bluuebunny/crossref_metadata_2025_split huggingface dataset:
The efficacy of PD-1 antibody sintilimab on ground glass opacity lesions in patients with early-stage multiple primary lung cancer (CCTC-1901, NCT04026841).
Authors: Cheng Bo , Cheng Bo , Li Caichen , Zhao Yi , He Jianxing 
Published: June 2021

8545 Background: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) have been proven its significant efficacy on advanced non-small cell lung cancer (NSCLC). However, it remains unknown and is of great interest whether the PD-1 antibody affects early-stage lung cancer. Here, we reported the preliminary efficacy and safety outcomes of sintilimab on these early-stage GGO lesions in patients (pts) with multiple primary lung cancer in the CCTC-1901 study, the first trial evaluating PD-1 antibody in preinvasive or low invasive lung cancer worldwide. Methods: This single-center, phase II, Simon's two-stage design trial included pts who had a pathological diagnosis of resected lung cancer and at least one unresectable GGO lesion suspicious malignant which evaluated by a multidisciplinary team's consensus. The enrolled pts received 4 cycles of intravenous sintilimab 200 mg every 3 weeks. The primary endpoint is the objective response rate (ORR) of unresectable GGO lesions. For persistent GGO lesions that did not respond to treatment, either observation or second operation was taken. Also, immune biomarkers (T/B/NK subpopulation etc.) were monitored during treatment to validate the immune activity. Results: A total of 36 pts were included, with median age 59.5 (53.5-69), 66.7% females, 80.6% never smokers. All resected lesions were adenocarcinomas, of which 52.8% were EGFR mutated. 49 unresected GGOs (pure 11[22.4%], mixed 38[77.6%]) were defined as target lesions from 36 enrolled pts, with a mean size of 13.20±5.06 mm. The ORR (RECIST v1.1) was 5.6% (2/36, 1 PR and 1 CR); none of the pts had PD. Additionally, 3 non-target lesions (unresected solid lesions) from 3 included pts showed PR after the treatment of sintilimab, and the rest lesions (target or non-target) of 31 pts performed SD. Grade 1-2 fatigue (13, 36%), rash (13, 36%) and arthralgia (8, 22%) were the most common treatment-related adverse events (TrAEs), and no grade 3-5 TrAEs occurred. The proportion of CD8+ T-cell and the ratio of CD8+/CD4+ in 5 patients who showed PR of unresected lesions were significantly higher compared to those with SD lesions at baseline (CD8+ 36.6% vs 24.6%, p < 0.01; CD8+/CD4+ 1.09±0.18 vs 0.64±0.22, p < 0.01). Conclusions: This study is the first to confirm that PD-1 antibody sintilimab has immune-related antitumor activity on GGO-featured lung cancer and could be well tolerated among pts with early-stage lung cancer. Clinical trial information: NCT04026841.
NRG-RTOG 1106/ACRIN 6697: A phase IIR trial of standard versus adaptive (mid-treatment PET-based) chemoradiotherapy for stage III NSCLC—Results and comparison to NRG-RTOG 0617 (non-personalized RT dose escalation).
Authors: Kong Feng-Ming Spring , Hu Chen , Ten Haken Randall , Xiao Ying , Matuszak Martha , Hirsh Vera , Pryma Daniel A. , Siegel Barry A. , Gelblum Daphna Y. , Hayman James , Robinson Clifford Grant , Loo Billy W. , Videtic Gregory M.M. , Faria Sergio , Ferguson Catherine , Dunlap Neal E. , Kundapur Vijayananda , Paulus Rebecca , Bradley Jeffrey D. , Machtay Mitchell 
Published: June 2021

8548 Background: NRG-RTOG 0617 (R0617) found that non-personalized dose escalation of radiotherapy (RT) with concurrent chemotherapy was deleterious. NRG-RTOG 1106/ACRIN 6697 (R1106) studied adaptive chemoradiotherapy, using tumor and patient individualized RT dose intensification simultaneously with field reduction, based upon mid-treatment FDG-PET. Methods: The control arms of both studies used 60 Gy (+ weekly carboplatin/paclitaxel). The investigational arm of R0617 used 74 Gy in 37 fractions, with no field/dose adaptation, while R1106 used mid-treatment FDG-PET (after ̃40 Gy) to design an individualized dose adaptive RT plan with daily-fraction size 2.2 to 3.8 Gy (up to 80.4 Gy/30 fractions), based upon a model of isotoxic lung risk. Nearly all (93%) patients had IMRT. No patients had consolidation immunotherapy. The primary endpoint for R1106 was local-regional-progression freedom (LRPF) assessed by central review. Other endpoints reported here were survival, toxicity, and institution-defined local/regional control. Results: From 2012-2017, 127 patients were enrolled to R1106 (43 in the standard and 84 in the adaptive arms), with a median follow-up of 3.6 years. The median actual RT dose in the adaptive arm was 71 Gy (Q1-Q3 68-76 Gy). The 2-year LRPF was 59.5% versus 54.6% (p=0.66) for standard versus adaptive RT; the 3-year survival rates were 49.1% versus 47.5% (p=0.80). An exploratory analysis of 2-year in-field local primary tumor control and local-regional tumor control (institution-assessed) were 58.5% and 55.6% for standard RT, and 75.6% and 66.3% for adaptive RT, respectively. As shown in the table, there were no significant differences in cardiac or esophageal adverse events between the two arms; the adaptive RT arm had more Grade 3+ respiratory events (23.8% versus 14.3%). Conclusions: NRG-RTOG1106 did not meet its primary endpoint of demonstrating improved LRPF. Unlike R0617, there was no suggestion of a detrimental effect of adaptive dose-intensified RT on survival and cardiac events. Studies to refine personalized RT, especially in the immunotherapy era, should be considered. Outcome comparison between R0617 and R1106. Clinical trial information: NCT01507428. [Table: see text]
A phase II trial of abemaciclib in patients with p16ink4a negative, relapsed mesothelioma.
Authors: Fennell Dean Anthony , King Amy , Mohammed Seid , Branson Amy , Greystoke Alastair , Moody Sam , Hutka Margaret , Dawson Alan G. , Darlison Liz , Scotland Molly , Bhundia Vina , Bajaj Amrita , Morgan Bruno , Nicholson Adrian , Brookes Cassandra , Gaba Aarti , Wells-Jordan Peter , Richards Catherine Jane , Thomas Anne 
Published: June 2021

8558 Background: Genetically stratified therapy for malignant mesothelioma (MM) is lacking. MMs frequently harbour loss of chromosome 9p21.3 locus (CDKN2A) associated with shorter survival. CDKN2A encodes the tumour suppressor p16ink4a, an endogenous suppressor of CDK4 and CDK6. Genetic reconstitution of p16ink4a into CDKN2A suppresses MM in preclinical models, underpinning the rationale for targeting of CDK4/6 in p16ink4a negative MM. We therefore developed a multi-centre molecularly stratified phase IIa trial to test this hypothesis as arm 2 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST2). Methods: Patients with histologically confirmed MM (pleural or peritoneal) were molecularly screened by immunohistochemistry for p16ink4a, BAP1, BRCA1, and PDL1 (Dako 22C3). Patients with p16ink4a negative MM were eligible. Key inclusion factors: histological confirmation of MM with an available archival tissue block, ECOG performance status 0-1, prior platinum-based 1st line chemotherapy (any line allowed), evidence of disease progression with measurable disease by CT (RECIST 1.1), and adequate haematological/organ function. Patients received Abemaciclib (Ab) 200mg bd po daily in q21 day cycles. Primary endpoint was disease control rate at 12 weeks (DCR12w). The null hypothesis was rejected if ≥ 11 patients had disease control (A’Hern design). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate and toxicity (NCI CTCAE 4.03). Patients could undergo an optional re-biopsy upon disease progression. Results: Between November 2019 and March 2020, 26 patients with p16ink4a negative MM received at least one dose of Ab. The median age of pts was 67 (range, 64-74) years, 89% were male, 80.8% epithelioid, 84.6% ECOG PS1, > 1 prior systemic therapy 62%. All patients received at least one cycle with 27% completing 6 cycles. No dose reductions occurred in 53.9% of pts. DCR12w: 54% (95% confidence limit (CI), 36% – 71%), DCR24w: 23% (95%CI, 9% – 44%). Best responses (within 24w): partial - 15% (95%CI, 4- 35%), one occurring after 18 weeks; stable disease - 53.8% (33.4 – 73.4%); progression - 7.7% (0.9 – 25.1%). Adverse events (any cause): ≥ grade 3 toxicities affected 5.7% of pts. Conclusions: MiST2 met its primary endpoint, warranting further clinical evaluation of Ab. Whole exome sequencing of the cohort is ongoing to explore genomic correlates of de novo and acquired resistance. Clinical trial information: NCT03654833.
Efficacy and safety analysis of anlotinib combined with etoposide plus cisplatin/carboplatin as first-line therapy for extensive-stage small cell lung cancer (SCLC): The final results from a phase II single-arm trial.
Authors: Kong Tiandong , Chen Lu , Duan Fangfang , Hou Xiaoxia , Wang Liuyan , Zhou Hanli , Wang Lanrong , Hu Shanshan , Liu Danna 
Published: June 2021

8560 Background: In recent years, the therapeutic regimens of extensive-stage small cell lung cancer (ES-SCLC) have progressed a lot. The most significant clinical studies include IMpower133 and CASPIAN. However, the relevant results showed that the combination of PD-L1 monoclonal antibody and EC regimen chemotherapy as first-line treatment of small cell lung cancer have a median PFS (progession-free survival) of about 5 months, which is comparable to that of simple chemotherapy. Therefore, the EP/EC is still the standard treatment for extensive-stage small cell lung cancer. Meanwhile, we noticed that anlotinib (multi-target small molecule oral VEGF inhibitor) has a curative effect on patients with extensive-stage SCLC as a third-line or above treatment in the ALTER 1202 study in China. Therefore, we tried to add anlotinib to the first-line treatment with EP/EC regimen in patients with ES-SCLC to observe the efficacy and safety. Methods: Eligible ES-SCLC pts (18̃75 years old, initial treatment, no obvious heart, liver and kidney dysfunction) were received anlotinib (12mg QD from day 1 to 14 of a 21-day cycle) + etoposide(100mg/m2, d1̃3 of a 21-day cycle)+CBP (AUC = 4̃5,d1,Q3W) or DDP (70̃75mg/m2, d1,Q3W) for 4̃6 cycles, then anlotinib maintenance (12mg QD from day 1 to 14 of a 21-day cycle) until the disease progresses or intolerable adverse reactions occur. During the treatment, dose reduction of anlotinib was permitted, which could be reduced to 10mg or 8mg if it was intolerable. The main observation endpoints were ORR, PFS and adverse events. Results: Between January 2019 and August 2020, a total of 20 patients with extensive-stage SCLC were enrolled in the study, with an average age of 66.2 ± 8.1(45-75) years old, 17 males (85%) and 3 females (15%). The median PFS was 10 months (95% CI: 7.809-12.191), median OS was 15 months (95%CI:10.639-19.361), ORR (objective remission rate) was 90% and DCR (disease control rate) was 100%. The most common grade 3 or 4 adverse events related to the trial regimen included: neutropenia was 10/20 (50.0%), thrombocytopenia was 5/20 (25.0%), anemia, nausea and fatigue were all 2/20 (10%), hypertension, transaminase elevation and hoarseness were all 1/20 (5%). Conclusions: Anlotinib combined with EP/EC regimen has better PFS, OS, ORR and DCR for the initial treatment of extensive-stage SCLC, and a manageable safety profile. A randomized, controlled phase III clinical study will be conducted to confirm this conclusion. Clinical trial information: ChiCTR2000035043.
Cancer activation pathways of thymic epithelial tumors (TETs) by targeted gene expression analysis.
Authors: Benitez Jose Carlos , Job Bastien , Thomas de Montpreville Vincent , Lacroix Ludovic , Saulnier Patrick , Arana Riad , Lambotte Olivier ,   Cancer and Autoimmune/inflammatory Diseases Relationships Foundation, Mussot Sacha , Mercier Olaf , Fadel Elie , Scoazec Jean-Yves , Besse Benjamin 
Published: June 2021

8575 Background: TETs are rare malignancies of the anterior mediastinum. Clinical behavior varies from mild thymoma (T) A to aggressive thymic carcinoma (TC). The biology of TETs is poorly understood and knowledge of the transcriptomic fingerprint of T and TC is limited. Additionally, up to 30% of patients (pts) will develop associated autoimmune disorders (AIDs). We aimed to characterize the main cancer activation pathways of the TET subgroups. Methods: We selected a representative balanced set of Ts and TCs to analyze 24 main cancer activation pathways using HTG Oncology biomarkers panel (2562 genes) by RNA sequencing. Tumor representative paraffin-embedded blocks were macrodissected for gene expression analysis. We analyzed epidemiologic, clinical and pathological characteristics of pts with TET’s and correlated with genes expression based on cancer Hallmarks. Results: From January 2010 to December 2019, 219 pts were included in the cohort. Molecular results of 194 pts were available. Median age at diagnosis was 56 (9-83) years. 54.1% were women. 65/194 (33.5%) reported AIDs. T B2 was the most frequent (n=41, 21.1%), followed by B1, AB, B3, TC and A. RNA expression analysis identified 2 main clusters, corresponding mainly to T (cluster 2) and TC (cluster 1) respectively (p<0.0001) (Table). Tumors of cluster 1 (TCs predominant) shown activated pathways (MYC [gene ratio= 0.5]; p<0.0001). In cluster 2 (T predominant), activated pathways differed among subgroups: B1 (E2F[0.5], G2M checkpoint [0.45]; p<0.001), B2 (E2F [>0.4]; p<0.0001). Routes were mostly suppressed: A (MYC [>0.5], E2F[>0.4], G2M checkpoint[>0.45], mitotic spindle[>0.35], MTOR [<0.35]; p<0.001), AB (INFα [>0.5], inflammatory response [>0.45], INTɣ [0.45], NFkb [>0.4], MTOR[>0.4]; p<0.001), B1 (EMT [0.6], angiogenesis [>0.5], INFα [0.5], homeostasis [0.5], NFkb [0.5], INTɣ [>0.45], myogenesis [<0.4]; p<0.0001), B2 (INFα [>0.65], INTɣ [>0.5], NFkb [0.5], EMT [0.45], inflammatory response [<0.4]; p< 0.0001), B3 (EMT [0.6], MYC [0.45]; p<0.001). Among pts reporting AIDs 61 and 4 were associated to cluster 2 and 1, respectively (p=0.017). Conclusions: We describe differential molecular characteristics among histological subgroups in 2 clusters. The analysis suggests new therapeutic venues. Additional analysis will be presented on outliers and response to treatment.[Table: see text]
Cell-free circulating tumor DNA (cfDNA) analysis of advanced thymic epithelial tumors (TETs).
Authors: Dada Hiba I. , Drusbosky Leylah , Giaccone Giuseppe 
Published: June 2021

8577 Background: Thymic epithelial tumors (TETs) are rare tumors originating from the epithelial cells of the thymus. Thymomas tend to be slowly growing, whereas thymic carcinomas are more aggressive and often metastasize wildly. TETs have a very low tumor mutational burden (TMB). cfDNA has been used in several tumor types to describe the molecular characteristics and select treatment options, especially in absence of tissue availability. There is no information on the cfDNA detected in TETs. The purpose of this study was to identify common genomic alterations occurring in circulating tumor DNA (ctDNA) in patients with advanced TETs, detected using a cfDNA assay. Methods: We retrospectively evaluated 157 TET samples from the Guardant Health database between November 2017 – November 2020. The cfDNA analysis interrogated single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes using a commercially available liquid biopsy assay (Guardant360; Guardant Health, Redwood City, CA) . We evaluated the frequency of genomic alterations based on diagnosis, age, and sex. Results: In this cohort, 66% of the patients had thymic carcinoma and 34% had thymoma. The median age was 60 years, and 59% of patients were male. 126 patients (80%) of this cohort had ≥1 somatic alteration detected. The most prevalent mutations detected are TP53 (55%), KIT (13%), EGFR (12%), BRCA2 (11%), PIK3CA (10%), ARID1A (10%), ATM (10%), KRAS (9%), APC (9%), and BRAF (9%). Mutations were more commonly observed in thymic carcinomas than thymomas, but statistical significance was not reached due to the small sample size. Frequencies of the observed genomic alterations are shown in the table below. Conclusions: This study confirms that advanced stage TETs shed tumor DNA into the circulation that can be picked up in the majority of patients, using a solid tumor platform, despite the low TMB typically observed in these tumors. This assay can potentially be used to monitor response to therapy. A more targeted gene panel, enriched for genes commonly mutated in TETs (e.g. GTF2I, BAP1, CYLD) might provide further insights in the future in the management of TETs.[Table: see text]
Biomarker tissue journey among patients (pts) with untreated metastatic non-small cell lung cancer (mNSCLC) in the U.S. Oncology Network community practices.
Authors: Robert Nicholas J. , Nwokeji Esmond D. , Espirito Janet L. , Chen Liwei , Karhade Mandar , Evangelist Makenzi Colleen , Spira Alexander I. , Neubauer Marcus A. , Bullock Susie A. , Coleman Robert L. ,   on behalf of MYLUNG Consortium Collaborators: The U.S. Oncology Network and sponsors
Published: June 2021

9004 Background: Given the importance of molecular testing and targeted therapy for mNSCLC, the MYLUNG (Molecularly Informed Lung Cancer Treatment in a Community Cancer Network) consortium pragmatic study assessed real-world biomarker testing rates and turnaround times (TAT) within The US Oncology Network of over 1,000 providers across the United States. Methods: This was a retrospective observational chart review study of pts with mNSCLC initiating first-line (1L) systemic therapy between 04/01/2018 and 03/31/2020. iKnowMed electronic health records were used to examine timing of biomarker testing: before 1L therapy (cohort 1), after 1L therapy (cohort 2) or no testing (cohort 3). We assessed testing rates for ALK, BRAF, EGFR, ROS1, and PD-L1; use of full next-generation sequencing panel (NGS); time from mNSCLC diagnosis (dx) to 1L therapy; TAT from biomarker orders to results; and time from mNSCLC dx to test results. Results: We identified 3474 adults. Median age was 69 years (range 23-90), 51% female, 74% with adenocarcinoma and 76% with a documented ECOG performance status of 0 or 1. Testing rates are shown in table: 90% of pts had at least one biomarker test and 46% received all 5 biomarker tests. Changes in testing rates from 2018 to 2020 were 51% to 59% for BRAF, 71% to 71% for EGFR, 71% to 70% for ALK, 69% to 67% for ROS1, 82% to 84% for PD-L1, and 42% to 49% for pts tested for all 5 biomarkers. NGS testing increased from 33% to 44% (p<0.0001). The median (interquartile range [IQR]) time from mNSCLC dx to 1L therapy for all pts was 35 (22, 55) days. Median (IQR) TAT from biomarker testing orders to results ranged from 10 (6, 17) to 15 (10, 22) days for the individual biomarkers; and time from mNSCLC dx to biomarker results ranged from 14 (7, 26) to 21 (12, 36) days by biomarker. Conclusions: This real-world study showed that most pts received at least one biomarker test prior to 1L, but <50% received all 5 tests. NGS testing occurred in <50% of pts but increased over the periods examined. Median time from dx to 1L therapy was about 5 weeks and TAT from orders to results about 2 weeks. Analyses by histology and other trends will be reported. These data will be compared to the next phase of the MYLUNG study, which will evaluate contemporary ordering practices and TATs prospectively[Table: see text]
Concordance of tissue- and plasma-derived genomic profiling in CheckMate 9LA, using the FoundationOne CDx and GuardantOMNI assays.
Authors: Baden Jonathan F. , Sausen Mark , Kalinava Natallia , Geese William J. , Balli David , Neely Jaclyn , Green George 
Published: June 2021

9010 Background: Blood-based profiling of genomic features including tumor mutational burden (TMB) has generally demonstrated positive correlations with tissue-derived assessments from paired tumor samples. However, both technical and biological factors contributing to discordance between these measurements and underlying sequence alterations need further investigation for the successful adoption of noninvasive tumor profiling. We explored the genomic landscape, including the association between tissue TMB (tTMB) and blood TMB (bTMB), in samples from patients with stage IV non-small cell lung cancer (NSCLC) enrolled in CheckMate 9LA (NCT03215706), a phase 3, randomized clinical trial of nivolumab + ipilimumab in combination with 2 cycles of chemotherapy (chemo) vs 4 cycles of chemo as first-line treatment for NSCLC. Methods: Tissue- (FoundationOne CDx [F1CDx]) and blood-based (GuardantOMNI [OMNI]) genomic data obtained from both treatment arms were utilized for our retrospective analysis of genomic variants and complex biomarkers, including tTMB and bTMB. In total, 692 tissue and 646 plasma samples were analyzed. Results: Following the established criteria for the validated F1CDx and OMNI platforms, 464 tissue and 537 plasma samples passed quality control, resulting in ascertainment levels of 67% for tTMB and 83% for bTMB. Across 344 paired tissue and plasma samples, tTMB and bTMB scores were found to be moderately correlated (Spearman’s r = 0.56; P < 0.001); median tTMB score was 7.7 mutations per megabase (mut/Mb) and median bTMB score was 13.5 mut/Mb. For the prespecified cutoffs of 10 mut/Mb for tTMB and 16 mut/Mb for bTMB, the positive, negative, and overall percentage agreements between assays were 65%, 79%, and 73%, respectively. Interestingly, 2 discordant sample pairs had considerably higher bTMB than tTMB (76.1 vs 3.8 and 172.6 vs 5.0 mut/Mb for bTMB and tTMB, respectively) and both had high microsatellite instability from blood-based assessments. OMNI and F1CDx data from 477 patients were evaluable for the analysis of short sequence variants (single nucleotide variations and indels). OMNI detected 4557 variants, F1CDx detected 4620, and 2903 (46% of total reported variants) were detected by both assays. Conclusions: In CheckMate 9LA, data from paired samples revealed the complementary nature of TMB assessments from tissue and blood and suggest that both approaches may have the potential to identify genomic alterations that may be useful in the management of patients with NSCLC. Further interrogation of the biological and analytical factors affecting tumor- and blood-derived genomic profiling is warranted to support their implementation in clinical settings. Clinical trial information: NCT03215706.