bluuebunny/crossref_metadata_2025 huggingface dataset:
Lenalidomide-based monotherapy versus augmented therapy for maintenance in standard risk multiple myeloma patients with no complete response post autologous hematopoietic cell transplantation.
Authors: Awada Hussein , Hajj Ali Adel , Tabaja Chadi , Khouri Jack , Anwer Faiz
Published: June 2023

8055

Background: Standard risk (SR) multiple myeloma (MM) is typically characterized by the absence of poor prognostic cytogenetic aberrations, and better outcomes. However, outcomes in SR MM remain far from homogeneous, especially in patients undergoing autologous hematopoietic cell transplant (AHCT). While many patients do well initially, relapse is inevitable. Here, we studied the role of lenalidomide (R) maintenance therapy in determining outcomes in SR MM with no complete response (non-CR) post-AHCT. Methods: We retrospectively reviewed all MM patients who underwent AHCT at the Cleveland Clinic between January 1, 2011 and January 15, 2021. Electronic medical charts were accessed to retrieve data on demographic characteristics, comorbidities, International Scoring System (ISS) staging, cytogenetic risk categorization, serum and bone marrow studies, as well as maintenance therapy. SR MM was considered in patients who did not have t(4;14), t(14;16), t(14;20), del(17p), or gain(1q). Remission status was determined by serum studies at 3 months post-AHCT. The primary endpoint was median time to either progression or death, reported as time to event (TTE) determined by Kaplan Meier analysis. Results: A total of 517 patients were reviewed, of whom 279 were determined as SR MM. Further stratification yielded 100 non-CR SR patients on lenalidomide-based maintenance, of whom 87 were on R monotherapy and 13 on R combination. Comparison between the R-monotherapy and combination groups showed similar age at AHCT (60.5 vs 56 years, P=0.07), time to transplant (23.5 vs 30.8%, P=0.7), albumin levels (<3.5 g/dL 25 vs 25%, P=1), Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score (≥3 43.5 vs 30.8%, P=0.5), Male preponderance (58.8 vs 69.2%, P=0.6), ethnicity (White 82.4 vs 76.9%, P=0.7), ISS stages (I 41 vs 45.5%, II 41 vs 36.4%, III 17.9 vs 18.2%, P=0.9), pre-AHCT lines of therapy (≥2 31.8 vs 38.5%, P=0.8), and pre-AHCT bone marrow plasma cells (≥10%:9.5 vs 7.7%, P=1), respectively. The only significant difference between the two groups was in the MM immunoglobulin subtype (IgG 80 vs 50%, P=0.02). Kaplan-Meier analysis for median TTE revealed that the R monotherapy group had a significantly shorter median TTE at 38.1 months versus 68.6 months (P=0.03) for the R combination group. Conclusions: SR MM patients who do not achieve a CR post-AHCT have better outcomes with R-combination rather than monotherapy.
Presence of hyperdiploidy and history of tobacco use in African American patients with SMM.
Authors: Parikh Rujul H , Goyal Subir , Liu Yuan , Hofmeister Craig C. , Kaufman Jonathan L. , Heffner Leonard T. , Boise Lawrence H , Gupta Vikas Anand , Dhodapkar Madhav V. , Lonial Sagar , Nooka Ajay K. , Joseph Nisha S
Published: June 2023

8062

Background: Smoldering multiple myeloma (SMM) has a clinically variable course in progression to active myeloma (MM). Accurate risk stratification is essential in identifying which patients may benefit from early therapeutic intervention. Current models do not account for the potential impact of race on risk of progression to SMM. Here, we seek to identify independent risk factors for progression in African American (AA) versus white patients in a real-world single institutional database of SMM patients. Methods: We retrospectively identified 224 patients (pts) with untreated SMM from 2007 to 2021 treated at our institution. Patient demographics and disease characteristics were obtained from our IRB-approved myeloma database. TTP was defined as the time from diagnosis of SMM to diagnosis of active MM, estimated by Kaplan-Meier and compared by log-rank test. Univariate analyses were performed using Cox proportional hazard models for TTP. Results: A total of 224 pts (AA 35%, white 47%, other/unknown 17%) were identified with median age 62y (range 32-82). Median follow-up was 4.3y in Whites and 5y in AA pts. Notable characteristics include M/F 45%/54%, IgG/IgA/FLC 76%/17%/6%, 30% current/past smoker (median 15 pack-years), 12% alcohol use (≥10 drinks/wk), 45% with BMI > 30. Multiple cytogenetic abnormalities were defined as presence of ≥2 of the following: t(4;14), t(14;16), gain(1q21), del(1p), del(13), or del(17p). The median TTP (mTTP) was 6.8 [95% CI (3.7, 8.2)] years in whites and 5.6 [95% CI (4.6, 11.8)] years in AA. On univariate analysis, M-spike > 1.5, involved K/L ratio > 12, and bone marrow PC > 20% were associated with increased risk of progression for both AA and whites (all p < 0.05). As expected, gain of 1q21 was associated with increased risk of progression for both groups, though more pronounced in AA (HR 2.94, p = 0.025) versus whites (HR 2.33, p = 0.013). Hyperdiploidy was associated with shorter mTTP in AA (HR 3.03, p = 0.004) compared to whites (HR 1.39, p = 0.3). Multiple cytogenetic abnormalities was associated with shorter mTTP in whites (HR 2.63, p = 0.004) but was not statistically significant in AA (HR 2.63, p = 0.104). Interestingly, tobacco use was associated with shorter mTTP in Blacks (HR 2.94, p = 0.005) but not in whites (HR 0.96, p = 0.85). Conclusions: Understanding the potential impact of racial background on progression from SMM to MM is critical in the appropriate management of all patients with SMM. In this database, with a large proportion of AA patients, hyperdiploidy and +1q portend high risk of progression in AA patients. Further study is needed to better classify these potential differences to ensure risk stratification models are applicable to all patients.
Surgical outcomes of patients with resectable non-small-cell lung cancer receiving neoadjuvant immunotherapy with nivolumab plus relatlimab or nivolumab: Findings from the prospective, randomized, multicentric phase II study NEOpredict-Lung.
Authors: Aigner Clemens , Du Pont Bert , Hartemink Koen , Wiesweg Marcel , Vanbockrijck Michel , Darwiche Kaid , Hegedus Balazs , Schramm Alexander , Hautzel Hubertus , Maes Brigitte , Theegarten Dirk , Schildhaus Hans-Ulrich , Baas Paul , Cuppens Kristof , Schuler Martin H. , Plönes Till
Published: June 2023

8500

Background: Feasibility of surgical resection for non-small-cell lung cancer (NSCLC) after preoperative immune checkpoint inhibitor therapy (PICIT) with PD-1/PD-L1 and CTLA-4 inhibitors has been established. This study reports the first data on surgery after preoperative LAG-3 inhibition in NSCLC patients. Methods: Patients with histologically confirmed NSCLC stage IB, II or IIIA (UICC 8th edition) were randomized to receive two preoperative doses (q14d) of nivolumab (240 mg, arm A), or nivolumab (240 mg) plus relatlimab (80 mg, arm B). Primary study endpoint was the number of patients undergoing curatively intended surgery within 43 days of initiation of PICIT. Surgery was performed following the institutional standards. Outcomes and perioperative events were prospectively recorded. Results: 60 patients (29 female) were randomized 1:1 from 4/2020 to 7/2022. All patients were operated within 43 days after initiation of PICIT. Median age in arm A was 65 (43-78) years and 67 (44-81) years in arm B. Clinical UICC stages were similar between both arms. Central tumor location was present in 50% in arm A and 45% in arm B. R0 resection was achieved in 57 patients (95% ITT population, 98,3% curatively resected population). Two patients had pleural carcinosis only detected at surgery, and 1 patient had R1 resection. Resection was performed by lobectomy (n=23 and 24), bilobectomy (2 and 1), sleeve lobectomy (5 and 4) and combined lobectomy+segmentectomy (0 and 1). Surgical approach was either by videothoracoscopy (n=60% and 63,3%) or thoracotomy (n=40% and 36,6%). Conversion was required in 3 vs. 2 patients. Median operation time was 149 (77-234) and 165 (61-205) minutes. Median number of resected lymph nodes was 15 (3-52) and 10 (3-50). Intraoperative bleeding from the pulmonary artery was observed in 1 patient in each arm and was managed without sequelae. Postoperative complications occurred in 33,3% and 26,6%. Median hospital stay was 7 (2-22) and 5,5 (2-24) days. Complete or major histopathological response was observed in 27% and 30%. Overall perioperative 30-day mortality was 0%. No negative impact on adjuvant therapy was observed. The 12 months OS rate across both arms was 96% (95% Cl: 83-99%), the DFS rate was 91 % (78-97%). Conclusions: Curative surgical resection following neoadjuvant combined PD-1/LAG-3 inhibition was equally safe and feasible as after PD-1 inhibition alone. Perioperative course, complications rate and outcome are comparable to other neoadjuvant regimens. Standard adjuvant therapies can be safely administered in this setting. Clinical trial information: NCT04205552 .
Association of somatic mutations and histologic subtype/grade on prognosis and PD-L1 expression in mesothelioma.
Authors: Zhu Allen , Husain Aliya N. , Hermina Andrew , Mitchell Owen , Mueller Jeffrey S. , Drazer Michael William , Kindler Hedy L. , Kwon Jung Woo
Published: June 2023

8507

Background: Mesothelioma includes epithelioid, sarcomatoid, and biphasic histologic subtypes, and the epithelioid subtype is histologically graded based on mitotic count and nuclear atypia. Correlation between the most common somatic mutations ( BAP1, NF2, TP53, CDKN2A), and overall survival is poorly understood. High PD-L1 expression is a poor prognostic factor for survival and may be a predictor of response to immunotherapy. Few studies have evaluated the relationships between these factors. Methods: We performed a retrospective study in 217 patients with pleural, peritoneal and bicavitary mesothelioma as part of an IRB-approved biobanking protocol. Histologic subtype, grade of epithelioid mesothelioma, tumor stage, and overall survival time were determined. Next-generation DNA sequencing (NGS) was used to identify the prevalence of somatic mutations. PD-L1 immunohistochemistry was obtained on 184 samples and quantified as percentage of tumor cells. Histologic subtype, nuclear grade, clinical stage, PD-L1 expression, survival time, and the prevalence of each mutation were compared using chi-squared, Kruskal-Wallis, or Cox proportional hazard tests. All p-values were determined in R version 4.2.0 using a two-sided alpha error of 0.05 to mark statistical significance. Results: The most frequent somatic mutations were found in BAP1 (99/217, 45.6%), CDKN2A (47/217, 21.7%), TP53 (37/217, 17.1%), and NF2 (31/217, 14.3%). Patients with CDKN2A-mutated mesothelioma experienced shorter survival (p=0.032). TP53 mutations were associated with higher nuclear grade (p=0.015), higher mitotic count (p=0.013), and greater nuclear atypia (p=0.015). TP53 mutations were more prevalent in pleural than peritoneal mesothelioma (p=0.016) and in tumors without lymph node metastasis (p=0.05). As expected, patients with epithelioid mesothelioma had superior overall survival (p=0.02) and their tumors had lower PD-L1 expression (p=0.007) than either sarcomatoid or biphasic mesotheliomas. Neither PD-L1 expression nor mutations in BAP1, NF2, CDKN2A, or TERT were associated with nuclear grade, atypia, or mitotic count. No association was found between BAP1 or NF2 mutations and tumor stage, lymph node metastasis, or PD-L1 expression. Conclusions: To our knowledge, this is the first study of this scale to correlate PD-L1 expression, somatic mutation data, histologic features, and survival in mesothelioma patients. The most significant findings were that patients with CDKN2A mutations had shorter survival and TP53 mutations, which were more prevalent in pleural mesotheliomas, were associated with higher nuclear grade, higher mitotic count, and greater nuclear atypia. An ongoing analysis evaluates the contribution of germline mutations, which occurred in a significant proportion (15.7%) of this mesothelioma patient cohort.
Bemcentinib and pembrolizumab in patients with relapsed mesothelioma: MIST3, a phase IIa trial with cellular and molecular correlates of efficacy.
Authors: Krebs Matthew G , Branson Amy , Barber Shaun , Poile Charlotte , King Amy , Greystoke Alastair , Moody Sam , Nolan Luke , Scotland Molly , Darlison Liz , Bajaj Amrita , Morgan Bruno , Brookes Cassandra , Wells-Jordan Peter , Richards Catherine Jane , Thomas Anne L. , Fennell Dean Anthony
Published: June 2023

8511

Background: AXL receptor tyrosine kinase is a key facilitator of immune escape and drug resistance, conferring a more aggressive phenotype. Targeting the PD1-PDL1 axis has demonstrated significant efficacy in patients with relapsed malignant mesothelioma (MM), however, responses are only observed in a fraction of patients. Preclinical studies suggest that dual PD1 and AXL inhibition is synergistic. We developed a multi-centre, molecularly stratified phase IIa trial to evaluate the efficacy of AXL/PD-1 inhibition with bemcentinib (Bem)/pembrolizumab (Pem) and to uncover cellular and molecular determinants of efficacy as arm 3 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST3). Methods: Patients with pleural mesothelioma were enrolled. Key inclusion factors were ECOG performance status (PS) 0-1, prior platinum-based chemotherapy (maximum of 2 prior lines allowed), evidence of disease progression with measurable disease by CT (Modified RECIST 1.1), and adequate haematological/organ function. All patients received 200mg Pem IV q3W in combination with Bem, loading dose 400mg PO for the first 3 days and then 200mg od q3w. Primary endpoint was disease control rate at 12 weeks (DCR12w). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate (ORR) and toxicity (NCI CTCAE 4.03). Pre-treatment fresh biopsy was required to enable multiplex immunofluorescence, whole exome and RNA transcriptome sequencing. Gut microbiome 16s RNA sequencing also was undertaken at baseline (n=21). Results: Between September 2020 and March 2022, 26 patients with MM started treatment and received at least one dose of Pem Bem. Median age was 72.5 (range, 55-85) years, 88% were male 12% were female, Histology: 88% epithelioid, 8% Biphasic, 4% Sarcomatoid, ECOG PS1 77%, > 1 prior systemic therapy 35%. The median cycles of Pem Bem was 4 (IQR, 2-11). The DCR12w was 46.2% (12/26) (90% confidence limit (CI), 29.2% –63.4 %;), ORR was 15.4% (95%CI, 4.4- 34.9%; all PR)) with stable disease in 57.7% (36.9 – 76.6%); DCR24w was 38.5% (10/26) (95%CI, 20.2% – 59.4%). Adverse events (any cause): ≥ grade 3 toxicities affected 38% of pts and there were no treatment-related deaths. The most frequent adverse events recorded were fatigue in 12/26 (46%) patients and nausea in 11/26 (42%) patients. Conclusions: MiST3 met its primary endpoint and warrants further evaluation. Analysis of the cellular and molecular correlates of response are ongoing and will be presented. Clinical trial information: NCT03654833 .
Associations between patient-reported nutritional status, survival, and toxicity among patients with limited stage small-cell lung cancer (LS SCLC) in a randomized trial of high-dose, twice-daily (BID) thoracic radiotherapy (TRT).
Authors: Taranova Evgenia , Gronberg Bjorn H. Henning , Halvorsen Tarje Onsøien , Killingberg Kristin Toftaker , Slaaen Marit , Aanerud Marianne
Published: June 2023

8519

Background: Up to 1/3 of LS SCLC patients are cured by chemoradiotherapy (CRT), but severe toxicity is frequent and population-based studies show that many patients do not receive standard CRT. More knowledge on how to predict who experiences side-effects or achieves long term disease control is needed. Poor nutritional status is strongly associated with inferior survival in many types of cancer including non-small cell lung cancer, but little is known about whether this is the case in LS SCLC. We investigated whether nutritional status reported by patients on the Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) was associated with toxicity and survival among participants in a trial comparing high dose with standard dose twice-daily TRT in LS-SCLC (NCT02041845, n=170). Methods: Patients received four courses of platinum/etoposide chemotherapy and were randomized to TRT of 60 Gy/40 fractions or 45 Gy/30 fractions. Patients completed PG-SGA SF before treatment commenced and were categorized as having low (PG-SGA SF score 0–3.9), intermediate (4.0–8.9) and high (≥9) risk of malnutrition. Toxicity was graded according to CTCAE 4.0. Median follow-up for survival was 49 months. Results: 113/170 (66.5%) patients completed PG-SGA SF at baseline. Median age was 65 years, 46.0% were men, 88.5% had PS 0-1, 87.6% stage III disease and 22.1% weight loss of >5% the three months before inclusion. Median PG-SGA SF score was 3.0, 52.2% of patients had low, 29.2% intermediate, and 18.6% high risk of malnutrition. Numerically, there were more patients with stage III, PS 1-2 and pleural fluid among those at high risk. There was no difference in mean no. of chemotherapy courses (low: 3.85, intermediate: 3.88, high: 3.90, p=0.95) or TRT completion (low: 96.6%, intermediate: 97.0%, high: 95.2%, p=1.0). There were no statistically significant differences in proportions who experienced grade 3-4 toxicity (low: 88%, intermediate: 91%, high: 86%, p=0.86), median PFS (low: 15.1 months, intermediate: 11.8 months, high: NR, p=0.23), 2-year survival (low: 68%, intermediate: 52%, high: 67%, p=0.28) or median OS (low: 38.1 months, intermediate: 25.8 months, high: NR, p=0.15). Patients with weight loss >5% did not experience more grade 3-4 toxicity (92% vs. 87%, p=0.73), had similar median PFS (24.0 vs. 15.9 months, p=0.69), 2-year survival (64.0% vs. 66.2%, p=0.84) and median OS (30.6 vs. 35.1 months, p=0.93) as those without. Conclusions: Our study suggest that LS SCLC patients tolerate and should receive concurrent chemotherapy and twice-daily TRT regardless of nutritional status and weight loss.
A study of tumor neoantigen burden and HLA-LOH by whole-exome sequencing to characterize immune biomarkers of lung cancer.
Authors: Wang Wei , Liao Wenting , Zhen Baoling , Ji Tianrong , Du Chen , Cheng Shaochen , Chen Yaru , Yang Jie
Published: June 2023

8527

Background: Lung cancer is a leading cause of cancer-related death worldwide. Precision immunotherapy, such as the use of immune checkpoint inhibitors (ICIs), has been shown to improve the survival of lung cancer patients. Cancer cells with high amount of neoantigens are more likely to be captured by immune cells and thus patients with high Tumor Mutation Burden(TMB) and high Tumor Neoantigen Burden(TNB) are estimated to be prone to ICIs treatment. HLA class Ⅰ is one of the main factors affecting the prognosis of ICI in treatment. Studies have indicated that patients with highly heterozygous HLA-I are more likely to have better responses to ICI treatment. Some specific HLA-Ⅰ genotypes and somatic mutations can affect the prognosis of ICIs treatment. Methods: In this study, we performed whole-exome sequencing (WES) of 200 pairs of tumor and gDNA samples from lung cancer patients. Tumor sample comes from tumor tissue or paraffin-embedded tissue and gDNA is extracted from white blood cells from peripheral blood. We analyze the WES data to obtain the TMB and HLA types of each sample. Then the peptide affinity of MHC-I genes were quantified based on IC50(nM) by netMHCpan software, and the level of neoantigen affinity were classified as strong (IC50≤50nM), weak (50nM < IC50≤500nM), and negative (IC50 > 500nM). TNB is defined as the number of high- affinity neoantigens per megabase of interrogated genomic sequence. Then we conducted linear regression analysis to study the statistical relationship between TMB and TNB. Finally, we analyzed the LOH status at the major region of HLA (HLA-A, HLA-B, and HLA-C) and classified the individuals who have LOH at all three types of HLA as HLA-LOH strong positive, samples with one or two LOH among the three HLA types as weak positive, and samples have no LOH are classified as HLA-LOH negative. Results: Among the 200 samples, the median value of TMB and TNB is 3.25 Muts/Mb and 1.09 Neos/Mb, respectively. 8.5% of the sample have high TMB(TMB≥10). TMB and TNB are also significantly positively correlated (p-value < 0.0001). For HLA typing, 82.0% HLA-A, 96.0% HLA-B, and 92.5% HLA-C are heterozygous. The dominant HLA types are: (A*11:01), (A*02:01), (B*46:01), (B*40:01), (C*01:02), and (C*07:02). As for LOH status among the three HLA types, 14.57% of the individuals are HLA-LOH strong positive, 31.66% are HLA-LOH weak positive, and 53.77% of the samples are HLA-LOH negative. Lastly, the average numbers of detected high-affinity neoantigens are statistically significantly related to the occurrence of HLA-LOH (Analysis of Variance p-value < 0.01). Conclusions: HLA-LOH occurs in nearly half of our lung cancer samples, and it is associated with TMB-High and TNB-High. The analysis of HLA-LOH refines the prediction of neoantigen and gain understanding of drug resistance and immunotherapy.
Prevalence of EGFR mutations in patients with resected stage I-III non-squamous NSCLC: Results from the EARLY-EGFR study.
Authors: Soo Ross A. , Reungwetwattana Thanyanan , Perroud Herman Andres , Batra Ullas , Kilickap Saadettin , Gallegos Luis Fernando Tejado , Donner Natalia , Alsayed Mohamed , Huggenberger Reto , Dao Tu Van
Published: June 2023

8531

Background: The prevalence of EGFR mutations ( EGFRm) in resected stage I-III NSCLC remains controversial as prior research studies were retrospective in nature. EARLY-EGFR is the first prospective, international study to determine the prevalence of EGFRm and treatment patterns in patients (pts) with early-stage NSCLC. Methods: EARLY-EGFR (NCT04742192), a non-interventional real-world study, captured data on EGFRm status, treatment patterns, demographic, clinical and pathological characteristics in consecutively enrolled pts with surgically resected stage IA-IIIB (AJCC 8th) non-squamous NSCLC (Mar 2021 – Oct 2022). The primary endpoint was prevalence of EGFRm and secondary endpoints included prevalence of EGFRm subtypes and treatment patterns. Results: Of 601 pts (median [range] age: 62 [30-86] yrs) enrolled at 33 centers across Middle East and Africa (n=16), Latin America (n=80), and Asia (n=505), 317 (52.7%) were females, 354 (58.9%) were never smokers. The majority had stage IA-IB NSCLC (64.1%) involving right lung (62.9%), no nodal involvement (81.5%), T1a-T2b tumor (82.7%), adenocarcinoma histology (98.7%), and 105/420 (25.0%) tumors were poorly differentiated. About 23.3% (130/559) were diagnosed through a screening program; 60/539 (11.1%) reported family history of lung cancer. The overall prevalence of EGFRm was 50.7% (300/592). Exon-19 deletions accounted for 50.3%, L858R mutations for 35.7%, and compound mutations for 2.3% of mutations. EGFRm tumors were found to be PD-L1 positive in 38.5% of cases (15/39). Women had higher EGFRm rate than men (63.6% vs 36.2%). Compared with EGFR wild type (wt), pts with EGFRm were more likely to be never smokers (39.5% vs 60.5%) and have stage I/II NSCLC (46.5% vs 53.5%) (Table). Of 216 stage II/III NSCLC pts, only 51.4% received systemic adjuvant therapy. Significantly higher EGFRm rates in stages I and II than in stage III NSCLC (p<0.001 and p=0.050) were found, while no significant difference was found between stages I and II NSCLC (p=0.158). Conclusions: In this first prospective, real-world study of EGFRm prevalence in resected NSCLC, stage III and smoking were independent predictors associated with decreased odds of EGFRm. The results highlight the need to adhere to ASCO adjuvant chemotherapy guidelines, as only half of stage II/III NSCLC pts received adjuvant systemic therapy. Clinical trial information: NCT04742192 . [Table: see text]
Multi-genomic analysis of compound and uncommon EGFR mutations in patients with non-small cell lung cancer.
Authors: Park Jayoung , Lee Yu Min , Ka Sojeong , Kim Seoree , Kim In-Ho , Sung Yeoun Eun , Jung Chan-Kwon , Shin Jung-Young , Chun Sang Hoon , Lee Young Ho , Kang Jin Hyoung , Kim Joori
Published: June 2023

8534

Background: There are similar and different properties between the epidermal growth factor receptor mutations (mEGFR), which are classified into common, uncommon, and compound mutation subtypes depending on their location and pattern on the EGFR gene. We investigated the RWD and RNA expression profile of uncommon and compound mutations in the mEGFR+ NSCLC patients. Methods: We collected the medical information for stage I-IIIA mEGFR+ NSCLC patients receiving curative surgical resection in Seoul St. Mary’s Hospital. We explored the RNA expression profile using multiplex IF and High-Plex Digital Spatial Profiling. A total of 18,676 DEG libraries were constructed, and 151 significance genes with > 2-fold changes, 4-log 2 normalized read counts, and p-value = 0.05 (up and down) were identified. Results: In hospital cohort, 941 mEGFR+ cases of total 6,609 cases consist of common, 860 (91.4%), uncommon, 60 (7.4%), and compound, 21 (2.2%). Median relapse-free survival in uncommon and compound mEGFRs (31.4M and 33.7M) was shorter than common mEGFRs (40.1M, p = 0.877), but median overall survival did not differ between the groups. CNS recurrence rates in the uncommon and compound mEGFRs (40.0% and 35.3%) tended to be higher than that of common mEGFRs (27.4%, p = 0.361). Spatial RNA-seq data of the ratio of deconvolution individual cells showed that genes involved in inflammatory and immune response were relatively lower in mEGFR+ groups. According to the difference in DEG library through clustering heat map, uncommon or compound mEGFR in the immune, inflammatory response category, extracellular matrix, RNA splicing gene category, JAK-STAT, p53, PI3K-AKT, and notch signaling pathway related genes were down regulated compared to common mEGFR+ group. Gene ontology string analysis revealed RNA expression of genes in compound mEGFR was functionally associated with chemokine production (23.4%), electron transfer activity (14.9%) and T cell selection (8.5%), and, in uncommon mEGFRs, was associated with regulation of oligopeptide transport (26.1%), hypermethylation of CpG island (21.7%), and CD4+ CD25+ αβ regulatory T cell lineage commitment (13.0%), compared to common mEGFR+ groups. Based on the GSEA, relatively highly clustered genes in compound mEGFR were the protein modification process, G-protein coupled receptor, regulation of cytosolic calcium ion concentration, and IL-5 production pathways, and lower ES levels in oxidative phosphorylation and RNA processing pathways, when compared to common mEGFR+ groups. Conclusions: In conclusion, our results suggest that uncommon and compound mEGFR+ subtypes exhibiting distinguished RNA expression profile of functional signaling pathways and protein network be not same disease entity as common mEGFR+ subtype.
Real-life efficacy of nivolumab plus ipilimumab combination in untreated, unresectable malignant pleural mesotheliomas: Result of French early access program—MESOIMMUNE – GFPC 04-2021.
Authors: Bylicki Olivier , Guisier Florian , Daniel Catherine , Swalduz Aurélie , Grolleau Emmanuel , Bernardi Marie , Hominal Stephane , Cloarec Nicolas , Deshayes Simon , Raimbourg Judith , Veillon Remi , Oulkhouir Youssef , Audigier-Valette Clarisse , Gobert Aurélien , Falchero Lionel , Thibonnier Lise , Chasseray Matthieu , Raynaud-Donzel Christine , Decroisette Chantal , Greillier Laurent
Published: June 2023

8536

Background: The SOC for unresectable malignant pleural mesothelioma (MPM) has changed in 2020 with the combination nivolumab plus ipilimumab (NIVO+IPI) results of CheckMate 743 study. As CheckMate 743 was therapeutic trial in selected MPM patients (pts), additional data would be of interest to confirm the results in real-life setting. Methods: The present multicenter, retrospective study assessed the outcomes of NIVO+IPI, via an early access program (EAP) in France, in pts with treatment naïve unresectable MPM. The primary objective was investigator-assessed real world progression-free survival (rwPFS) from initiation of NIVO+IPI, defined as time from first dose of NIVO+IPI to first documentation of objective disease progression or death from any cause. The secondary objectives were real world OS (rwOS), objective response rate (ORR), and safety of NIVO+IPI combination. Results: From April 1, 2021 to Feb 15, 2022 (last day of EAP) there were 143 pts included out of 350 pts treated by EAP for unresectable MPM in 44 centers. Population characteristics are described in the table. With a median follow-up of 14.1 months, median rwPFS was 7.8 months (95%CI 6.2-9.5). rwPFS rates no differ according to histological subtypes: rwPFS for epithelioid MPM was 8.1 months (95%CI 6.0-12.6) and 7.4 months (95% CI 5.3-11.2) for other histological subtypes. The median rwOS was not reached (NR), 1-year survival rate was 65% (95% CI 57-75%). Median rwOS was NR and 13.1 (95% CI 7.8- NA) in epithelioid and non-epithelioid MPM, respectively. At 1 year, 71.2% of pts with epithelioid MPM are still alive versus 51.2% in pts with other histological subtypes. ORR was 23.9% (95% CI 16.9-32.0%) with median time to response of 3.68 months (2.33-5.09) after introduction of NIVO+IPI. Disease control rate was 80.4%. Grade 3-4 adverse events (AE) occurred in 37.8%. Severe immune-related AE occurred in 13.9% of patients. Five deaths were associated with treatment-related AEs according to investigators judgment. Conclusions: While pt’s characteristics differed from the pivotal trial, notably with older and unselected patients, efficacy outcomes that we observed here compares favorably with CheckMate 743 results. Tolerance looks acceptable in real-life setting despite 5 toxic deaths reported. Extended follow-up of our cohort will allow consolidation of the results. Clinical trial information: NCT05308966 . [Table: see text]
Long-term outcomes of single and five fraction schedules of stereotactic body radiation therapy for early-stage central or peripheral NSCLC: Neither fractionation nor location matter?
Authors: Huang Karen , Prasad Sharan , Ma Sung Jun , Iovoli Austin , Farrugia Mark , Malik Nadia Karen , Singh Anurag K.
Published: June 2023

8538

Background: Due to concerns with toxicity, treatment of early-stage non-small cell lung cancer (NSCLC) with stereotactic body radiation therapy (SBRT) often involves different fractionation schemes for peripheral and centrally located tumors. There is a paucity of long-term SBRT survival outcomes comparing peripheral versus central NSCLC. Methods: This is a single-institution observational cohort study of patients diagnosed with early-stage NSCLC (T1-2N0M0) who underwent 27 Gy in 1 fraction or 50 Gy in 5 fractions with heterogeneity correction at Roswell Park Comprehensive Cancer Center between September 2008 to December 2018. All patients treated with single-fraction SBRT had peripheral NSCLC and those treated with five-fraction SBRT had central NSCLC. Clinically relevant variables including age, gender, race, Karnofsky Performance Status (KPS), histology (adenocarcinoma, squamous cell carcinoma, NSCLC not otherwise specified), T stage, smoking status, tumor location, and the year of SBRT delivery were obtained retrospectively. Cox multivariable analysis (MVA), Kaplan-Meier plot, and log-rank test were performed to evaluate progression-free survival (PFS) and overall survival (OS). Fine-Gray competing risk MVA was performed to evaluate local failure (LF), nodal failure (NF), and distant failure (DF) with death as a competing event. To reduce selection bias, propensity score matching was performed between single- versus five-fraction SBRT cohorts. Results: A total of 265 patients (142 female [53.6%]; median age 77 years) met our criteria. There were 74 (27.9%) and 191 (72.1%) patients with central tumors treated with five-fraction SBRT and peripheral tumors treated with single-fraction SBRT, respectively. On Cox MVA, there was no statistically significant difference in OS (peripheral vs central tumors: adjusted hazards ratio [aHR] 1.04, 95% confidence interval [CI] 0.74-1.46, p=0.81) and PFS (peripheral vs central tumors: aHR 1.05, 95% CI 0.76-1.45, p=0.77). On Fine-Gray competing risk MVA comparing peripheral vs. central tumors, there was no statistically significant difference in LF, NF, and DF. After propensity score matching, 68 matched pairs were identified for peripheral vs. central tumors with similar results. Conclusions: Among patients with early-stage NSCLC treated with SBRT central versus peripheral location was associated with similar long-term survival and tumor recurrence outcomes.
The RESECT study: Factors associated with overall survival (OS) and relapse-free survival (RFS) among patients with stages I–III resected NSCLC without known EGFR mutations.
Authors: Gray Jhanelle Elaine , Salomonsen Rachel , Georgoulia Nefeli , Diaz Perez Ignacio , Wang Alice , Cai Ling , Wetherill Graham , Xiao Yang , Fielden Claire , Altorki Nasser K.
Published: June 2023

8541

Background: Approximately one-third of patients with Stages I–III resected non-small-cell lung cancer (NSCLC) do not survive 5 years from diagnosis. This retrospective observational study analyzed factors associated with OS and real-world (rw) RFS among Stage I–III NSCLC patients before the introduction of immuno-oncology (IO) treatment. Methods: We analyzed data from the US CancerLinQ database for adult patients with no known EGFR mutations and no other cancers, who were diagnosed with Stage I–III NSCLC from 2014–2019 and had surgical resection within 140 days after initial diagnosis. 3081 patients met the study criteria of whom 1677 were Stage I, 853 were Stage II, and 551 were Stage III; 4 Stage I patients who received neoadjuvant or perioperative treatment were excluded (too few for analysis). Most patients received surgery only (71.5%); the rest also received adjuvant (24.7%), neoadjuvant (2.4%) or perioperative (1.5%) treatment, most often chemotherapy ± radiotherapy. Key demographics, clinical characteristics, treatment patterns, and relevant 2-way interactions were considered for inclusion in the model, based on Cox regression analyses and medical insights. Multivariable Cox regression analysis (backwards selection, p<0.05) was used to model OS and rwRFS. Results: In the multivariable analyses (in which no Stage I patients with neoadjuvant or perioperative treatment were included), factors associated with both OS and rwRFS (p<0.05) were disease stage, race, ethnicity, year of diagnosis, ECOG performance status, and neoadjuvant treatment. Factors associated with OS (p<0.05), but not rwRFS, were age, sex, time from diagnosis to surgery, and type of surgery. Factors associated with rwRFS (p<0.05), but not OS, were geographic region, nodal status, and adjuvant treatment in Stage II and III patients but not Stage I patients. Conclusions: This study identified several risk factors associated with OS and rwRFS, many of which are known. Notably, in this analysis, neoadjuvant treatment was associated with both improved OS and rwRFS in Stage II–III patients and was not evaluable in Stage I patients. However, adjuvant treatment was only associated with improved rwRFS, and only in Stage II–III patients. Based on these findings, there remains an unmet need for Stage I–III NSCLC patients. The recent introduction of IO treatment in this setting may help improve patient outcomes.
Two-year lung cancer survival between 2000 to 2020: Results from 3 French nationwide cohorts.
Authors: Debieuvre Didier , Monnet Isabelle , Bylicki Olivier , Schneider Sophie , Goupil Francois , Godbert Benoit , Dussopt Christine , Pegliasco Herve , Portel Laurent , Chikouche Reda , Masson Philippe , Jaafar Mohamad , Marty Clothilde , EL Khanjari Fethi , Obert Julie , Picaud Marjorie , Bravard Anne Sophie , Le Floch Herve , Letierce Alexia , Morel Hugues
Published: June 2023

8542

Background: Each decade since 2000, the French College of General Hospital Pulmonologists (CPHG) conducts the KBP study, a real-life nationwide prospective multicenter study on LC in non-academic public hospital (NPH). Here, we report the two-year survival (2-y) rate among the 2020 cohort and the comparisons with the 2000 and 2010 cohorts. Methods: Collection of all consecutive diagnosed LC, all stage and all histology, between 01/01 and 12/31 in NPH pulmonology or oncology units in 2000, 2010 and 2020 with the same methodology. A Scientific Committee controlled inclusion exhaustivity and quality in each center. Survival rates were calculated using the Kaplan-Meier method and risk factors were assessed using Cox models. Results: 8,999 patients were included in 82 centers in 2020. The 2-y survival rate was 40.3%, the median overall survival was 15.3 months. Compared to 2000, mortality rates at 2 years decreased significantly (-19.1%), while early (1 month and 3 months) mortality remains similar. Survival improved in 20 years whatever histologic types (Table). Factors associated with 2-y survival were sex (36.1% vs 48.1% respectively for male and female respectively, significantly increased over 20 years: + 15.3% for M and + 24.5% for F), high age (>80 y-o), poor ECOG status (3 or 4) and advanced disease. As expected in 2020, TNM stage was still determining for 2-year mortality, 15.2 [12.6-17.7] stage I vs 75.6 [74.4-76.8] stage IV. In 2020 the Covid-19 infection (n=283) impacted the survival (HR = 4.02 95%CI [3.33-4.86]) on multivariate analysis adjusted to age, sex, tobacco consumption, histology, ECOG status, TNM stage. Conclusions: These results confirmed the major improvement in the last two decades for LC. 5-years survival will provide us more enlightenment. [Table: see text]
Sequential intravenous chemotherapy with drug-eluting bead bronchial arterial chemoembolization for the treatment of stages III and IV lung squamous cell carcinoma: A retrospective controlled clinical study.
Authors: Tu Jianfei , Lai Lingqiang , Zhang Dengke , Ying Xihui , Chen Li , Wu Jiahao , Chen Jie
Published: June 2023

8548

Background: To determine the differences in efficacy and safety between drug-eluting bead bronchial arterial chemoembolization (DEB-BACE) combined with intravenous chemotherapy and systemic chemotherapy alone for the treatment of stages III and IV lung squamous cell carcinoma (LSCC). Methods: 136 patients with stages III and IV LSCC were retrospectively recruited between January 2018 and August 2021 and divided into group A (chemotherapy-only, N = 95) and group B (DEB-BACE combined with intravenous chemotherapy, N = 41). The short-term efficacy, hemoptysis and dyspnea remission rates, and incidence of adverse reactions were compared between the two groups. Survival estimation was performed by Kaplan-Meier, and the Log-rank test was performed to compare survival differences between groups. Results: The One-month DCR (90.2% vs. 49.5%) and ORR (75.6% vs. 38.9%) were better in group B than in group A (both P < 0.05). Progression-free survival (PFS) was 8.0 months in Group B and 6.0 months in Group A, a statistically significant difference (P < 0.05). The PFS rates at 6, 12, and 24 months were 63.4%, 24.4%, 0.0%, 43.2%, 13.7%, and 0.0% in groups B and A, respectively, this difference was significant (P < 0.05). The median overall survival was better in group B than in group A (19.0 vs 14.0 months, P < 0.05). The OS rates at 6, 12, and 24 months were 100%, 85.4%, 26.8%, 78.9%, 56.8%, and 22.1% in groups B and A, respectively, with statistically significant differences (P < 0.05). The hemoptysis and dyspnea remission rates were better in group B than in group A within one month after treatment (P < 0.05), however, in terms of the incidence of adverse reactions, incidences, such as post-treatment fatigue and bone marrow suppression, were significantly lower in Group B than in Group A during the follow-up period (P < 0.05). Conclusions: DEB-BACE combined with intravenous chemotherapy is effective for the treatment of advanced LSCC, with lower adverse reactions, and significant improvement in patients' hemoptysis and dyspnea symptoms, which is worthy of clinical application.
Association of circulating CD103+ T cells with major pathological response in a randomized phase 2 trial of neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small cell lung cancer.
Authors: Walsh Zachary , Melms Johannes C , Rogava Meri , Caprio Lindsay , Ager Casey , Amin Amit Dipak , Ho Patricia , Malbari Murtaza , Mittal Vivek , McGraw Timothy , Altorki Nasser K. , Izar Benjamin
Published: June 2023

8550

Background: We previously reported results of a randomized phase 2 study, demonstrating a higher rate of major pathological response to durvalumab in combination with stereotactic body radiotherapy (SBRT) compared to durvalumab alone in patients with localized (stage I-IIIA) non-small cell lung cancer (NSCLC). Biomarkers of response in NSCLC are poorly understood. To address this, we evaluated sequentially collected peripheral blood mononuclear cells (PBMCs) from study participants to identify easily accessible biomarkers associated with major pathological responses. Methods: PBMCs were obtained from study participants at defined pre-treatment, peri-operative, and post-operative timepoints. We performed 25-marker spectral flow cytometric analysis of the T cell compartment in these samples and used dimensionality reduction and clustering programs to identify populations of interest. Results: Our analysis of these samples revealed populations of both CD4+ and CD8+ T cells with hallmarks of prior antigen exposure and tissue residency (CD103+, CCR7-, CD45RA-), suggesting tumor-experienced T cells circulating into the blood. Greater pre-treatment frequency of these T cell populations was associated with major pathological responses to neoadjuvant therapy. This observation was consistent when evaluating patients with major pathological responses across both treatment arms, and within the durvalumab plus SBRT group, where we had enough patients with major pathological responses. Maturation of disease-free survival data from this trial will enable us to evaluate the association of these biomarkers with long-term survival. Conclusions: Together, these data reveal an unexpected population of T cells in the peripheral blood with features of tissue-residency, which are associated with major pathological responses, and suggest that re-circulation of tumor-experienced T cells may represent a predictive biomarker for neoadjuvant treatment of NSCLC.
Genomic comparison of MET exon 14 skipping and MET amplified non-small cell lung cancer.
Authors: Minne Rachel , Luo Natalie , Traynor Anne M. , Huang Minxuan , De Tullio Luisina , Godden Jen , Stoppler Melissa Conrad , Kimple Randall J. , Baschnagel Andrew
Published: June 2023

8553

Background: In non-small cell lung cancer (NSCLC), the MET tyrosine kinase receptor can be dysregulated by mutations and/or gene amplification. The most common MET mutation is in exon 14 (METex14), leading to impaired receptor degradation and increased MET-mediated signaling causing sustained tumor proliferation. MET amplification also leads to continued MET signaling and oncogenesis and can be a mechanism of resistance to targeted therapy. We sought to compare the genomic landscape of METex14 and high-level MET amplified tumors, both of which can be targeted with tyrosine kinase inhibitors. Methods: We analyzed 18,047 NSCLC tumors (any stage/subtype) sequenced with Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). Tumors were queried for METex14 mutations, high MET amplification (METamp), defined as copy number gain (CNG) ≥10, and other MET mutations (METother). Immuno-oncology (IO) biomarkers were compared across MET-altered and MET wild-type (METwt) groups. The prevalence of somatic gene alterations was compared similarly with the false-discovery rate (FDR) adjustment. Results: A total of 276 (1.53%) METex14, 138 (0.76%) METamp, 27 (0.15%) METother, and 17,606 (97.56%) METwt tumors were identified. Across groups, patients with METex14 were older, more likely to be female, and nonsmokers. METex14 exhibited the lowest tumor mutational burden (TMB) and lowest neoantigen tumor burden (NTB). PD-L1 positivity rates were higher in METex14 tumors compared to METamp and METwt tumors. MET log10 gene expression was highest in METamp. METamp exhibited the lowest proportion of CD4 T cells and the highest proportion of NK cells. Compared to METex14, METamp exhibited increased prevalence of TP53 (83% vs 37%), TFEC (46% vs 1.1%), CFTR (37% vs 1.4%), EGFR (31% vs. 7.6%), WNT2 (11% vs 0.4%), KEAP1 (14% vs 0.7%), and STK11 (8% vs 1.4%), and decreased prevalence of MDM2 (4.3% vs. 14%), and FRS2 (2.9% vs. 12%). Conclusions: In this large population-based analysis of MET-altered NSCLC, METex14 tumors exhibited differences in IO biomarkers and the somatic landscape compared to non-METex14 NSCLC tumors. Variations in immune profiles may affect immunotherapy selection in MET-altered NSCLC and require further exploration. [Table: see text]
Development of a novel blood-based RNA gene expression platform for early-stage lung cancer diagnosis.
Authors: Keiser Martin J , Cormier-May Elizabeth , Alderdice Matthew , Kavanagh Joy N , Stiles Brendon Matthew
Published: June 2023

8557

Background: Blood-based methods using circulating tumor DNA (ctDNA) and cell-free DNA (cfDNA) are under development for early and less invasive detection of lung cancer, although detection of the earliest stage cancers (stages 0-II) using these modalities is suboptimal. We hypothesized that a machine learning approach using RNA gene expression may offer important information on the biology of the patient, allowing for gene expression profiles to be used as a surrogate measurement of cancer disease phenotype and as a promising direction for early detection of lung cancer. In a previous study, 23 miRNA biomarkers were successfully discovered and validated for the non-invasive diagnostic classification of lung adenocarcinoma, achieving 97.7% sensitivity, 98.7% specificity in blood obtained from 383 clinical subjects. The aim of this study was to train a machine learning algorithm, from the 23 miRNA features, to test the signature for early lung cancer detection. Methods: A large and diverse clinical cohort was obtained from the NIH Gene Expression Omnibus database, GEO Accession Number GSE137140 ( n=3,744), comprised of miRNA extracted from serum samples consisting of subjects with pre-operative lung cancer ( n=1,566) and non-cancer controls ( n=2,178). Our analytic plan leveraged machine learning methods derived from XGBoost classification, a popular supervised-learning algorithm that uses sequentially built shallow decision trees to provide accurate results and avoidance of overfitting. The algorithm was trained using XGBoost 1.4.1.1 R library programmed with R v3.6.3. Results: The lung cancer cohort was heavily weighted towards early-stage lung cancer (87.7% stage I/II), including representation across prevalent histologic types (adenocarcinoma 77.8%, non-adenocarcinoma 22.2%) and those who self-reported as never smokers (37.9%). The 23-miRNA signature achieved 98% sensitivity, 89% specificity in the held-out test set (Table). When incorporating age and gender, the 23-miRNA signature achieved 95.5% sensitivity, 90.3% specificity. Conclusions: A machine learning approach using RNA gene expression in patient serum achieved high sensitivity and specificity in a large, predominantly early-stage, lung cancer cohort. A multi-analyte, multimodal approach that leverages machine learning algorithms with RNA gene expression profiles and available demographics and clinical risk-factors, represents the possibility to accurately detect lung cancer in the earliest stages. This approach has successfully been translated from microarray to PCR instrumentation, with further validation of this machine learning method and approach currently underway. [Table: see text]