with millions of regular users around the world. The recreational use of cannabis is reflective of its neuropsychiatric effects such as anxiolysis and euphoria. However, cannabis appears to have an emerging therapeutic role, especially in chronic disease and as an adjunct to cancer treatment. Increasing evidence supports cannabis in the management of chemotherapy induced nausea and vomiting and for pain management, but studies are limited particularly by difficulties associated with standardized dosing estimates and inability to accurately assess biologic activities of compounds in cannabis and derivative products. Smoking cannabis has not been proven to be a risk factor in the development of lung cancer but the data are limited by small studies, misclassification due to self-reporting of usage, small numbers of heavy cannabis smoking and confounding of risk associated with known causative agents for lung cancer such as parallel chronic tobacco use. Cannabis and its biologically effective derivatives warrant additional research, ideally controlled trials where the CBD and the THC strength and usage are controlled and documented.
Computational analysis of epidermal growth factor receptor mutations predicts differential drug sensitivity profiles towards kinase inhibitors J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31 Sravani Akula, Swapna Kamasani, SreeKanth Sivan, Vijjulatha Manga, Dashavantha Reddy Vudem, Rama Krishna Kancha
Introduction A significant proportion of lung cancer patients carry mutations in the epidermal growth factor receptor (EGFR) kinase domain. The presence of a deletion mutation in exon 19 or L858R point mutation in the EGFR kinase domain were shown to cause enhanced efficacy of inhibitor treatment in NSCLC patients. Several less frequent (“Uncommon”) mutations in the EGFR kinase domain with potential implications in treatment response were also reported. The role of a limited number of uncommon mutations in drug sensitivity was experimentally verified. However, a huge number of these mutations remain uncharacterized for inhibitor sensitivity/resistance. Methods A large scale computational analysis of clinically reported 298 point mutants of EGFR kinase domain has been performed and drug sensitivity profiles for each mutant towards seven kinase inhibitors has been determined by molecular docking. In addition, the relative inhibitor binding affinity (RIBA) towards each drug as compared to that of the ATP was calculated for each mutant. Results The inhibitor sensitivity profiles predicted in this study for a set of previously characterized mutants correlated well with the published clinical, experimental and computational data. Both the single and compound mutations displayed differential inhibitor sensitivity towards first and next generation kinase inhibitors. Conclusions The present study provides predicted drug sensitivity profiles for a large panel of uncommon EGFR mutations towards multiple inhibitors which may help clinicians in deciding mutant-specific treatment strategies.
Differences in longitudinal health utility between stereotactic body radiation therapy and surgery in stage I non-small cell lung cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31 Henri B. Wolff, Leonie Alberts, Elisabeth A. Kastelijn, Birgit I. Lissenberg-Witte, Jos W. Twisk, Frank J. Lagerwaard, Suresh Senan, Sherif Y. El Sharouni, Franz M.N.H. Schramel, Veerle M.H. Coupé
Introduction There is an ongoing debate on the optimal treatment for stage I non-small cell lung cancer (NSCLC), with increasing evidence for comparable health outcomes after surgery or stereotactic body radiation therapy (SBRT). For clinical decision making, the experienced quality of life, summarized as health utility, is of importance to choose between treatments. In this study, we evaluated differences in longitudinal health utility in stage I NSCLC in the first year after surgical resection versus SBRT, before any recurrence of disease. We also assessed the impact of potential prognostic variables on health utility. Methods Prospectively collected databases containing stage I NSCLC patients treated with either SBRT or surgery were pooled from two large hospitals in the Netherlands. Quality of life data was measured by the QLQ-C30 questionnaire at baseline, and 3, 6 and 12 months after treatment. Health utility (EQ-5D) was calculated from the QLQ-C30 questionnaire using a mapping algorithm. Propensity score matching was used to adjust for selection bias. Treatment effects were estimated for the matched patients using a longitudinal mixed model approach. Results After correction for ECOG score, gender and age, the difference in 1-year averaged health utility between the SBRT and surgery groups was 0.026 (95% CI -0.028 — 0.080). Differences in health utility decreased over time. Conclusions A small, and not statistically significant difference in health utility was found between stage I NSCLC patients treated with either surgery or SBRT. Current analysis strengthens existing evidence that SBRT is an equivalent treatment option for early stage NSCLC. Comparative cost-effectiveness remains to be determined.
Histologic Lung Cancer Incidence Rates and Trends vary by Race/Ethnicity and Residential County J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31 Keisha A. Houston, Khadijah A. Mitchell, Jessica King, Arica White, Bríd M. Ryan
Introduction Lung cancer incidence is higher among NH blacks compared with NH white and Hispanic populations in the U.S. However, national cancer estimates may not always reflect the cancer burden in terms of disparities and incidence in small geographic areas, especially urban-rural disparities. Moreover, there is a gap in the literature regarding rural-urban disparities in terms of cancer histology. Methods Using population-based cancer registry data—Surveillance, Epidemiology and End Results (SEER) and National Program of Cancer Registries (NPCR)—we present age-adjusted histologic rates and trends by race/ethnicity, and residential county location at the time of first cancer diagnosis. Rate ratios were calculated to examine racial/ethnic differences in rates. Annual percent change (APC) was calculated to measure changes in rates over time. Results We find that declines in squamous cell carcinoma (SCC) are occurring fastest in metropolitan counties, while rates of adenocarcinoma increased fastest in counties non-adjacent to metropolitan areas. Further, while NH black men have increased lung cancer incidence compared with NH white and Hispanic men in all geographic locations, we find that the degree of the disparity increases with increasing rurality of residence. Finally, we report that among women diagnosed at less than 55 years of age, the incidence of SCC and adenocarcinoma was higher for NH blacks compared with NH whites. Conclusions Our results highlight disparities among NH blacks in non-adjacent rural areas. These findings may have significant impact for the implementation of smoking cessation and lung cancer screening programs.
Safety of Combined PD-1 Pathway Inhibition and Intracranial Radiation Therapy in Non-Small Cell Lung Cancer J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31 Harper G. Hubbeling, Emily F. Schapira, Nora K. Horick, Kelly E.H. Goodwin, Jessica J. Lin, Kevin S. Oh, Alice T. Shaw, William A. Mehan, Helen A. Shih, Justin F. Gainor
Introduction Intracranial metastases are a common cause of morbidity and mortality in patients with advanced non-small cell lung cancer (NSCLC), and are frequently managed with radiation therapy (RT). The safety of cranial RT in the setting of treatment with immune checkpoint inhibitors (ICIs) has not been established. Methods We identified advanced NSCLC patients with brain metastases who received cranial RT and were treated with or without PD-1/PD-L1 inhibitors between August 2013 and September 2016. RT-related adverse events (AEs) were retrospectively evaluated and analyzed according to ICI treatment status, cranial RT type, and timing of RT with respect to ICI. Results Of 163 patients, 50 (31%) patients received ICIs while 113 (69%) were ICI-naive. Overall, 94 (58%), 28 (17%) and 101 (62%) patients received stereotactic radiosurgery (SRS), partial brain irradiation (PBI), and/or whole brain RT (WBRT), respectively. Fifty percent of patient received >1 radiation course. We observed no significant difference in rates of all-grade AEs and grade ≥3 AEs between ICI-naive and ICI-treated patients across different cranial RT types (grade ≥3 AEs: 8% ICI- vs. 9% ICI+ for SRS [P=1.00]; 8% ICI- vs. 10% ICI+ for WBRT [P=0.71]). Additionally, there was no difference in AE rates based on the timing of ICI administration with respect to RT. Conclusions Treatment with ICI and cranial RT was not associated with a significant increase in RT-related AEs, suggesting that use of PD-1/PD-L1 inhibitors in patients receiving cranial RT may have an acceptable safety profile. Nonetheless, additional studies are needed to validate this approach.
Association of PD-L1 expression with tumor-infiltrating immune cells and mutation burden in high-grade neuroendocrine carcinoma of the lung J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31 Hye Sook Kim, Jeong Hyeon Lee, Soo Jeong Nam, Chan-Young Ock, Jae-Woo Moon, Chong Woo Yoo, Geon Kook Lee, Ji-Youn Han
Background The immune microenvironment of high-grade neuroendocrine carcinoma (HGNEC) of the lung, including programmed death-ligand 1 (PD-L1) expression, has not been well characterized. Methods Based on immunohistochemistry (IHC) results, PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) were scored as follows: TC0 and IC0 were defined as PD-L1 expression <1%, TC1 and IC1 as ≥1% but <10%, TC2 and IC2 as ≥10% but <50%, and TC3 and IC3 as ≥50%. Phosphatase and tensin homolog (PTEN) IHC was scored as either lost or retained expression. The Ion AmpliSeq Comprehensive Cancer Panel was used to identify mutations in all coding exons of 409 cancer-related genes. Results A total of 192 patients with large-cell neuroendocrine carcinoma (LCNEC; n = 72) and small cell lung cancer (SCLC; n=120) were studied. The prevalence of PD-L1 expression on TC was 15.1% (29/192). IC infiltration and PD-L1 expression on IC were observed in 34.4% (66/192) and 31.3% (60/192) of patients, respectively. The prevalence of IC infiltration and PD-L1 expression on IC were more strongly correlated with LCNEC than with SCLC (57.6% vs. 23.3%, P<.01; 45.8% vs. 22.5%, P<.01), and high nonsynonymous mutations (P=.05 and .04). PTEN loss was found in 9.5% (18/189) of patients and showed no correlation with PD-L1 expression. Progression-free survival was better in patients with IC infiltration than in those without IC infiltration (median 11.3 vs. 6.8 months, P<.01) and in patients with PD-L1 expression of IC1/2/3 compared to those with IC0 (median 11.3 vs. 7.0 months, P=.03). Conclusion These findings suggest that the PD-1/PD-L1 pathway is activated in the microenvironment of pulmonary HGNEC and correlated with a higher mutation burden.
The role of systemic therapy in the management of stage I large cell neuroendocrine carcinoma of the lung J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31 Lara Kujtan, Varsha Muthukumar, Kevin F. Kennedy, John Russell Davis, Ashiq Masood, Janakiraman Subramanian
Introduction The optimal treatment strategy for resected stage I large cell neuroendocrine carcinoma of the lung (LCNEC) remains unknown. In this analysis, we evaluate the impact of systemic chemotherapy on patients with stage I LCNEC who have undergone surgical resection. Methods The study population included patients who underwent surgical resection for LCNEC and had pathologic stage I disease. We compared overall survival between patients who underwent surgical resection alone, and those who underwent surgical resection plus chemotherapy. Overall survival (OS) was estimated using the Kaplan-Meier method, and comparisons were analyzed using multivariable Cox models and propensity score matched analyses. Results From 2004 to 2013, 1232 patients underwent surgical resection for stage I LCNEC in the NCDB, including 957 (77.7%) patients who underwent surgical resection alone and 275 (22.3%) who received both surgery plus systemic chemotherapy. Five-year survival was significantly improved in patients who received chemotherapy (hazard ratio (HR) =0.54, 95% confidence interval (CI) 0.43-0.68, p<0.001; 5-year survival, 64.5% versus 48.4%). Multivariable Cox modeling confirmed the survival benefit from chemotherapy for patients with resected stage I LCNEC (HR 0.54, 95% CI 0.43-0.68, p <0.0001). The survival benefit was further confirmed by propensity matched analysis. In addition, older (age > 70 years), comorbid white patients who underwent sublobar resections for tumors >20mm have worse survival outcomes. Conclusion In this largest reported retrospective study of resected stage I LCNEC patients, survival was improved in patients who received chemotherapy, in both stage IA and stage IB LCNEC.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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