Metastatic Lung Cancer Research Articles

Impact of lung biomarker testing on out-of-pocket costs for metastatic non-small cell lung cancer.

11087 Background: Biomarker testing in metastatic non-small lung cancer (NSCLC) is critical for appropriate selection of therapy options. Claims-based datasets offer real-world information on the use and cost of biomarker testing across the United States. Methods: We used de-identified administrative claims data from Optum’s Clinformatics Data Mart Database (CDM) from 2013 to 2021 to assess for trends in biomarker testing. Eligible patients were adults with two or more lung cancer diagnosis codes and with two or more claims of a secondary malignant neoplasm. Patients were excluded if they had another primary cancer or did not have continuous insurance coverage twelve months prior and six months after diagnosis. We assessed claims-based out-of-pocket (OOP) costs associated with testing and treatment. Descriptive statistics were used to assess biomarker testing rates, and multivariable analyses (MVA) were performed to assess factors associated with testing. Results: A total of 4377 patients with metastatic NSCLC were eligible (mean age 60 years (SD: 8.33 years), 49.6% female, 76.7% former smokers). Testing rates within two months of diagnosis increased from 58.15% in 2013 to 69.96% in 2021. On MVA, biomarker testing was associated with younger age, being non-smokers, living in Mountain geographic region, or having point-of-service insurance plans. Biomarker testing was associated with a median OOP cost of $98 (IQR: $43.87-$306.58). Patients who underwent biomarker testing had a median total OOP cost of all services within 6 months of diagnosis of $3560.20 (IQR: $1538.37-$6199.44) compared to $1979.58 (IQR: $725.75-$4003.06) for those who did not undergo biomarker testing. Conclusions: Using claims data, we find that 70% of patients with metastatic NSCLC undergo biomarker testing within two months of diagnosis with metastatic disease. Most patients undergo biomarker testing early in their treatment course (0-60 days), suggesting that testing is appropriately being obtained early on in their treatment course, but this testing is associated with substantially higher overall OOP costs to patients.

Disparities and outcomes of immune checkpoint inhibitor therapies in LMICs: Retrospective study on current state, efficacy, and challenges in Armenia.

e23315 Background: The escalating incidence of cancer in Armenia is a global trend, underscoring the urgency for innovative treatments, including immune checkpoint inhibitors (ICIs). This study, a first in the region, investigates ICIs' real-world impact, emphasizing the current state and critical gaps in access to care. Methods: We conducted a retrospective review of 224 patients, excluding 32, resulting in 192 patients treated with ICIs between 2017 and 2023 across four major oncology centres. The review covered demographic and clinical data, genetic testing, treatment regimens, and survival outcomes, analyzed using the STATA 18 BE. Results: The mean age of the patients was 61.4 years, with 69.27% being male. Lung cancer was the most common diagnosis (42.19%, n = 81), followed by melanoma (11.98%, n = 23) and gastric cancer (10.94%, n = 21). Survival outcomes varied, with melanoma patients exhibiting a mean overall survival (OS) of 33.26 months, lung cancer patients 19.69 months, and gastric cancer patients 20.50 months; the survival difference between patients with metastases and without was not statistically significant. Patients receiving ICIs in the second or later lines of treatment had a 2.12-fold lower chance of survival compared to those receiving them as first-line treatment (95% CI 1.16-3.88, p = 0.014). 78% of patients received ICIs in the metastatic setting and only 22% in curative. In two centres, among 185 patients with metastatic lung cancer, only 23.2% (43 patients) received ICIs, and of these, about 50% underwent mutation testing, with only 4 assessed via broad panel NGS. A significant 76.8% (142 patients) did not receive immunotherapy. Furthermore, 34% of those starting ICI treatment were forced to discontinue due to financial hardships. Pembrolizumab and Nivolumab were the most widely used agents, but the choice varies significantly between centres. Conclusions: The financial barrier is substantial: the cost of one pembro cycle on the black market, at $3,000, is 3.8 times the annual income of those at the national poverty line, more than twice the income of the lower middle-income class, and represents over 60% of the country's GDP per capita. Median cycle lengths for ICIs, such as 6.5 for Ipil+Nivo and 5.61 for Pembro, are below the NCCN's standard recommendations, highlighting the profound impact of financial constraints on treatment adherence and duration. This study reveals the stark reality of ICI accessibility and affordability in Armenia, where a significant portion of cancer patients are unable to benefit from these potentially life-extending treatments. Additionally, a preference bias towards selecting treatments without nationwide guidelines was observed, alongside the absence of a national E-health database, underscoring the need for policymaker attention, insurance adjustments, and more precise, prospective data collection.

Clinical characteristic and survival outcomes of patients with advanced NSCLC according to KRAS mutational status in the French real-life ESME cohort

The RAS/MEK signaling pathway is essential in carcinogenesis and frequently altered in non-small-cell lung cancer (NSCLC), notably by KRAS mutations (KRASm) that affect 25%-30% of non-squamous NSCLC. This study aims to explore the impact of KRASm subtypes on disease phenotype and survival outcomes. We conducted a retrospective analysis of the French Epidemiological Strategy and Medical Economics database for advanced or metastatic lung cancer from 2011 to 2021. Patient demographics, histology, KRASm status, treatment strategies, and outcomes were assessed. Of 10 177 assessable patients for KRAS status, 17.6% had KRAS p.G12C mutation, 22.6% had KRAS non-p.G12C mutation, and 59.8% were KRASwt. KRASm patients were more often smokers (96.3%) compared with KRASwt (85.8%). A higher proportion of programmed death-ligand 1 ≥50% was found for KRASm patients: 43.5% versus 38.0% (P < 0.01). KRASm correlated with poorer outcomes. First-line median progression-free survival was shorter in the KRASm than the KRASwt cohort: 4.0 months [95% confidence interval (CI) 3.7-4.3 months] versus 5.1 months (95% CI 4.8-5.3 months), P < 0.001. First-line overall survival was shorter for KRASm than KRASwt patients: 12.6 months (95% CI 11.6-13.6 months) versus 15.4 months (95% CI 14.6-16.2 months), P= 0.012. First-line chemoimmunotherapy offered better overall survival in KRAS p.G12C (48.8 months) compared with KRAS non-p.G12C (24.0 months) and KRASwt (22.5 months) patients. Second-line overall survival with immunotherapy was superior in the KRAS p.G12C subgroup: 12.6 months (95% CI 8.1-18.6 months) compared with 9.4 months (95% CI 8.0-11.4 months) for KRAS non-p.G12C and 9.6 months (8.4-11.0 months) for KRASwt patients. We highlighted distinct clinical profiles and survival outcomes according to KRASm subtypes. Notably KRAS p.G12C mutations may provide increased sensitivity to immunotherapy, suggesting potential therapeutic implications for sequencing or combination of therapies. Further research on the impact of emerging KRAS specific inhibitors are warranted in real-world cohorts.

Unveiling disparities: Metastatic lung cancer incidence across income strata in metropolitan residencies.

e20616 Background: Over recent years, there has been growing interest in the field of lung cancer. Great efforts have been invested in recent years to improve screening and mortality outcomes with respect to lung cancer, particularly metastatic lung cancer (mLC). In the dynamic landscape of metropolitan residencies (MR), this study delves into the impact of household income (HI) on the occurrence of mLC. Unraveling the intricacies of these disparities is crucial for advancing our understanding of healthcare access and outcomes in urban settings. Methods: Appropriating data from the Surveillance, Epidemiology, and End Results (SEER) database, we looked at the incidence rates of mLC among adults aged 55-80 years by HI levels ( &lt; $35,000, $45,000-49,999, $55,000-$59,999, $65,000-69,999 and $75,000+) in MR from 2004 to 2017. Age-adjusted rates were calculated, and joinpoint regression models were used to estimate the average annual percentage change (AAPC) in incidence across different subgroups. Results: The study population included a total of 321,281 individuals diagnosed with mLC. The incidence of mLC declined rapidly from 2004 to 2017 across all HI groups in metropolitan residence; the AAPC for HIs $45,000-49,999 was -0.70%, $55,000-59,999 was -2.11%, $65,000-69,999 was -4.32% and $75,000+ was -3.72%. Of note, there was not enough data to characterize the trend for HIs &lt; $35,000. Conclusions: Our study revealed an overall decline in the incidence of mLC since 2004 across all HI groups in MRs. Although the trend is one of diminution across all groups, there is however, still some differences in incidence rates amongst different HI groups. This study elucidates the vital role HI plays in influencing the landscape of mLC in metropolitan areas. Recognizing and addressing these disparities is crucial for developing comprehensive public health strategies aimed at reducing the burden of advanced lung cancer and promoting equal access to quality healthcare.

Application of ctDNA sequencing in patients with metastasized lung cancer.

e20033 Background: Circulating tumor DNA (ctDNA) is a form of cell-free DNA (cfDNA) found in blood that originates from tumor cells, which has emerged as a promising non-invasive biomarker in monitoring cancer prognosis and precision medicine with the advancement of deep sequencing. Here we compared the mutational landscape between solid tumor and cfDNA in metastasis-free and metastasized lung cancer patients using targeted NGS to investigate the feasibility of ctDNA sequencing in monitoring cancer prognosis. Methods: Blood-derived cfDNA samples and formalin-fixed paraffin embedded tissue were collected from 217 Chinese patients with metastatic lung cancer (n = 39) or metastasis-free lung cancer (n = 178). Blood samples were collected after surgery. Panel sequencing targeting 680 cancer-related genes was performed on both samples. Somatic single nucleotide variations and indels were analyzed. Results: Among the 178 metastasis-free patients, 89.3% of the patients have at least one mutation both detected in tumor and blood samples. On average, 50.4% of tumor mutations were detected in blood for each patients. EGFR, TP53, CSMD3, LRP1B and SYNE1 were the top five most frequently mutated genes, with the proportion of tumor mutation found in blood of 89.1%, 80.2%, 70.0%, 61.3% and 64.3% respectively. In the metastasized cohort, all 39 individuals have at least one tumor mutations found in blood, achieving a concordance of 100%. On average, 59.9% of tumor mutations were detected in blood for each patients. Notably, the proportion of tumor mutations detected in blood for each patients is significantly higher than the metastasis-free cohort (unpaired T-test, p = 0.0167). EGFR, TP53, RBM10, PIK3CA and CSMD3 were the top five most frequently mutated genes, with the proportion of tumor mutation found in blood of 93.5%, 80.8%, 57.1%, 83.3% and 42.9% respectively. Moreover, the proportion of patients having EGFR p.L858R mutation in metastasized cohort was higher than the metastasis-free cohort (54.3% vs 32.8%). While within the metastasized cohort, blood samples detected a higher proportion of EGFR p.T790M (12.9% vs 7.69%) but a lower proportion of EGFR exon19 deletion (p.E746_A750del, 19.4% vs 27.7%) comparing to tumor sample, which can indicate drug resistance. Conclusions: We demonstrated a high mutation detection concordance between tumor and blood using targeted NGS, with an exceptional performance especially in driver oncogenes like EGFR and TP53. Our findings showed that metastasized lung cancer patients exhibit a higher positive concordance rate compared to metastasis-free cohort using ctDNA. We also showed a varied mutational landscape between ctDNA and tumor sequencing in metastasized lung cancer patients. Overall, this study not only reaffirms the viability of using blood as an alternative of tissue biopsy, but also provides new insights on application of ctDNA monitoring lung cancer metastasis and its clinically targetable mutations.

Ubiquitin ligase subunit FBXO9 inhibits V-ATPase assembly and lung cancer metastasis.

e20520 Background: The evolutionarily conserved protein FBXO9 acts as a substrate receptor for the SKP1-cullin-1-RBX1 ubiquitin ligase and is implicated in cancer, exhibiting either tumor-suppressive or oncogenic effects depending on the specific tumor type. However, their role in lung cancer metastasis remains unclear. Methods: Lentiviral vectors carrying miRNA-based shRNA sequences for gene-specific knockdown were generated, and Lenti-CRISPR-Cas9 vectors containing gene-specific sgRNA sequences were designed. Gene overexpression was achieved using doxycycline-inducible lentiviral constructs, while gene knockdown or knockout cells were generated using shRNA and CRISPR-Cas9, respectively. Functional assays included migration, clonogenic survival assays, tumor sphere assays, and protein interaction studies using mass spectrometry, immunoprecipitation, and immunoblot analysis. Results: This study identified FBXO9 as a crucial regulator that suppresses lung cancer cell migration, tumor sphere growth and restricts metastasis. We showed that FBXO9 facilitates the ubiquitination of the catalytic subunit A (ATP6V1A) of the Vacuolar-type H+-ATPase (V-ATPase), resulting in its interaction with the cytoplasmic chaperone HSPA8 and subsequent sequestration within the cytoplasm. This process hinders the assembly of functional V-ATPase, resulting in reduced vesicular acidification. In contrast, depletion of FBXO9 reduced ATP6V1A ubiquitination, resulting in increased V-ATPase assembly and vesicular acidification, thus promoting pro-metastatic Wnt signaling and metastasis of lung cancer cells. Furthermore, we demonstrated the effectiveness of inhibitors targeting V-ATPase in inhibiting lung cancer metastasis in a mouse model. Finally, we established a correlation between lower FBXO9 levels and poorer survival outcomes in patients with lung cancer. Conclusions: These findings collectively elucidate the critical role of FBXO9 in regulating V-ATPase assembly and provide a molecular basis for FBXO9's function in inhibiting lung cancer metastasis. This highlights the potential therapeutic opportunities of FBXO9 supplementation.

The journey of patients with lung cancer: The gap between symptom onset and treatment.

e23119 Background: Prompt access to health care services is a priority in public health policies. The aim of this study was to map the journey of patients (pts) diagnosed with lung cancer (LC) and determine the time interval (TI) from symptom onset (SO) to treatment initiation and assess the impact on survival. Methods: A retrospective cohort study was conducted at the University Hospital of Larissa. Pts’ demographic and disease-related data were captured from medical records. The TI from SO to first doctor visit (StD), SO to first oncologist visit (StO), diagnosis to treatment initiation (DtT) and SO to treatment initiation (StT) were estimated. Overall survival (OS) was defined as the TI between treatment initiation and the date of death or the date of last follow-up. OS were estimated using the Kaplan–Meier analysis and the comparisons were computed with the log-rank test. Results: Overall, 251 sequential pts with metastatic LC were included in the study. Pts’ mean age was 71 years (range 35-88). The majority were men (82%) and 24%, 32%, 28% and 16% were diagnosed with small cell lung cancer (SCLC), squamous cell (SCC), adenocarcinoma (ADC) and large cell (LCC) LC, respectively. The median StD and StO was 32 (0-212) days and 102 (11-608) days, respectively. No difference was detected across genders, age ( &gt; or &lt; 70), family history of cancer or not, and area of residence (rural, urban). The median StT and DtT was 123 (30-851) days and 26 (1-105) days, respectively, with this time intervals being shorter among pts with SCLC compared to pts with non-small cell LC (NSCLC) ( p: 0.006 and p&lt; 0.001, respectively). Pts with sort StT intervals had significantly improved OS, compared to pts with longer StT intervals (SCLC p:0.044, NSCLC p:0.004). Conclusions: To the best of our knowledge, this is the first study aiming to determine specific TI from SO to treatment initiation for pts with LC in Greece and assess the potential impact on OS. Our data revealed a substantially prolonged StT (~4months) that is associated with worse survival rates. This indicates a need to improve public awareness of LC symptoms, enable pts’ access to specialized health care services and facilitate earlier diagnosis and treatment.

The treatment modalities and radiotherapy pattern in patients with primary lung cancer in Japan.

e20070 Background: In Japan, lung cancer has high incidence and mortality among all cancers. The study is to understand the existing status of the treatment modalities in Japan, especially for radiotherapy (RT). Methods: This was a retrospective cohort study using the Japan Medical Data Center (JMDC) database. A cohort of adult patients with at least two diagnosis codes of primary lung cancer (ICD-10-CM: C34) during January 1st, 2015-March 31st, 2023, and initiated lung cancer treatment was included in the study. The initial treatment episode was defined as a period with the first single or multiple treatments before a 90-day gap. Patients were followed up until a record of death, or the last enrollment in JMDC. The cohort was stratified into four exclusive groups: Group A: ≥1 record of distant metastasis; Group B-1: ≥1 record of regional metastasis; Group B-2: no record of surgery and no metastasis; Group C: ≥1 record of surgery and no metastasis. The characteristics, initial treatment episode and RT patterns were described across the four groups. Results: A total of 9,373 patients were included, with Group A 1,625 (17.3%), Group B-1 527 (5.6%), Group B-2 2084 (22.2%), and Group C 5137 (54.8%). The median follow-up was 21.2 months of the cohort. The median (IQR) time to initial treatment episode from the initial diagnosis was 27 (27), 35 (40), 34 (47) and 38 (36) days for the four groups, respectively. Most of patients in group A (74.1%), B-1 (70.8%), and B-2 (67.6%) had a &gt;3 months duration of initial treatment, and only 32.7% in group C. For treatment involved in the initial treatment episode, RT was accounted for 59.2%, 29.8%, 43.4%, and 4.7% in four groups respectively. For treatment categories in Groups A, B-1, and B-2, RT only was performed in 15.5%, 2.2% and 6.9% of patients with single treatment; and RT was commonly performed with chemotherapy in multiple treatments, with proportions of 83.6%, 95.3% and 95.6% among no surgery. For RT with chemotherapy group, the median RT fractions are 22, 36 and 42, covering a median duration of 35, 43 and 43 days of RT. Conclusions: In Japan, the initial treatment episode usually starts in 30 days and lasts more than 3 months for metastasis and unresectable primary lung cancer. RT only is not commonly performed, and RT with chemotherapy is commonly performed in initial treatment episode. [Table: see text]

Hematologic parameters as predictors of overall survival in metastatic solid tumor and aggressive lymphoma.

e23053 Background: Aggressive cancer is associated with an increased rate of thrombosis. In addition to body mass index (BMI), the Khorana score has identified several hematologic parameters associated with an increased risk of thrombosis. In this study, we assessed the relationship of these parameters with overall survival. Methods: Using data from our tumor registry, we selected patients with aggressive lymphomas (AL), glioblastoma multiforme (GBM), metastatic prostate (MP), metastatic lung (ML), and metastatic colorectal (MCRC) cancer from 2018 to 2023. Laboratory data were extracted from our electronic medical record, with a timeframe of 90 days before and 30 days after first contact, but prior to initiating treatment. We analyzed the relationship of hemoglobin (Hgb), white blood cell (WBC) count, platelet (Plt) count, and body mass index (BMI), with overall survival (OS). Each cancer type was analyzed as a separate group and multivariable analysis was controlled by sex and age at diagnosis. Dichotomizing the variables from categories of the Khorana score, we evaluated the relationship of such variables and OS using Kaplan-Meier Analysis and Cox Proportional Hazards Models. Patients were censored at two years of follow-up. Data analysis was done using R (version 4.3). Results: Of 2,362 patients, 55% were male, and median age was 63 years. (Cancer types: 622 ML, 604 AL, 453 GBM, 281 MCRC, 203 MP, and 199 MB). An initial, pre-treatment Hgb &lt; 10 g/dL was associated with a shorter OS in patients with ML, MCRC, MP, and AL patients. Plt ≥350 x 109/L was associated with a shorter OS in ML and MCRC patients. WBC &gt; 11 x 109/L was associated with a shorter OS in ML, AL, and MCRC, and a BMI ≥35 was associated with a shorter OS only in GBM patients (Table). Conclusions: While not in all cancer types, the hematologic parameters of the Khorana score that predict thrombosis correlate with a reduced overall survival. This effect was significant for different parameters in different cancers. The increased hazard ratio is beyond that which would be expected from thrombosis-related mortality. Our study is limited to data from our single institution and the retrospective nature of the study. [Table: see text]

18F-FDG PET/CT imaging and the characterization of synchronous primary lung cancer versus intrapulmonary metastasis and primary versus metastatic lung cancer: a narrative review

18F-FDG PET/CT imaging and the characterization of synchronous primary lung cancer versus intrapulmonary metastasis and primary versus metastatic lung cancer: a narrative review

Remodelin delays non-small cell lung cancer progression by inhibiting NAT10 via the EMT pathway.

Lung cancer remains the foremost reason of cancer-related mortality, with invasion and metastasis profoundly influencing patient prognosis. N-acetyltransferase 10 (NAT10) catalyzes the exclusive N (4)-acetylcytidine (ac4C) modification in eukaryotic RNA. NAT10 dysregulation is linked to various diseases, yet its role in non-small cell lung cancer (NSCLC) invasion and metastasis remains unclear. Our study delves into the clinical significance and functional aspects of NAT10 in NSCLC. We investigated NAT10's clinical relevance using The Cancer Genome Atlas (TCGA) and a group of 98 NSCLC patients. Employing WB, qRT-PCR, and IHC analyses, we assessed NAT10 expression in NSCLC tissues, bronchial epithelial cells (BECs), NSCLC cell lines, and mouse xenografts. Further, knockdown and overexpression techniques (siRNA, shRNA, and plasmid) were employed to evaluate NAT10's effects. A series of assays were carried out, including CCK-8, colony formation, wound healing, and transwell assays, to elucidate NAT10's role in proliferation, invasion, and metastasis. Additionally, we utilized lung cancer patient-derived 3D organoids, mouse xenograft models, and Remodelin (NAT10 inhibitor) to corroborate these findings. Our investigations revealed high NAT10 expression in NSCLC tissues, cell lines and mouse xenograft models. High NAT10 level correlated with advanced T stage, lymph node metastasis and poor overall survive. NAT10 knockdown curtailed proliferation, invasion, and migration, whereas NAT10 overexpression yielded contrary effects. Furthermore, diminished NAT10 levels correlated with increased E-cadherin level whereas decreased N-cadherin and vimentin expressions, while heightened NAT10 expression displayed contrasting results. Notably, Remodelin efficiently attenuated NSCLC proliferation, invasion, and migration by inhibiting NAT10 through the epithelial-mesenchymal transition (EMT) pathway. Our data underscore NAT10 as a potential therapeutic target for NSCLC, presenting avenues for targeted intervention against lung cancer through NAT10 inhibition.

Evaluating reflexive NGS and testing rates in community oncology.

e23302 Background: In oncology, NGS allows for the identification of DNA sequence variations within a cancer. The goal of testing is to identify/define therapeutic targets &amp; improve patient outcomes, employing specific therapies directed at those targets. In breast cancer, reflex tumor testing (ER/PR/Her2neu) has been performed for &gt; 20 yrs. In CRC, as published by ASCO, guideline-adherent biomarker testing rates for RAS, BRAF, &amp; MSI/MMR-d were 41%, 43%, and 51%, respectively1. In lung cancer, recent data has shown overall testing rates minimally better at 58%2. Methods: The study was conducted on historical data of lung, colorectal, and breast cancer patients seen in Verdi community oncology clinics between 4/1/2022-7/31/2023. Clinical &amp; social health data were collected &amp; abstracted from patient medical history (Doctor’s notes, Pathology studies, NGS results). The database contains demographic &amp; clinical data features for each patient. Results: 153 lung cancer patients were identified, median age 71(44 – 96). 82 F, 71 M. 85% of patients were smokers (130 smokers, 22 non-smokers, 1 unknown). Self-identified race: Asian 1, Black 22, white 106, 24 patients declined to identify. 61.9% (65) of later stage (≥IIB) patients had NGS testing. Of 258 colon/rectal cancer patients (anal cancer was excluded), median age 67(29-96), 122 M,146 F. Self-identified race: Asian 3, Black 26, 181 white, 34 patients declined to identify, 14 were unknown. Overall, 34.5% (89) of patients had NGS testing, and 76.2% (34) of Stage IV patients. There were 511 breast cancer patients, median age 63(25-85), 506 F, 5 M. Self-identified race: Asian/HPI 2, Black 137, white 299, 56 patients declined to identify, 17 were unknown. 100% had NGS, with minimum testing of ER/PR/Her2neu status. In the lung &amp; colorectal patients, statistically significant differences in rates of testing were seen in males (p &lt; 0.0001), older age (p &lt; 0.0001), and non-whites (p = 0.002). Conclusions: Testing at Verdi clinics were higher than reported testing. We propose that to improve testing rates, NGS should be reflexively ordered in other tumor types, as is the standard of care in breast cancer. This would eliminate many issues, including waiting time patients must undergo when testing is not ordered until the patient is seen by the medical oncologist. Proactive testing allows potential targeted treatments to be delivered in real-time and thus improve patient outcomes. 1Genomic Profiling for KRAS, NRAS, BRAF, Microsatellite Instability, and Mismatch Repair Deficiency Among Patients With Metastatic Colon Cancer. JCO Precision Oncology (2019)3(3). 2Improving biomarker testing in advanced non-small cell lung cancer and metastatic colorectal cancer: experience from a large community oncology network in the USA. Future Oncology (2023)19(20),1397-1414.

Uptake of recommendations for broadening clinical trial eligibility criteria for patients with brain metastasis and leptomeningeal disease in lung cancer clinical trials: A systematic review.

e23007 Background: Brain metastasis (BM) in patients with lung cancer are relatively frequent (~20%). Clinical trials (CTs) often exclude patients with BM due to concerns about life expectancy, functional status, and toxicity. Restrictive eligibility criteria deter patients with BM from receiving investigational treatments that may be beneficial. In 2017, ASCO, Friends of Cancer Research (FoCR), and the US FDA recommended to expand eligibility criteria to assist in design more representative trials. We examined the uptake of these guidelines in BM/leptomeningeal disease (LMD) inclusion criteria among registered lung cancer CTs. Methods: We extracted eligibility criteria of US-based, phase I/II/III interventional CTs for patients with metastatic lung cancer registered in ClinicalTrials.gov between 10/2012 to 01/2024. CTs registered one year within ASCO/FoCR/FDA published their recommendations were excluded. For each trial, two independent reviewers screened eligibility criteria and classified patients with BM as fully included (active/untreated disease), partially included (treated/stable disease), or excluded, and LMD as included or excluded. Discrepancies were resolved by a third reviewer. Fisher’s exact tests and odds ratio (OR) were obtained by logistic regression. Results: Among 307 CTs, patients with BM were partially included in most CTs (228, 74.3%), excluded in 9 (2.9%) and not mentioned in 35 trials (11.4%). Patients with active BM were included in 35 trials (11.4%). The use of steroids was accepted in 69 trials (22.5%). Only 18 trials (5.8%) included patients with LMD. Most patients with LMD were excluded (135, 44.0%) or not mentioned as criterion (154, 50.2%). A statistically significant difference was observed in the inclusion of patients with BM pre- vs post-recommendations ( p= 0.046). Yet, there was not significant difference in trials with active BM and LMD pre- vs post-recommendations. CTs including patients with active BM or LMD were more likely to appear in CTs explicitly measuring central nervous system outcomes (OR = 4.3; p= 0.002; OR = 14.3; p= 7e-5, respectively). Conclusions: Although existing recommendations to broaden CTs eligibility criteria to include patients with BM showed a significant change, patients with active BM and LMD remained excluded from lung cancer trials. Designing CTs including patients with active BM/LMD is likely to improve patient accrual, increase access to clinical trials and further characterize the investigational drug’s safety and efficacy in this patient population. Exclusion criteria should be clearly justified, and expected toxicity should be reflected in the rationale. As new targeted therapies emerge in lung cancer realm, eligibility criteria should be modernized to fit patients who will be using novel therapies once they are available.

Safety, efficacy, pharmacokinetics, and pharmacodynamics of the illudofulvene drug CAP-0121.

e15120 Background: Irofulven is an anticancer agent derived from illudin S initially investigated due to its unique mechanism of action and potential to overcome multi-drug resistance. This study investigates the pharmacokinetics/pharmacodynamics (PK/PD) and efficacy and safety of the second-generation drug, CAP-0121 (Califia Pharma). Methods: 24-hour comprehensive PK was performed at two different intravenous (IV) doses in canines for irofulven (0.2 mg/kg and 1 mg/kg; MTD) and CAP-0121 (1 mg/kg and 3 mg/kg). Plasma concentrations were measured by LC-MS/MS and PK parameters were calculated for both drugs using noncompartmental methods (Phoenix WinNonlin, version 8.4). PK parameters included area under the concentration vs time curve (AUC), maximum observed concentration (Cmax), clearance (CL), volume of distribution (Vd), and elimination half-life (t1/2). Canine chemistry/hematology/coagulation/urine panels, were measured across 28 days to ascertain the maximum tolerated dose (MTD). Both platelet and neutrophil count reversibility was also assessed. Mice xenograft models implanted with a drug resistant human ovarian cancer (A2870), or a drug-resistant human metastatic lung cancer (MV522), were dosed with irofulven (9 mg/kg; MTD) and CAP-0121 (15, 20, and 25 mg/kg) and resulting tumor mass, % change in body weight, and platelet counts were compared relative to vehicle only. Results: Systemic exposure, CL, Vd, and t1/2 were similar between irofulven and CAP-0121 at a 1 mg/kg IV dose. For irofulven, AUC increased approximately proportionally at doses of 0.2 mg/kg and 1 mg/kg. For CAP-0121, exposure also increased proportionally at doses of 1 mg/kg and 3 mg/kg. MTD of CAP-0121 was found to be 3-fold higher in canines compared to irofulven as 3-fold more CAP-0121 was required to match the platelet reduction observed with irofulven; platelet and neutrophil nadir was rapidly reversible for CAP-0121. Canine nadir platelets and neutrophil counts were 3-fold higher for CAP-0121 vs irofulven at the same dose (1 mg/kg). There was no evidence of any canine systemic organ toxicity (gross, histologic, blood and urine analysis) for CAP-0121 at either dose. CAP-0121 was superior to irofulven (p &lt; 0.02) with regards to final tumor weights in mice xenograft models, even though MTD was not reached for CAP-0121; a change in body weight and platelet loss was not observed for CAP-0121 at up 25 mg/kg in mice. With regards to in vitro anticancer cytotoxic activity, the two drug-resistant xenograft models confirm the superiority of CAP-0121 over irofulven. This study demonstrates that CAP-0121 has favorable PK parameters and a wider therapeutic window in humans compared to irofulven, emphasizing the potential anticancer utility of CAP-0121 for solid cancers without prolonged thrombocytopenia. Conclusions: Further investigation in clinical trials is warranted to confirm these preclinical observations.

Effect of combinatorial immune checkpoint blockade on myocardial expression of NLRP-3 and secretion of H-FABP, NT-Pro-BNP, interleukin-1β, and interleukin-6: Biochemical implications in cardio-immuno-oncology.

e24016 Background: Immune checkpoint blockade in monotherapy or combinatorial regimens with chemotherapy or radiotherapy have become an integral part of oncology in recent years. Monoclonal antibodies against CTLA-4 or PD-1 or PDL-1 are the most studied ICIs in randomized clinical trials, however, more recently, an anti-LAG3 (Lymphocyte activation gene-3) antibody, Relatlimab, has been approved by FDA in combination with Nivolumab for metastatic melanoma therapy. Moreover, Atezolizumab is actually under study in association with Ipilimumab for therapy of metastatic lung cancer. Myocarditis, vasculitis and endothelitis are rarely observed in these patients on monotherapy, however new combination therapies could expose patients to more adverse cardiovascular events. Methods: human cardiomyocytes, human peripheral blood lymphocytes (hPBMCs) and combinatorial ICIs (PD-L1 and CTLA-4 or PD-1 and LAG-3 blocking agents, at 100 nM) for 48 h. After treatments, cardiac cell lysis and secretion of biomarkers of cardiotoxicity (H-FABP, troponin-T, BNP, NT-Pro-BNP), NLRP3-inflammasome and Interleukin 1 and 6 were determined through colorimetric and enzymatic assays. Mitochondrial functions were studied in cardiomyocyte cell lysates through quantification of intracellular Ca++, ATP content and NADH:ubiquinone oxidoreductase core subunit S1 (Ndufs1) levels. Histone deacetylases type 4 (HDAC-4) protein levels were also determined in cardiomyocyte cell lysates to study potential epigenetic changes induced by immunotherapy regimens. Results: Both combinations of immune checkpoint inhibitors exert more potent cardiotoxic side effects compared to monotherapies against human cardiac cells co-cultured with human lymphocytes. LDH release from cardiac cells was 43% higher in PD-L1/CTLA-4 blocking agents, and 35.7% higher in PD-1/LAG-3 blocking agents compared to monotherapies. HDAC4 and intracellular Ca++ levels were increased, instead ATP content and Ndufs1 were reduced in myocardial cell lysates (p &lt; 0.001 vs untreated cells). Troponin-T, BNP, NT-Pro-BNP and H-FABP, were also strongly increased in combination therapy compared to monotherapy regimen. NLRP3 expression, IL-6 and IL-1β levels were also increased by PDL-1/CTLA-4 and PD-1/LAG-3 combined blocking agents compared to untreated cells and monotherapies. Conclusions: Data of the present study, although in vitro, indicate that combinatorial immune checkpoint blockade, induce a pro- inflammatory phenotype, thus indicating that these therapies should be closely monitored by the multidisciplinary team consisting of oncologists, cardiologists and immunologists.

SPPADE symptom prevalence and severity in a diverse sample of patients living with metastatic cancers.

11108 Background: Advances in cancer treatment have led to a growing population of patients living with metastatic cancer. Symptom burden for these patients is understudied. Our objective is to report the prevalence and severity of SPPADE symptoms (sleep disturbance, pain, physical function impairment, anxiety, depression, and low energy /fatigue) in a large cohort of patients with metastatic cancer. Methods: These data are drawn from the Enhanced, EHR-facilitated Cancer Symptom Control (E2C2) stepped wedge pragmatic trial evaluating a symptom management intervention for cancer patients (NCT03892967). This analysis was limited to those identified with metastatic disease using ICD- codes and a natural language processing algorithm prior to or within 30 days of their baseline symptom survey. Symptom severity was measured on a 0-10 scale with scores of 1-3 categorized as “mild”, 4-6 as “moderate”, and ≥7 as “severe.” A SPPADE composite score was calculated by summing six individual symptom scores and is an indicator of total symptom burden. We report descriptive statistics for each symptom by severity category. We also test for differences in SPPADE composite score by race, disability status, employment status, education and cancer type using Kruskal-Wallis tests. Results: 12,824 patients with metastatic disease completed a survey between March 2019 and January 2023. Discretized score distributions for the SPPADE symptoms are reported in the Table. The SPPADE composite mean score for the cohort was 17.6 (SD +/- 12.0). Significant differences were found in total symptom burden by sociodemographic and clinical characteristics ( p&lt;0.01): Higher total symptom burden (Mean [SD])was experienced by individuals who were American Indian/Alaska Native (AI/AN) (23.8[13.5]) or African American (AA) (20.5[14.7]), disabled (24.0[12.8]) or unemployed (21.1[13.0]), and had a high school education (20.0[13.3]) or less than high school education (18.5[12.4]). There were also statistically significant differences ( p&lt;0.01) in symptom burden across cancer types, with patients with metastatic lung cancer reporting the highest symptom burden (20.0[12.2]) and those with metastatic melanoma reporting the lowest (14.7[11.4]). Conclusions: SPPADE symptoms are common in patients with metastatic cancer, especially fatigue, sleep disturbance, and physical function impairment. Symptom burden is especially high in AI/AN, AA, disabled/unemployed, and less educated patients. Further research is needed to tailor symptom interventions among those living with metastatic disease. [Table: see text]

The role of neutrophil-derived myeloperoxidase (MPO) in non-small cell lung cancer metastasis

The role of neutrophil-derived myeloperoxidase (MPO) in non-small cell lung cancer metastasis

Nanotechnology for the theranostic opportunity of breast cancer lung metastasis: recent advancements and future challenges.

Lung metastasis of breast cancer is rapidly becoming a thorny problem in the treatment of patients with breast cancer and an obstacle to long-term survival. The main challenges of treatment are the absence of therapeutic targets and drug resistance, which promotes the development of nanotechnology in the diagnosis and treatment process. Taking advantage of the controllability and targeting of nanotechnology, drug-targeted delivery, controlled sustained release, multi-drug combination, improved drug efficacy, and reduced side effects can be realized in the process of the diagnosis and treatment of metastatic breast cancer (MBC). Several nanotechnology-based theranostic strategies have been investigated in breast cancer lung metastases (BCLM): targeted drug delivery, imaging analysis, immunotherapy, gene therapy, and multi-modality combined therapy, and some clinical applications are in the research phase. In this review, we present current nanotechnology-based diagnosis and treatment approaches for patients of incurable breast cancer with lung metastases, and we hope to be able to summarize more effective and promising nano-drug diagnosis and treatment systems that aim to improve the survival of patients with advanced MBC. We describe nanoplatform-based experimental studies and clinical trials targeting the tumor and the tumor microenvironment (TME) for BCLM to obtain more targeted treatment and in the future treatment steps for patients to provide a pioneering strategy.

Early diagnostic value of ECT whole-body bone imaging combined with PINP and β-CTX for bone metastasis of lung cancer.

This research was aimed at investigating the early diagnostic value of emission computed tomograph (ECT) whole-body bone imaging combined with PINP and β-CTX for bone metastasis of lung cancer. Case data of 86 lung cancer patients were categorized into lung cancer with bone metastasis (LCWBM, 46 cases) and lung cancer without bone metastasis (LCWOBM, 40 cases) groups according to the presence or absence of bone metastasis. Patients' general information were collected. ECT whole-body bone imaging was used to detect bone metastases and the grading of the extent of disease (EOD) in both groups, and electrochemiluminescence was utilized to detect the serum levels of PINP and β-CTX. Spearman correlation analysis was employed to evaluate the correlation between EOD grading and PINP and β-CTX levels. Logistic univariate and multivariate regression was implemented to analyze the risk factors of bone metastasis of lung cancer. Receiver operating characteristic (ROC) curve was applied to analyze the diagnostic efficacy of the single test of ECT whole-body bone imaging, PINP, or β-CTX and the combination of the three tests. The differences in pathological type, clinical stage and EOD grading, the number of positive ECT cases, and the expression levels of PINP and β-CTX between the LCWBM and LCWOBM groups were statistically significant. In LCWBM patients with different EOD grading, the trends of the expression of PINP and β-CTX were grade 3 > grade 2 > grade 1 and grade 0. Further correlation analyses revealed that EOD grading showed a significant positive correlation with the PINP and β-CTX expression levels. Univariate logistic regression analysis demonstrated that adenocarcinoma, TNM stage IV, ECT positivity, and high expression of PINP and β-CTX were associated with bone metastasis of lung cancer, and multivariate logistic regression analysis indicated that ECT positivity, high expression of PINP and β-CTX were independent risk factors for bone metastasis of lung cancer. The area under the curve (AUC) of ECT, PINP, and β-CTX alone for the diagnosis of bone metastasis of lung cancer were 0.872, 0.888, and 0.874, respectively, and the AUC for the combined diagnosis of the three was 0.963, which was greater than that of any one of the individual indices, with a sensitivity of 86.96% and a specificity of 97.50% at a Youden index of 0.845. ECT whole-body bone imaging combined with PINP and β-CTX has high diagnostic value for bone metastasis of lung cancer.

Validation of a Blood-Based Protein Biomarker Panel for a Risk Assessment of Lethal Lung Cancer in the Physicians' Health Study.

This study aimed to assess a four-marker protein panel (4MP)'s performance, including the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19, for predicting lung cancer in a cohort enriched with never- and ever-smokers. Blinded pre-diagnostic plasma samples collected within 2 years prior to a lung cancer diagnosis from 25 cases and 100 sex-, age-, and smoking-matched controls were obtained from the Physicians' Health Study (PHS). The 4MP yielded AUC performance estimates of 0.76 (95% CI: 0.61-0.92) and 0.69 (95% CI: 0.56-0.82) for predicting lung cancer within one year and within two years of diagnosis, respectively. When stratifying into ever-smokers and never-smokers, the 4MP had respective AUCs of 0.77 (95% CI: 0.63-0.92) and 0.72 (95% CI: 0.17-1.00) for a 1-year risk of lung cancer. The AUCs of the 4MP for predicting metastatic lung cancer within one year and two years of the blood draw were 0.95 (95% CI: 0.87-1.00) and 0.78 (95% CI: 0.62-0.94), respectively. Our findings indicate that a blood-based biomarker panel may be useful in identifying ever- and never-smokers at high risk of a diagnosis of lung cancer within one-to-two years.