Search

Non–small cell lung cancer; Brain metastases; Somatic mutations Càncer de pulmó de cèl·lules no petites; Metàstasis cerebrals; Mutacions somàtiques Cáncer de pulmón de células no pequeñas; Metástasis cerebrales; Mutaciones somáticas Introduction In the phase 3 CheckMate 9LA study, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy alone. We report updated efficacy and safety (≥3 y of follow-up), clinical outcomes in patients with baseline brain metastases, and exploratory somatic mutation analyses. Methods Adults with stage IV or recurrent NSCLC, no known sensitizing EGFR or ALK alterations, and Eastern Cooperative Oncology Group performance status less than or equal to 1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy alone (four cycles). Assessments included OS, progression-free survival (PFS), and objective response rate. Exploratory analyses included systemic and intracranial efficacy in patients with or without baseline brain metastases, in addition to OS and PFS by KRAS, TP53, STK11, and KEAP1 somatic mutation status in patients with nonsquamous NSCLC. Results With a minimum follow-up of 36.1 months, nivolumab plus ipilimumab with chemotherapy continued to prolong OS versus chemotherapy alone in the intent-to-treat population (median [hazard ratio; 95% confidence interval] OS: 15.8 versus 11.0 mo [0.74; 0.62–0.87]; 3-y OS: 27% versus 19%). Efficacy outcomes were improved in patients with pretreated baseline brain metastases (median [hazard ratio; 95% confidence interval] OS: 19.3 versus 6.8 mo [0.45; 0.29–0.70]; systemic PFS: 9.7 versus 4.1 mo [0.44; 0.28–0.69]; intracranial PFS: 11.4 versus 4.6 mo [0.42; 0.26–0.68]). A trend of OS benefit was observed in patients treated with nivolumab plus ipilimumab with chemotherapy versus chemotherapy alone, despite KRAS, TP53, and STK11 tumor mutations. Extended follow-up revealed no new safety signals. Conclusions With a 3-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy continued to have long-term, durable efficacy versus chemotherapy alone; a manageable safety profile; and survival benefit in patients with or without baseline brain metastases or select somatic mutations, further supporting the regimen as first-line treatment for patients with metastatic NSCLC. This study was supported by Bristol Myers Squibb (Princeton, NJ).

Small cell lung cancer (SCLC) is an extremely aggressive neuroendocrine tumor, accounting for approximated 13% of all lung cancer cases. SCLC is characterized by rapid growth and early metastasis. Despite marked improvements in the number and efficacy of targeted, therapeutic options and overall survival rates in SCLC have remained nearly unchanged for almost three decades. The lack of significant progress can be attributed to our poor understanding of the biology of SCLC. Although immune checkpoint inhibitors were recently approved as front-line therapies for SCLC, we still need to better understand the mechanisms responsible for the selective vulnerability of some SCLCs to these inhibitors. Recent work utilizing sequencing data and single cell analyses identified four distinct subsets of SCLC, based on the expression levels of the transcription factors ASCL1, NEUROD1, POU2F3 and YAP1. Each subset was found to have its own distinct biology and therapeutic vulnerabilities. However, these subsets appear to be phenotypically unstable, representing snapshots in the gradual evolution of a tumor that exhibits significant plasticity. Tumor evolution, a product of this plasticity, results in the emergence of significant intratumoral heterogeneity which plays an important role in multiple aspects of SCLC development and progression, including cell survival and proliferation, metastasis and angiogenesis. The recent paradigm shifting discoveries in the biology of SCLC are now beginning to inform the design of new therapeutic strategies for the management of this intractable disease.

Background Early detection of lung cancer in asymptomatic patients remains challenging, especially for stage I. Considering the substantial interaction with tumor immunogenicity, we hypothesized that lung cancer-associated TCR (LC-aTCR) may serve as potential biomarker in early detection of stage I lung cancer. Methods Individuals who received low-dose computed tomography (LDCT) screening were enrolled in the study. Surgical tissues and peripheral blood specimens were collected and performed with DNA-based T cell repertoire (TCR) sequencing. The motif-based algorithm was used to deconstruct specific lung cancer-associated TCRs (LC-aTCRs). Results A total of 146 individuals participating in the real-world LDCT screening project were enrolled in this study, including 52 patients with pathologically-confirmed stage I lung cancer and 94 non-cancer controls. We developed a motif-based algorithm to define 80 LC-aTCRs in the training cohort. Moreover, in the validation cohort, high sensitivity and specificity was showed in stage I lung cancer with 72% and 91% respectively, and the AUC of the ROC curve was 0.91 (95% CI: 0.85 ∼ 0.96). Conclusion This work provides inspiration for stage I lung cancer detection by using blood TCR profiling data. The combination of TCR-based assay and routine screening deserves further testing in larger cohorts.

Background Next-generation sequencing of circulating cell-free DNA (cfDNA) can identify sensitizing and resistance mutations in non–small-cell lung cancer (NSCLC). cfDNA is helpful when tissue is insufficient for genomic testing or repeat biopsy is not feasible or poses unacceptable risk. Here we report the experience of cfDNA testing at the time of diagnosis and how this intervention can help avoid further invasive interventions, how it can be used to determine initiation of therapy, and how variation allele frequency of the somatic alteration affects response to subsequent treatment. Patients and Methods This is a single-institution retrospective study of patients with advanced NSCLC who had cfDNA from plasma tested using the Guardant360 panel, which identifies somatic genomic alterations by massive parallel sequencing of target genes. An institutional Clinical Laboratory Improvement Amendments tissue panel using fluorescence in situ hybridization (for MET, RET, ROS1, and ALK) and next-generation sequencing for selected genes was used for tissue analysis. Actionable mutations are those with US Food and Drug Administration–approved targeted therapies (EGFR, ALK, ROS, BRAF, NTRK fusions) or therapies soon to be approved (RET fusions and MET amplifications, or MET exon 14 skipping mutation). Results A total of 163 blood samples from 143 patients were evaluated, 82 at diagnosis and 81 at disease progression. A total of 94 cases had tissue and cfDNA testing performed within 12 weeks of each other. Seventy-six (81%) of 94 cases were concordant, of which 22 cases were concordantly positive and 54 concordantly negative. Eighteen (19%) of 94 cases were discordant, of which 11 had negative blood and positive tissue results, and 7 had positive blood and negative tissue results. cfDNA testing had a sensitivity of 67% (95% confidence interval [CI], 51%, 83%), specificity of 89% (95% CI, 81%, 97%), negative predictive value of 83% (95% CI, 74%, 92%), and positive predictive value of 76% (95% CI, 60%, 91%). Nineteen (21%) of 82 cfDNA samples analyzed at diagnosis had actionable mutations identified (4 EGFR exon 19 deletion, 2 EGFR exon 21 L858R, 2 EGFR L861Q, 1 L861R, 4 EML4-ALK fusion, 2 CD74-ROS1 fusion, 2 MET exon 14 skipping mutation, 2 KIF5B-RET fusion). Of the 82 patients with cfDNA testing performed at the time of diagnosis, 8 patients (10%) initiated targeted therapy on the basis of cfDNA results only, with 6 patients experiencing partial response, 1 patient complete response, and 1 patient stable disease. The response rate for patients who initiated targeted therapies on the basis of cfDNA only at diagnosis was 88%. Variant allele frequency had no impact on response. Conclusions Initiation of targeted therapy for advanced NSCLC was feasible based only on identification of actionable mutations by cfDNA testing in 9% of the cases for which tissue diagnosis could not be obtained. Actionable targets were identified by cfDNA in 20% of the samples sent at diagnosis. A substantial number of patients benefited from cfDNA testing at initial diagnosis because it identified actionable mutations that led to appropriate targeted treatments.

OBJECTIVES: Despite growing evidence that checkpoint inhibitor immunotherapy (IO) toxicity is associated with improved treatment response, the relationship between immune-related adverse events (irAEs) and overall survival (OS) among older adults [age ≥ 70 years (y)] remains unknown. The study goal was to determine differences in OS based on age and ≥ grade 3 (G3) irAEs. MATERIALS AND METHODS: This was a retrospective cohort study of 673 patients with advanced cancer. Patients who received ≥1 dose of IO at our institution from 2011–2018 were eligible. The primary outcome was OS from the start of first line of IO treatment, compared between four patient groups stratified by age and ≥G3 irAEs with adjustment for patient characteristics using a Cox proportional hazards model. RESULTS AND CONCLUSION: Among all 673 patients, 35.4% were ≥70y, 39.8% had melanoma, and 45.6% received single-agent nivolumab. Incidence and types of ≥G3 irAEs did not differ by age. Median OS was significantly longer for all patients with ≥G3 irAEs (unadjusted 21.7 vs. 11.9 months, P=0.007). There was no difference in OS among patients ≥70y with ≥G3 irAEs (HR 0.94, 95% CI 0.61–1.47, P=0.79) in the multivariable analysis. Patients

Introduction Although chemoradiotherapy (CRT) is the standard of care for patients with unresectable stage III non–small-cell lung cancer (LA-NSCLC), most patients relapse. Tecemotide is a MUC1 antigen-specific cancer immunotherapy vaccine. Bevacizumab improves survival in advanced nonsquamous (NS)-NSCLC and has a role in immune modulation. This phase II trial tested the combination of tecemotide and bevacizumab following CRT in patients with LA-NSCLC. Patients and Methods Subjects with stage III NS-NSCLC suitable for CRT received carboplatin/paclitaxel weekly + 66 Gy followed by 2 cycles of consolidation carboplatin/paclitaxel ≤ 4 weeks of completion of CRT (Step 1). Patients with partial response/stable disease after consolidation therapy were registered onto step 2, which was 6 weekly tecemotide injections followed by every 6 weekly injections and bevacizumab every 3 weeks for up to 34 doses. The primary endpoint was to determine the safety of this regimen. Results Seventy patients were enrolled; 68 patients (median age, 63 years; 56% male; 57% stage IIIA) initiated therapy, but only 39 patients completed CRT and consolidation therapy per protocol, primarily owing to disease progression or toxicity. Thirty-three patients (median age, 61 years; 58% male; 61% stage IIIA) were registered to step 2 (tecemotide + bevacizumab). The median number of step 2 cycles received was 11 (range, 2-25). Step 2 worst toxicity included grade 3, N = 9; grade 4, N = 1; and grade 5, N = 1. Grade 5 toxicity in step 2 was esophageal perforation attributed to bevacizumab. Among the treated and eligible patients (n = 32) who were treated on step 2, the median overall survival was 42.7 months (95% confidence interval, 21.7-63.3 months), and the median progression-free survival was 14.9 months (95% confidence interval, 11.0-20.9 months) from step 1 registration. Conclusions This cooperative group trial met its endpoint, demonstrating tolerability of bevacizumab + tecemotide after CRT and consolidation. In this selected group of patients, the median progression-free survival and overall survival are encouraging. Given that consolidation immunotherapy is now a standard of care following CRT in patients with LA-NSCLC, these results support a role for continued investigation of antiangiogenic and immunotherapy combinations in LA-NSCLC.

Introduction Recent clinical studies have identified tumor mutation burden (TMB) as a promising therapeutic biomarker of anti-tumor immune checkpoint blockade. However, given the relatively slow turnaround time and high expense in measuring TMB, tobacco smoking history (TSH) is an attractive replacement biomarker. The carcinogenic effects of tobacco smoking may be modified by the protective effects of genome stability genes. This study aims to test the associations between tobacco smoking, genome stability gene inactivation, and TMB. Methods Publicly available TSH and DNA somatic alteration data from NSCLC were downloaded from The Cancer Genome Atlas. Correlations and enrichments were calculated with Spearman and Fisher’s exact test methods, respectively. Multivariate modeling of TMB was performed with penalized linear regression. Results 85% of never smokers in adenocarcinomas (LUAD) had low TMB, but a positive TSH was not predictive of hypermutancy. The limited utility of TSH in predicting TMB was reproduced on an independent LUAD dataset. To expand our search for predictors of TMB, we further investigated the contributions of genome stability related genes (GSGs) to TMB. 242/461 (52%) and 300/465 (65%) patients with LUAD and squamous carcinomas (LUSC), respectively, showed evidence of loss of function in at least one of the 182 GSGs. 182 GSGs from 16 pathways were assessed for associations with TMB high tumor status using Fisher’s exact test. We performed univariate gene and pathway enrichments in TMB high tumors and found roles forPOLE, REV3L, and FANCE genes, as well as several key GSG pathways. Conclusions This study comprehensively tested the association between GSG, tobacco smoking, and TMB in NSCLC. In LUAD, never-smoking status was predictive of low TMB, but overall TSH was not an adequate surrogate biomarker for TMB in NSCLC. Furthermore, we identified an association between GSG inactivation and TMB.

This study aimed to evaluate the prognostic and potential therapeutic value of expanded molecular testing of resected early-stage lung ACA.We analyzed 324 patients who underwent lobectomy and lymphadenectomy for clinical Stage III lung ACA between 2011-2017. Molecular testing was routinely performed, first by PCR-based Sanger sequencing and FISH and then expanded to a 20 and then 50-gene next generation sequencing (NGS) panel. The frequency of mutations by testing method and their association with disease-free (DFS) and overall survival (OS) were tested.A total of 241 patients (74.4%) had at least one somatic mutation detected, with KRAS exon 2 (38.1%) and EGFR (17.9%) being the most common. TP53 was the most frequent co-existing mutation. Detection of at least one mutation increased from 49% with selective PCR/FISH testing to 82% with limited NGS/FISH, and 91% with extended NGS/FISH (p0.001). The rate of actionable mutations increased from 18% to 32% and 45% with expansion of molecular testing, respectively (p = 0.001). Using NGS, an additional 10 cases with EGFR mutations, and other rare mutations were found, including BRAF (5.9%), MET (5.6%), ERBB2 (4.1%), PIK3CA (2.3%), and DDR2 (2.1%). The expansion of FISH testing resulted in one additional detection of ROS1 and RET (1%) rearrangement. KRAS mutation was associated with worse DFS (HR 1.87; 95%CI 1.14-3.06) and OS (HR 2.09; 95%CI 1.11-3.92). BRAF mutation detected in NGS tested patients was also associated with decreased DFS (HR3.80; 95%CI 1.46-9.89) and OS (HR 7.37; 95%CI 2.36-22.99) on multivariate analysis.The expansion of molecular testing has resulted in a substantial increase in the detection of potentially therapeutically significant mutations in resected early-stage ACA. KRAS and BRAF mutation status by NGS was prognostic for relapse and survival. These data emphasize opportunities for clinical trials in a growing number surgical ACA patients with available targeted therapies.

The outcomes of patients with SCLC have not yet been substantially impacted by the revolution in precision oncology, primarily owing to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. Although, these results are encouraging, many patients do not respond to, or rapidly recur after, current regimens, necessitating alternative or complementary therapeutic strategies. In this review, we discuss ongoing investigations into the pathobiology of this recalcitrant cancer and the therapeutic vulnerabilities that are exposed by the disease state. Included within this discussion, is a snapshot of the current biomarker and clinical trial landscapes for SCLC. Finally, we identify key knowledge gaps that should be addressed to advance the field in pursuit of reduced SCLC mortality. This review largely summarizes work presented at the Third Biennial International Association for the Study of Lung Cancer SCLC Meeting.

Objectives The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) osimertinib has shown promising efficacy both in EGFR-mutant, T790M positive non-small cell lung cancer (NSCLC) patients who have become resistant to 1st or 2nd generation EGFR TKIs and patients with sensitizing EGFR mutations as the first line therapy. However, the degree and duration of response to osimertinib are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors could play a role in clinical outcomes and/or mechanisms of resistance. Materials and methods We conducted a retrospective multicenter study of lung cancer patients who had developed resistance to osimertinib. Genomic profiling was done for all the patients by using targeted next-generation sequencing encompassing 59–1021 cancer-related genes. Results and conclusion Known EGFR-dependent resistant mutations and activation of alternative pathways were identified in 44 % of all the patients with great heterogeneity. Gain-of-function mutations of CTNNB1 were highly enriched in our cohort. Some other putative resistance mechanisms to osimertinib, such as the recurrent EGFR V834 L mutation, were also identified. Moreover, pathogenic mutations of TP53 were negatively related to the efficacy of osimertinib. To sum up, heterogeneity of resistance to osimertinib was not only manifested by inter-individual differences, but also embodied in its intra-individual diversity.

Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery.Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was major pathological response in patients without EGFR/ALK+ alterations. Pre- and post-treatment computed tomography, positron emission tomography, pulmonary function tests, and biospecimens were obtained. Adverse events were recorded by Common Terminology Criteria for Adverse Events v.4.0.From April 2017 to February 2020, 181 patients were entered in the study. Baseline characteristics were mean age, 65.1 years; female, 93 of 181 (51%); nonsquamous histology, 112 of 181 (62%); and clinical stages IIB to IIIB, 147 of 181 (81%). In patients without EGFR/ALK alterations who underwent surgery, the major pathological response rate was 20% (29/143; 95% confidence interval, 14-28) and the pathological complete response rate was 6% (8/143; 95% confidence interval, 2-11). There were no grade 4/5 treatment-related adverse events preoperatively. Of 159 patients (87.8%) undergoing surgery, 145 (91%) had pathologic complete resection. There were 5 (3%) intraoperative complications, no intraoperative deaths, and 2 postoperative deaths within 90 days, 1 treatment related. Median disease-free and overall survival have not been reached.Neoadjuvant atezolizumab in resectable stage IB to IIIB non-small cell lung cancer was well tolerated, yielded a 20% major pathological response rate, and allowed safe, complete surgical resection. These results strongly support the further development of immune checkpoint inhibitors as preoperative therapy in locally advanced non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a heterogeneous disease with genetic and environmental parameters that influence cell metabolism. Because of the complex interplay of environmental factors within the tumor microenvironment (TME) and the profound impact of these factors on the metabolic activities of tumor and immune cells, there is an emerging interest to advance the understanding of these diverse metabolic phenotypes in the TME. High levels of adenosine are characteristic of the TME, and adenosine can have a significant impact on both tumor cell growth and the immune response. Consistent with this, we showed in NSCLC data from TCGA that high expression of the A2BR leads to worse outcome and that expression of A2BR may be different for different mutation backgrounds. We then investigated the metabolic reprogramming of tumor cells and immune cells (T and dendritic cells) by adenosine. We used A2AR and A2BR antagonism or agonism as well as receptor knockout animals to explore whether these treatments altered specific immune compartments or conferred specific therapeutic vulnerabilities. Using the seahorse assay, we found that an A2BR antagonist modulates oxidative stress homeostasis in NSCLC cell lines. In addition, we found distinct metabolic roles of A2AR and A2BR receptors in T cell activation and dendritic cell maturation. These data suggest potential mechanisms and therapeutic benefits of A2 receptor antagonist therapy in NSCLC.

To evaluate whether and the degree to which patients with advanced NSCLC (aNSCLC) receiving lung cancer treatments will experience functional disability or have resilience and to identify characteristics associated with functional disability.We evaluated longitudinal data of patients with aNSCLC receiving treatment in the Beating Lung Cancer in Ohio prospective cohort study. Disability versus resilience in functional status (usual activities, mobility, and self-care) was measured monthly for 8 months using the EuroQol-5D-5L. Data captured included baseline demographics (Eastern Cooperative Oncology Group performance status), comorbidities, cancer and depressive symptoms (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder-7 scale), and cancer stress (impact of events). Group-based latent class trajectory modeling was used to determine clinically distinct functional disability trajectories jointly with attrition probability (death or withdrawal) in the study period.Among 207 participants, the mean age was 63.5 years (range: 34-92 y), 58.9% were male, 6.8% were African American or Black, 73.3% were former smokers, and 35% resided in rural areas. At baseline, participants had adenocarcinoma histological subtype (74.9%), 40.3% had brain metastases, and 46.1% had bone metastases. Participants received chemotherapy plus immunotherapy (46.9%), immunotherapy single agent (21.7%), targeted treatments (18.8%), or no treatment (12.6%). Three distinct functional trajectory groups were identified, as follows: none/mild (n = 79, 38.2%), moderate (n = 99, 47.8%), and severe disability (n = 29, 14.0%). Characteristics associated with severe disability included baseline Eastern Cooperative Oncology Group performance status greater than 1, worse dyspnea and pain, and higher Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 scale scores. At month 8, 95 participants (45.9%) displayed resilience, 11 (5.3%) experienced functional decline, and 69 (33.3%) were deceased.We identified three distinct functional trajectories among patients with aNSCLC. Risk stratification tools and targeted interventions designed to target these three groups are needed to improve functional resilience and prevent disability.

INTRODUCTION: Notch receptor family dysregulation can be tumor promoting or suppressing depending on cellular context. Our studies shed light on the mechanistic differences that are responsible for NOTCH1’s opposing roles in lung adenocarcinoma and lung squamous cell carcinoma. METHODS: We integrated transcriptional patient-derived datasets with gene co-expression analyses to elucidate mechanisms behind NOTCH1 function in subsets of non-small cell lung cancer. Differential co-expression was examined using hierarchical clustering and principal component analysis. Enrichment analyses was used to examine pathways associated with the underlying transcriptional networks. These pathways were validated in vitro and in vivo. Endogenously epitope-tagged NOTCH1 was used to identify novel interacting proteins. RESULTS: NOTCH1 co-expressed genes in lung adenocarcinoma and squamous carcinoma were distinct, and associated with either angiogenesis and immune system pathways or cell cycle control and mitosis pathways, respectively. Tissue culture and xenograft studies of lung adenocarcinoma and lung squamous models with NOTCH1 knockdown demonstrated growth differences and opposing effects on these pathways. Differential NOTCH1 interacting proteins were identified as potential mediators of these differences. CONCLUSIONS: Recognition of the opposing role of NOTCH1 in lung cancer, downstream pathways, and interacting proteins in each context may help direct the development of rational NOTCH1 pathway-dependent targeted therapies for specific tumor subsets of non-small cell lung cancer.

Immunotherapy is a mainstay of treatment for nonesmall-cell lung cancer. Serious immune-related adverse events (irAEs) occur; however, their effect on survival is unclear, and no defined risks factors have been elucidated. In the present study, we found no significant effect of irAE on survival in a landmark analysis, and no increased risk of pneumonitis in patients with previous radiation. Background: The risk factors for immune-related adverse events (irAEs) remain undefined. Recently, a correlation between irAEs and clinical benefit was suggested. We examined the risk factors for irAEs and their effect on survival in patients with nonesmall-cell lung cancer (NSCLC) who had received immunotherapy. Patients and Methods: We performed a retrospective review of patients with NSCLC treated with single-agent immunotherapy at our institution. irAEs were determined by treating physician diagnosis. A landmark analysis was performed at 3 months using log-rank tests and the Bonferroni method. Results: irAEs occurred in 27 of 91 patients (30%). The median overall survival (OS) for patients with irAEs was longer than that for patients without (24.3 vs. 5.3 months; hazard ratio, 2.75; 95% confidence interval, 1.54–4.92; P < .001). However, a landmark analysis of patients after 3 months of treatment revealed no difference in OS between patients with and without irAEs. No increased risk of pneumonitis was seen in patients with previous thoracic radiotherapy, although these patients had shorter survival (4.2 vs. 9.7 months; P =.004). Radiotherapy after the initiation of immunotherapy (n = 15) did not increase the risk of irAEs or pneumonitis; however, these patients had improved OS (17.3 vs. 6.0 months; P =.016). Conclusion: The development of irAEs did not significantly correlate with survival when controlling for the duration of therapy in a landmark analysis. We found no increased risk of pneumonitis or irAEs in patients who had received radiotherapy. Radiotherapy before immunotherapy was associated with shorter survival, and radiotherapy after immunotherapy was associated with improved survival.

Introduction In ret proto-oncogene (RET)–rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized. Methods A global, multi-institutional registry (cohort A, n = 114) and a bi-institutional data set (cohort B, n = 71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined. Results The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%–32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%–58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p = 0.0039) between RET-, ROS1-, and ALK receptor tyrosine kinase (ALK)–rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression-free survival of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3–2.9 months, n = 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression-free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0–4.9 months). Conclusions Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.

Introduction Despite apparently complete surgical resection, approximately half of resected early-stage lung cancer patients relapse and die of their disease. Adjuvant chemotherapy reduces this risk by only 5% to 8%. Thus, there is a need for better identifying who benefits from adjuvant therapy, the drivers of relapse, and novel targets in this setting. Methods RNA sequencing and liquid chromatography/liquid chromatography–mass spectrometry proteomics data were generated from 51 surgically resected non–small cell lung tumors with known recurrence status. Results We present a rationale and framework for the incorporation of high-content RNA and protein measurements into integrative biomarkers and show the potential of this approach for predicting risk of recurrence in a group of lung adenocarcinomas. In addition, we characterize the relationship between mRNA and protein measurements in lung adenocarcinoma and show that it is outcome specific. Conclusions Our results suggest that mRNA and protein data possess independent biological and clinical importance, which can be leveraged to create higher-powered expression biomarkers.

Introduction Real-world data on current treatment practices for non–small-cell lung cancer (NSCLC) are needed to understand the place in therapy and potential economic impact of newer therapies. Patients and Methods This retrospective cohort study identified patients ≥ 65 years old in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database with first-time diagnosis of stage IIIB/IV NSCLC from 2007-2011 who received second-line therapy after first-line platinum-based chemotherapy from 2007 through mid-2013. Second-line regimens, health care resource use, adverse events (AEs), and associated costs were analyzed descriptively. Overall survival was determined by Kaplan-Meier test. Costs were adjusted to 2013 US dollars. Results We identified 4033 patients with advanced NSCLC who received second-line therapy (47% of those who received first-line platinum-based chemotherapy). Mean (SD) age was 73 (5) years, 2246 (56%) were male; 1134 (28%) and 2899 (72%) had squamous and nonsquamous NSCLC, respectively. The 4 most common second-line regimens were pemetrexed (22%), docetaxel (12%), carboplatin/paclitaxel (11%), and gemcitabine (7%). Median overall survival from second-line therapy initiation was 7.3 months (95% confidence interval, 7.0-7.7). Dyspnea and anemia were the most common AEs of interest, affecting 29% and 26% of patients, respectively; atypical pneumonia was associated with the highest AE-related costs (mean, $5339). The mean total per-patient–per-month cost was $10,885; AE-related per-patient–per-month costs totaled $1036 (10%). Costs were highest for pemetrexed-treated patients. Conclusion These real-world data illustrate the variety of second-line regimens, poor prognosis, and high cost of second-line chemotherapy for patients with advanced NSCLC treated before the approval of immunotherapies for these patients.

Introduction Elderly patients account for the majority of lung cancer diagnoses but are poorly represented in clinical trials. We evaluated the overall survival (OS) of elderly patients with stage III NSCLC treated with definitive radiation compared with that of patients treated with definitive chemoradiation. Methods We conducted a comparative effectiveness study of radiation therapy versus chemoradiation in elderly (≥70 years old) patients with stage III NSCLC not treated surgically diagnosed from 2003 to 2014; the patients were identified by using the National Cancer Database. Two cohorts were evaluated: patients (n = 5023) treated with definitive radiation (≥59.4 Gy) and patients (n = 18,206) treated with definitive chemoradiation. Chemoradiation was further defined as concurrent (radiation and chemotherapy started within 30 days of each other) or sequential (radiation started >30 days after chemotherapy). We compared OS between the treatment groups by using the Kaplan-Meier method and Cox proportional hazards regression before and after propensity score matching (PSM). Results Treatment with chemoradiation was associated with improved OS versus that with radiation both before PSM (hazard ratio [HR] = 0.66, 95% confidence interval [CI]: 0.64-0.68, p Conclusions We found that definitive chemoradiation resulted in a survival advantage compared with definitive radiation in elderly patients. Sequential chemotherapy and radiation was superior to concurrent chemoradiation. Although prospective trials are needed, this analysis suggests that chemoradiation should be strongly considered for elderly patients and the optimal sequencing of chemotherapy and radiation remains an unanswered question for this patient population.

Despite tremendous advances in targeted therapies against lung adenocarcinoma, the majority of patients do not benefit from personalized treatments. A deeper understanding of potential therapeutic targets is crucial to increase the survival of patients. One promising target, ADAR, is amplified in 13% of lung adenocarcinomas and in-vitro studies have demonstrated the potential of its therapeutic inhibition to inhibit tumor growth. ADAR edits millions of adenosines to inosines within the transcriptome, and while previous studies of ADAR in cancer have solely focused on protein-coding edits, >99% of edits occur in non-protein coding regions. Here, we develop a pipeline to discover the regulatory potential of RNA editing sites across the entire transcriptome and apply it to lung adenocarcinoma tumors from The Cancer Genome Atlas. This method predicts that 1413 genes contain regulatory edits, predominantly in non-coding regions. Genes with the largest numbers of regulatory edits are enriched in both apoptotic and innate immune pathways, providing a link between these known functions of ADAR and its role in cancer. We further show that despite a positive association between ADAR RNA expression and apoptotic and immune pathways, ADAR copy number is negatively associated with apoptosis and several immune cell types' signatures.

Purpose/Objective(s) Primary tumor failure is common in patients treated with chemoradiation (CRT) for unresectable LA-NSCLC. Stereotactic body radiation therapy (SBRT) yields high rates of primary tumor control in Stage I NSCLC. This trial tested an SBRT boost to the primary tumor prior to the start of CRT to improve primary tumor control (PTC). Materials/Methods Patients with LA-NSCLC with primary tumor ≤10 cm were enrolled on a prospective phase II trial testing an SBRT boost in 2 fractions (central 6 Gy x 2, peripheral 8 Gy x 2) immediately followed by standard concurrent CRT (60 Gy in 30 fractions). Patients were staged with PET-CT, brain MRI, and underwent 4D-CT simulation for radiation planning using a customized immobilization device that enabled radiation planning for the sequential delivery of the SBRT boost and conventionally-fractionated radiation from the same CT dataset. Chemotherapy was carboplatin/paclitaxel (C/P) or cisplatin/etoposide. For patients receiving C/P, consolidation C/P for 2 cycles was given at the discretion of the medical oncologist. The trial was later amended to allow for consolidation durvalumab. The primary objective was to estimate PTC rate at 1-year with a hypothesis that the 1-year PTC rate is ≥90%. Secondary objectives were to establish the safety, feasibility, objective response rate (ORR; RECISTv1.1), and rates of regional & distant control, disease-free survival (DFS), and overall survival (OS). Exploratory functional MRI (fMRI) scans before and within the first 30 hrs of the first SBRT fraction were performed in 11 patients. Results The study enrolled 21 patients (10 male, 11 female), with median age 62 years (range 52-78). 16 patients received 6 Gy x 2 SBRT boost, while 5 patients received 8 Gy x 2 SBRT boost. 18 patients received C/P chemotherapy, of whom 9 patients received consolidation C/P. Six patients received consolidation durvalumab. Median pre-treatment primary tumor size was 5.0 cm (range 1.0-8.3). Median and mean follow-up were17.9 and 20.2 months, respectively. The most common toxicities were fatigue, neutropenia, leukopenia, lymphopenia, anemia, pneumonitis, fibrosis, dyspnea and esophagitis. Five grade 4 toxicities related to treatment occurred [lymphopenia (3), neutropenia (1), and leukopenia (1)], but no grade 5 toxicities related to treatment occurred. ORR at 3 and 6 months was 72.7% and 80.0%. The PTC rate was 100% and 92.3% at 1 and 2 years, respectively. The 2-year regional and distant control were 81.6% and 70.3%, respectively. Disease-free survival and overall survival at 2 yrs were 46.1% and 50.3%, respectively. Median survival was 37.8 months. fMRI detected a mean relative decrease in BOLD signal of -87.1% (P = 0.05). Conclusion Dose escalation to the primary tumor utilizing upfront SBRT appears feasible and safe. PTC was high and other oncologic endpoints compared favorably with the literature. Through the use of 1 CT simulation dataset, accurate calculation of the planned dose through the 2 sequentially-delivered plans is achievable.

Introduction: This study investigates the immune profile of the primary lung tumors and the corresponding brain metastasis from patients with NSCLC using multiplex fluorescence immunohistochemistry. Methods: The study evaluated 34 patients who underwent autopsy or surgical resection for brain metastasis and autopsy, surgical resection, or core biopsy for primary lung cancer. We compared the densities of various immune cells in the primary tumors and the brain metastases by multiplex fluorescence immunohistochemical analysis. Results: The density of CD4-positive (CD4+) T-cells, CD8-positive T-cells, and CD4+ Foxp3-positive T-cells were statistically higher in both tumor and stromal areas in primary lung cancer specimens when compared with brain metastases samples (p < 0.0001). Only CD204-positive cells were statistically higher in the tumor areas of the brain metastases (p = 0.0118). Tumor-infiltrating lymphocytes associated with brain metastases positively correlated with overall survival, but primary lung tumor-infiltrating lymphocytes did not. The density of CD4+ and CD4+ Foxp3-positive T-cells in brain metastases with radiation was statistically higher in the carcinoma and stromal areas compared with those without radiation (p = 0.0343, p = 0.0173). Conclusions: Our findings that CD204-positive cells were higher in brain metastases may have broader implications for treatment as these macrophages may be immunosuppressive and make the immune environment less reactive. Furthermore, the finding that the density of CD4+ T-cells was higher in cancer and stroma areas of brain metastases after radiotherapy supports the addition of immunotherapy to radiation therapy in the treatment of brain metastases in NSCLC.

Introduction Kilovoltge cone beam computed tomography (kV-CBCT) allows for tumor localization and response assessment during definitive chemoradiotherapy for locally advanced NSCLC. We hypothesize that significant tumor volume loss occurs early during radiotherapy and that the extent of volume loss correlates with clinical outcomes. Methods A total of 52 patients with locally advanced NSCLC treated with definitive chemoradiotherapy were reviewed. kV-CBCT images were used to contour primary gross tumor volumes at four time points during treatment. Patients were dichotomized according to absolute and relative volume changes at each time point. Statistical analyses were performed to evaluate correlations between volume changes and clinical outcomes. Results The median gross tumor volumes were 77.1, 48.3, 42.5, and 29.9 cm3 for fractions 1, 11, 21, and final, respectively. Greater relative volume loss between fractions 1 and 21 correlated with improved distant control (hazard ratio [HR] = 0.35, 95% confidence interval [CI]: 0.13–0.94, p = 0.038) and overall survival (HR = 0.40, 95% CI: 0.16–0.98, p = 0.046). Greater relative volume loss between fractions 11 and 21 correlated with improved progression-free survival (HR = 0.39, 95% CI: 0.17–0.88, p = 0.02) and trended toward improved overall survival (HR = 0.43, 95% CI: 0.17–1.06, p = 0.07). On multivariate analysis, greater relative volume loss between fractions 11 and 21 correlated with improved progression-free survival (HR = 0.39, 95% CI: 0.16–0.97, p = 0.041) and overall survival (HR = 0.31, 95% CI: 0.11–0.88, p = 0.027). Conclusions Significant primary tumor volume loss occurs early during radiotherapy for locally advanced NSCLC. Greater relative tumor volume loss during treatment correlates with improved disease control and overall survival. Thus, kV-CBCT has potential to be used as a practical prognostic imaging marker.