bluuebunny/crossref_metadata_2025_split huggingface dataset:
FGFR3-mutated urothelial carcinoma of bladder and upper tract including ureter and renal pelvis: A comparative genomic profiling study.
Authors: Basin Michael , Sager Rebecca A , Pavlick Dean , Necchi Andrea , Spiess Philippe E. , Li Roger , Kamat Ashish M. , Grivas Petros , Cheng Liang , Lin Douglas I. , Ross Jeffrey S. , Bratslavsky Gennady , Jacob Joseph M , Gupta Shilpa , Agarwal Neeraj , Basnet Alina 
Published: June 2024

4588 Background: Activating DNA sequence genomic alterations (GA) in the FGFR3 gene are known oncodrivers and relevant precision targets for patients with urothelial carcinoma. THOR-1 trial showed a significant overall survival benefit with erdafitinib (FGFR inhibitor) vs chemotherapy (taxane or vinflunine) in patients with advanced urothelial carcinoma of the bladder (UCB) or upper tract urothelial carcinoma (UTUC). PROOF-302 trial showed higher frequency of FGFR3 GA in UTUC (30%) vs UCB (13%). We sought to explore differences in frequency of FGFR3 alterations and the genomic landscapes of FGFR3-altered UCB, ureteral urothelial carcinoma (UUC) and renal pelvic urothelial carcinoma (RPUC). Methods: 10,798 UCB and 2,392 UTUC (871 UUC and 1521 RPUC) underwent hybrid capture-based comprehensive genomic profiling (CGP) to assess all classes of GA and measure MSI status, TMB level, genomic ancestry, genomic signature, germline mutations and HRD score. PD-L1 was determined by IHC Dako 22C3 using the TPS system. Results were compared using the Fisher Exact method with the Benjamini-Hochberg adjustment. Results: FGFR3mut+ status was significantly higher in RPUC (27.8%), followed by UUC (22.0%), and UCB (18.1%) (P<.0001) (Table). Patients with UCB were more often male compared to patients with UTUC. Median age, EUR ancestry, and GA/tumor were similar. “Targetable” GA in ERBB2 (P=.03), PIK3CA(P=.05), KDM6A (P=.0009) were more frequent in FGFR3mut+ UCB vs FGFR3mut+ UTUC. Targetable GA in PTEN, TSC1 and MTAP currently associated with drugs tested in trials were similar in UBC and UTUC. The KEGG ERBB and VEGF signaling pathways were more frequently identified in UCB (P=.036) and the MMR pathway more frequently identified in UTUC (P=.014). The HRD signature was similar in the groups. MSI-high status was significantly higher in UTUC vs UCB, but there was no significant difference in TMB or PD-L1 expression levels. Conclusions: Although histologically similar, the genomic landscape of FGFR3mut+ RPUC and UUC has notable differences with FGFR3mut+ UCB. Limitations include lack of clinical data annotation, inherent selection biases, and the retrospective nature of this work. Findings may impact clinical trial designs for UCB and UTUC, including evaluating combinations of anti-FGFR3 with other agents. CGP may also inform resistance mechanisms and putative biomarkers of response. [Table: see text]
Outcomes in high-risk subgroups after fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Up to 5.5 years of follow-up in the phase 2 CAPTIVATE study.
Authors: Wierda William G. , Jacobs Ryan , Barr Paul M. , Allan John N. , Siddiqi Tanya , Tedeschi Alessandra , Kipps Thomas J. , O'Brien Susan Mary , Badoux Xavier C. , Visentin Andrea , Lasica Masa , Carney Dennis , Elinder Camburn Anna , De La Serna Torroba Javier , Szafer-Glusman Edith , Zhou Cathy , Szoke Anita , Dean James P. , Ghia Paolo , Tam Constantine S. 
Published: June 2024

7009 Background: The phase 2 CAPTIVATE study evaluated first-line ibrutinib (Ibr) + venetoclax (Ven) for CLL/SLL in 2 cohorts: minimal residual disease (MRD)-guided randomized discontinuation (MRD cohort) and Fixed Duration (FD cohort). Ibr±Ven retreatment was allowed in patients (pts) who had progressive disease (PD). Here, we report outcomes for pts with high-risk genomic features from the FD cohort and retreatment outcomes in pts from the FD cohort and MRD cohort placebo arm. Methods: Pts aged ≤70 y with previously untreated CLL/SLL without restriction on genomic risk factors received 3 cycles of Ibr, then 12 cycles of Ibr+Ven (Ibr, 420 mg/d orally; Ven, 5-wk ramp up to 400 mg/d orally). On-study retreatment included single-agent Ibr (FD cohort or MRD cohort placebo arm); pts with PD >2 y after end of treatment (EOT) could be retreated with FD Ibr+Ven (FD cohort). Results: In the FD cohort (n=159) with a median follow-up of 61.2 mo (range, 0.8–66.3), 5-y PFS and OS rates (95% CI) were 67% (59–74) and 96% (91–98), respectively. 5-y PFS rates were higher in pts with undetectable MRD at 3 mo after EOT in peripheral blood (83%) or bone marrow (84%) vs those without (48% and 50%, respectively). 5-y PFS rates (95% CI) in pts with genomic risk factors were: del(17p)/mutated TP53 41% (21–59), complex karyotype 57% (37–72), del(11q) 64% (30–85), and unmutated IGHV 68% (50–80) (Table). In total, 18 second malignancies occurred in 13 pts (10 events in 8 pts during FD Ibr+Ven, 6 events in 4 pts after EOT and before retreatment, and 2 events in 2 pts during retreatment). Of 202 pts who completed Ibr+Ven (FD cohort, n=159; MRD cohort placebo arm, n=43), 63 have had PD to date; PD occurred >2 y after EOT in 43/63 pts (68%). 32/63 (51%) pts initiated retreatment with Ibr (n=25) or Ibr+Ven (n=7). With a median time on Ibr retreatment of 21.9 mo (range, 0.03–50.4), ORR was 86% in 22 evaluable pts (best response: 1 CR; 1 nodular PR; 17 PR; 2 SD; 1 PD [Richter transformation]). With a median time on Ibr+Ven retreatment of 13.8 mo (range, 3.7–15.1), ORR was 71% in 7 evaluable pts (best response: 1 CR; 4 PR; 1 PR with lymphocytosis; 1 SD). Conclusions: With up to 5.5 y of follow-up, FD Ibr+Ven continues to provide clinically meaningful PFS in pts with high-risk genomic features, as well as in the overall population. Ibr-based retreatment provides promising responses in pts needing subsequent therapy after the all-oral FD regimen of Ibr+Ven. Clinical trial information: NCT02910583 . [Table: see text]
Real-world outcomes of lisocabtagene maraleucel (liso-cel) in patients (pt) with Richter transformation (RT) from the Center for International Blood and Marrow Transplant Research (CIBMTR).
Authors: Winter Allison Marie , Bharadwaj Sushma , Herrera Alex Francisco , Iragavarapu Chaitanya , Mirza Sayeef , Palomba Maria Lia , Patel Sagar S. , Gharibo Mecide Meric , Bernasconi David , Krimmel Tracy , Liu Fei Fei , Roy Debasmita , Pasquini Marcelo C. 
Published: June 2024

7010 Background: Pts with RT have poor prognosis and no standard treatment options with median OS of 3–12 mo (Eyre TA. Hematology Am Soc Hematol Educ Program 2023), indicating an unmet need. We report the largest cohort of real-world pts with RT treated with commercial liso-cel, an autologous, CD19-directed, 4-1BB CAR T cell product. Methods: This analysis included US pts with RT from the CIBMTR who received commercial liso-cel between 02/2021 and 02/2023. Primary outcomes included ORR, CR rate, duration of response (DOR), PFS, OS, and safety (including cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] based on Lee 2018 criteria, and prolonged cytopenia defined as grade [gr] 4 thrombocytopenia and/or neutropenia persistent at 30 d after infusion). Results: At data cutoff (08/04/2023), 30 pts with RT were included. Demographics and baseline characteristics at liso-cel infusion are shown in the Table; additional data regarding the pts’ indolent disease and treatment history will be provided in the presentation. Median time from leukapheresis to liso-cel infusion was 35 d (range, 28–63). At median follow-up of 12.3 mo, ORR was 76% among evaluable pts (n = 29) with 66% in CR. Median time to first response was 1.1 mo (range, 0–3.1). Median DOR was not reached (NR); 12-mo DOR rate was 77% (95% CI, 49.5–91). Median PFS (n = 29) and median OS (n = 30) were NR; estimated 12-mo PFS was 54% (95% CI, 33–72) and 12-mo OS was 67% (95% CI, 44–83). Overall, 70% of pts had CRS (gr 3, 0; gr 4, 3%; gr 5, 3% [this pt also had hemophagocytic lymphohistiocytosis]); most common CRS treatments were corticosteroids and tocilizumab (23%) and tocilizumab (20%). ICANS was seen in 47% of pts (gr 3, 17%; gr 4, 10%; gr 5, 0) and most commonly treated with corticosteroids (23%), antiepileptics and corticosteroids (7%), and antiepileptics (7%). Prolonged cytopenia occurred in 17% of pts. One pt had a second primary malignancy (gastrointestinal). Eight (27%) pts died, including 7 because of progression. Conclusions: Pts with RT have poor prognosis with a high unmet need. Here, we show that liso-cel provided meaningful clinical benefit with low incidences of gr ≥ 3 CRS and ICANS observed. The high CR rate is promising in this difficult-to-treat population, and longer follow-up in a larger cohort is needed. [Table: see text]
Efficacy and safety of perioperative, neoadjuvant or adjuvant immunotherapy alone or in combination chemotherapy in early-stage non-small cell lung cancer: A systematic review and meta-analysis of randomized clinical trials.
Authors: Liu Hongbing , Meng Yunchang 
Published: June 2024

8025 Background: Adjuvant (AD), neoadjuvant(NE), or perioperative(PE) immunotherapy in early-stage non-small cell lung cancer (eNSCLC) has been validated in multiple clinical trials in recent years. However, the comparations of efficacy and safety among three treatment modalities remain unclear. Methods: The PubMed, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs) of immune checkpoint inhibitors (ICI) plus chemotherapy (CT) for eNSCLC. We calculated hazard ratios (HRs) or advantage ratios (ORs) for binary endpoints with 95% confidence intervals (CIs). Network meta-analysis was performed using a Bayesian framework to indirectly compare the three treatment modalities. Results: A total of 11 RCTs (2 NE, 6 PE, and 3 AD) including 6951 NSCLC patients were included. Among the three treatment modalities, indirect comparisons revealed that efficacy differed between PE and AD immunotherapy was only observed in the EFS/DFS (HR=0.68, 95%CI: 0.49-0.89). Compared with the control group, NE/PE immunotherapies significantly improved pathologic complete response (pCR) (OR=7.56, 95%CI: 5.24-10.92), major pathologic response(MPR) (OR=5.46, 95%CI: 3.97-7.51), EFS(HR=0.58, 95% CI: 0.50-0.67), and AD immunotherapy significantly improved DFS (HR=0.83, 95% CI: 0.73-0.94). No significant OS difference was observed in NE and AD setting (HR=0.62, 95% CI: 0.36-1.05; HR=0.90, 95% CI: 0.76-1.06, respectively), and only PE immunotherapy showed OS benefits(HR=0.67, 95%CI: 0.54-0.84). In addition, EFS was significantly improved in the PE treatment subgroup regardless of stage, pathologic response, histology, PD-L1 expression, and gender (Table), but no significant benefit in the EGFRm NSCLC subgroup(HR=0.54, 95% CI: 0.21-1.43). AD (OR 1.52, 95% CI: 1.01-2.30) and PE (OR 1.29, 95% CI: 1.08-1.54) immunotherapies were significantly associated with higher grade ≥3 adverse events (AEs) compared with controls. Rash was the most common grade ≥3 irAEs. Conclusions: PE immunotherapy seems to be more effective than NE and AD immunotherapy in three treatment modes. NE and PE immunotherapy significantly improved pCR, MPR, EFS, and AD immunotherapy significantly improved DFS in eNSCLC patients in comparison with the control group, but only PE immunotherapy significantly improved OS. [Table: see text]
Implications of EGFR expression in MAPK dependency and adaptive immunity status of EGFR-mutated lung adenocarcinoma.
Authors: Torasawa Masahiro , Yoshida Tatsuya , Shiraishi Kouya , Yagishita Shigehiro , Uehara Yuji , Miyakoshi Jun , Higashiyama Ryoko Inaba , Mochizuki Akifumi , Matsumoto Yuji , Shinno Yuki , Okuma Yusuke , Goto Yasushi , Horinouchi Hidehito , Hamamoto Ryuji , Yamamoto Noboru , Watanabe Shun-ichi , Yatabe Yasushi , Takahashi Kazuhisa , Kohno Takashi , Ohe Yuichiro 
Published: June 2024

8028 Background: EGFR expression (EGFR-exp) varies among patients (pts) with EGFR-mutated (m EGFR) NSCLC. It remains unknown how EGFR-exp status influences tumor and clinical characteristics in m EGFR NSCLC. Methods: Whole-exome and RNA sequencing were performed of pts with resectable early-stage (ES) and advanced-stage (AS) lung adenocarcinoma (LUAD) and EGFRmutations. EGFR-exp was classified into low or high groups based on median transcripts per million. We retrospectively examined the association between EGFR-exp, mutation status, copy number variations, EGFR clonality, and clinical outcomes. Additionally, we assessed EGFR signaling by evaluating the MAPK activation score, derived from the transcript levels of 10 MAPK target genes. Gene set enrichment analysis was used to compare transcriptional profiles, and immune cell (IC) infiltration was estimated through RNA deconvolution. Results: This study involved 450 and 45 pts in the ES and AS cohorts, respectively. In the AS cohort, all pts received osimertinib (Osi) as first-line treatment. The EGFR-exp low group exhibited a lower incidence of TP53 co-mutation and EGFR amplification, more subclonal EGFRmutations, and lower MAPK activation scores than the EGFR-exp high group (Table). Additionally, the EGFR-exp low group had significantly up-regulated adaptive immune responses pathway (q < 0.0001) and increased IC infiltration in the tumor microenvironment (TME) in both cohorts. The EGFR-exp low group in the ES cohort exhibited significantly longer relapse-free survival than the EGFR-exp high group (median, 105.9 vs. 37.1 months; hazard ratio, 0.6; p < 0.0001), and low EGFR-exp was a significant favorable factor for postoperative relapse (odds ratio [OR], 0.6; p = 0.04) in multivariate analysis. In the AS cohort, the EGFR-exp low group had a higher proportion of Osi non-responders than the EGFR-exp high group (34.8% vs 4.5%, respectively; p = 0.02), and low EGFR-exp was a significant risk factor for primary Osi resistance (OR, 29.1; p = 0.04) on multivariate analysis. Conclusions: Pts with low EGFR-exp in m EGFR LUAD demonstrated less activation of MAPK signaling, along with enhanced adaptive immunity and increased IC infiltration in the TME. These pts are less likely to experience postoperative relapse; however, they showed suboptimal benefit with Osi in AS setting. The EGFR-exp status can be valuable in decision making for adjuvant Osi and perioperative immunotherapy in pts with resectable m EGFR LUAD. [Table: see text]
Pre- and post-operative lung cancer recurrence prediction following curative surgery: A retrospective study using European radiomics and clinical data.
Authors: Valter Ann , Kordemets Tanel , Gasimova Aydan , Waterfield Price Noah , Freitag Lutz , Vachani Anil , Carbone David Paul , Oselin Kersti 
Published: June 2024

8066 Background: Accurately estimating the risk of lung cancer recurrence is vital for making informed treatment choices, both before surgery, such as the prescription of neo-adjuvant/peri-operative therapies and the extent of lung resection, and after surgery, such as the prescription of adjuvant therapies and planning follow-up strategies. In this study, we build on previous work demonstrating the predictive power of pre-operative patient demographic and imaging features and develop a machine-learning model using a combination of clinical and tumour radiomic features in the pre- and post-operative setting. Methods: We collected a dataset of 323 clinical stage I-IIIA lung cancer patients who underwent surgical treatment for lung cancer, of which 94 had lung cancer recurrence. This includes retrospectively collected CT images and associated patient demographic and diagnostic data from North Estonia Medical Centre (NEMC). The models were trained to predict the likelihood of recurrence on a diverse set of features, including radiomic features extracted from CT images and relevant clinical variables. Post-operative clinical factors such as pathological staging and tumor histology were only included in the post-operative model. An 8-fold cross-validation strategy was used, where, in each fold, 6 (of the 8 equally sized) subsets were used for training, one for model tuning, and one for validation. As a baseline, we compare the pre- and post-operative models to clinical and pathological staging, respectively. Performance was evaluated using the Area-Under-the-ROC-Curve (AUC) and sensitivity (at a fixed specificity of 90%). Results: Lung cancer recurrence classification results are tabulated below for the pre-operative models. We find that the pre-operative model (AUC=74.1%, Sens=35.29%) performs significantly better than clinical staging alone (AUC=65.4%, Sens=14.71%, p=0.025), and that the post-operative model (AUC=74.4%, Sens=26.47%) performs significantly better than pathological staging alone (AUC=67.3, Sens=22.4%, p=0.045). Top predictive features for both the pre-operative and post-operative models included clinical staging, tumor shape and textural radiomics, tumor size and tumor location. The post-operative model additionally included pathological staging and tumor histology. Conclusions: Based on this retrospective analysis, we find that the model outperforms staging prediction of lung cancer recurrence in pre- and post-operative settings. With further development, these algorithms could prove a valuable tool to aid the management of lung cancer patients. [Table: see text]
Phase Ib clinical study of first-line treatment with gefitinib in combination with bevacizumab and chemotherapy in advanced non-squamous non-small cell lung cancer with EGFR mutation.
Authors: Xiong Yanjuan , Ren Xiubao , Liu Liang 
Published: June 2024

8554 Background: The safety and efficacy of combination of gefitinib with chemotherapy and bevacizumab in treatment patients with epidermal growth factor receptor (EGFR) mutations are currently unknown. This phase Ib clinical trial was designed to evaluate the safety and preliminary efficacy of a combination therapy consisting of gefitinib, bevacizumab, pemetrexed, and carboplatin in patients with advanced non-squamous non–small cell lung cancer (NSCLC) harboring EGFR mutations. Methods: Eligible patients with EGFR-mutated advanced non-squamous NSCLC were recruited and received gefitinib combination with bevacizumab plus pemetrexed and carboplatin treatment. The primary endpoints were safety and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS). Results: From June 2019 to June 2021, 20 patients were enrolled in this trial. The median follow-up was 33.8 months (95% CI, 31.0-36.6). Grade ≥3 adverse events was 65%, including neutropenia (30%), thrombocytopenia (20%), nausea (20%), skin rash (20%), bleeding (10%), and increased ALT (10%). There was no death related to toxicity occurred. The median PFS was 28 months (95% CI, 20.4-35.6). the ORR was 95% (95% CI, 75.1%-99.9%), the DCR was 100% (95% CI, 83.2%-100%), and the median DOR was 26.4 months (95% CI, 18.9-33.9). The median OS has not been reached. Conclusions: The results of this study demonstrate that the four-drug combination regimen, led by gefitinib, is well-tolerated and effective for patients with EGFR-mutated advanced non-squamous NSCLC.
Survival outcome of metastatic pulmonary sarcomatoid carcinoma in immunotherapy era: An NCDB analysis.
Authors: Liu Bolun , Jiang Changchuan , Attwood Kristopher , Perimbeti Stuthi , Chen Hongbin , Deng Lei 
Published: June 2024

8555 Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC), with historically poor outcome. Excellent response of metastatic PSC to immunotherapy was previously reported, but its outcome compared with other NSCLCs is unknown in the immunotherapy era. Methods: NCDB was queried for stage IV NSCLC diagnosed from 2016 to 2020. Patients who were treated with chemotherapy only or immunotherapy only in the first course of treatment were included. Log-rank was used for survival analysis and adjusted by cox regression for age, gender, race, academic/integrated center, insurance, and comorbidity. Results: A total of 37,617 patients were identified, including 201 PSCs and 37,416 other NSCLCs. Pleomorphic (54%) was the most common PSC subtype. There was significant interaction between the survival effect of treatment and histology (interaction p = 0.024). When treated with immunotherapy alone, no significant difference was found between PSC and other NSCLCs (median survival 11.4 vs 12.4 months, logrank p = 0.56, HR 1.02, 95% CI 0.81 – 1.30). However, when treated with chemotherapy alone, PSC remained significantly associated with worse survival (median survival 4.5 vs. 8.5 months, logrank p <0.001, HR 0.67, 95% CI 0.54 – 0.83). Among PSC subtypes, spindle/giant cell PSCs were more likely to benefit from immunotherapy alone than pleomorphic PSCs (interaction p = 0.005), when compared with chemotherapy (Spindle/giant cell subtype: HR 0.24, 95% CI 0.14 – 0.42; Pleomorphic subtype: HR 0.60, 95% CI 0.37 – 0.99). Conclusions: Compared with other NSCLCs, PSC may not be associated with worse survival when treated with immunotherapy alone as it was when treated with chemotherapy. Distinct PSC subtypes may respond differently to immunotherapy and warrants further research. [Table: see text]
Enfortumab vedotin (EV) in non-squamous and squamous non–small cell lung cancer (NSCLC) cohorts of EV-202.
Authors: Muro Kei , Feinstein Trevor , Baranda Joaquina Celebre , Bonta Ioana , Kitazono Satoru , Gersten Todd A. , Gandhi Leena , Kudo Toshihiro , Kaplan Jason , Gorla Seema Rao , Liu Shubin , Wozniak Michele , Lee Anthony , Patil Tejas 
Published: June 2024

8585 Background: EV, a Nectin-4–directed antibody–drug conjugate, is approved for use in urothelial cancer. Nectin-4 is expressed in several solid tumors, including NSCLC. EV monotherapy was evaluated in non-squamous and squamous NSCLC cohorts in EV-202 (NCT04225117). Methods: This open-label, multicohort, phase 2 trial enrolled adults with locally advanced or metastatic solid tumors and ECOG PS 0–1. For NSCLC cohorts, patients (pts) had NSCLC not amenable to curative-intent treatment (tx), 1 platinum-based and ≤2 lines of cytotoxic tx for locally advanced or metastatic NSCLC, and prior PD-1/L1 inhibitor unless contraindicated. Nectin-4 expression was not required for inclusion but was assessed retrospectively. Pts received EV 1.25 mg/kg intravenously on days 1, 8, and 15 of each 28-d cycle until discontinuation. Interim analysis (IA) was conducted for each cohort when 20 pts were response-evaluable. If the cohort-specific minimum number of responders (non-squamous: 3; squamous: 2) was not met, enrollment could be closed. Primary endpoint was confirmed objective response rate (ORR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Antitumor activity was investigator-assessed per RECIST v1.1. Results: The non-squamous cohort met the minimum number of responders at IA and continued enrollment. Of 43 pts in this cohort as of Feb 21, 2022, median age was 67 y (range, 36–82), 51% were male, and 47% had ≥3 prior lines of systemic tx. Histology at diagnosis was adenocarcinoma for 38 (88%) pts. Efficacy and overall tx-related adverse event (TRAE) data are in the table. Common TRAEs in the non-squamous cohort were maculopapular rash and peripheral sensory neuropathy (both n=16, 37%), pruritus (n=15, 35%), and alopecia (n=14, 33%). Grade ≥3 TRAEs in >1 pt were maculopapular rash (n=3, 7%) and decreased neutrophil count (n=2, 5%). Selected TRAEs of special interest were skin reactions (n=24, 56%), peripheral neuropathy (n=16, 37%), and hyperglycemia (n=3, 7%). Only 1 of 20 pts in the squamous cohort had achieved a response at IA; thus, enrollment closed. The table shows data from the primary analysis (Jul 15, 2022; N=23). Conclusions: EV showed antitumor activity in heavily pretreated non-squamous NSCLC and manageable safety consistent with the known safety profile. The IA efficacy threshold was not met in squamous NSCLC. Clinical trial information: NCT04225117 . [Table: see text]