bluuebunny/crossref_metadata_2025_split huggingface dataset:
RATIONALE-307: Tislelizumab plus chemotherapy versus chemotherapy alone as first-line treatment for advanced squamous NSCLC in patients aged ≥ 65.
Authors: Wang Jie , Lu Shun , Yu Xinmin , Hu Yanping , Sun Yuping , Wang Zhijie , Zhao Jun , Yu Yan , Hu Chunhong , Yang Kunyu , Feng Guosheng , Ying Kejing , Zhuang Wu , Zhou Jianying , Wu Jingxun , Leaw Shiang Jiin , Zhang Jing , Lin Xiao , Yang Nong 
Published: June 2021

9102 Background: Tislelizumab is a humanized, monoclonal antibody with high affinity and specificity for the programmed cell death protein 1 (PD-1). It has demonstrated antitumor activity in advanced lung cancers. We conducted a Phase 3, multicenter, randomized open-label study (NCT03594747) to assess the safety and efficacy of tislelizumab plus chemotherapy in patients (pts) with advanced squamous NSCLC. As previously reported, tislelizumab (TIS) significantly improved progression free survival (PFS) and reduced the risk of progression. Here, we report results from a sub-group of pts aged ≥ 65 years. Methods: Eligible pts (aged 18-75 years) enrolled in China were treatment-naive for locally advanced or metastatic squamous NSCLC. Pts were stratified by disease stage (IIIB vs IV), and programmed death-ligand 1 (PD-L1) expression (<1% vs 1-49% vs 50% tumor cells), and randomized 1:1:1 to Arm A: TIS 200 mg + paclitaxel (P) 175 mg/m2 and carboplatin (C) area under the plasma concentration 5 (every 3 weeks [Q3W] on day 1); Arm B: TIS + nab-paclitaxel ( nab-P) 100 mg/m2 (Q3W on days 1, 8 and 15) + C (Q3W on Day 1); or Arm C: P + C (Q3W on day 1). P, nab-P and C were administered for 4 to 6 cycles. TIS was administered until loss of benefit, withdrawal of consent or start of a new anticancer therapy. In this sub-group analysis, pts aged ≥ 65 years were evaluated according to the primary endpoint (PFS) and key secondary endpoints (objective response rate and safety). Results: Overall, 127 pts aged ≥ 65 years were randomized to receive treatment. Median age of pts aged ≥ 65 was 68.0 years and 120 pts (94.5%) were male. In total, 18 (46.2%), 20 (38.5%), and 34 (94.4%) pts in Arms A, B and C, respectively, had discontinued treatment. In Arm C 22/34 pts had completed chemotherapy. The primary and secondary endpoints, PFS and ORR, were longer and higher, respectively, in Arms A and B, compared with Arm C (Table). Grade ≥ 3 treatment related adverse events (TRAEs) occurred in 33 (84.6%), 44 (84.6%) and 28 (82.4%) pts aged ≥ 65 years in Arms A, B and C, respectively, compared with 103 (85.8%), 99 (83.9%) and 94 (80.3%) pts aged ≥ 18 years enrolled in the study. The most commonly reported TRAEs in pts aged ≥ 65 years were anemia, decrease in neutrophil count, and alopecia. Conclusions: In this sub-group analysis, PFS and ORR were longer and higher, respectively, with TIS in pts aged ≥ 65 years with advanced squamous NSCLC. The safety profile of TIS in pts aged ≥ 65 years was similar to the safety profile for all aged pts aged ≥ 18 years. Clinical trial information: NCT03594747. [Table: see text]
Patterns of survival in NSCLC with de novo brain metastasis: SRS, WBRT, and no radiotherapy cohorts.
Authors: Saravia Diana , Bilani Nadeem , Elson Leah , Elimimian Elizabeth Blessing , Alley Evan W. , Naik Mihir , Nahleh Zeina A. , Arteta-Bulos Rafael 
Published: June 2021

9122 Background: Prognostic determinants in metastatic non-small cell lung cancer (mNSCLC) include numerous sociodemographic and clinical characteristics. We provide granular, real-world survival data in different cohorts of this heterogeneous population, stratifying by: age, Charlson/Deyo scoring (CDS) of comorbidity, tumor histology, and use of immunotherapy. Methods: This retrospective analysis uses the National Cancer Database (NCDB) to explore patterns of survival in patients diagnosed between 2010-2016 with mNSCLC involving the brain. Kaplan-Meier (KM) modeling was used to evaluate for differences in overall survival (OS) between 3 cohorts of patients: those undergoing 1) stereotactic radiosurgery (SRS), 2) whole-brain radiotherapy (WBRT), and 3) those not undergoing brain radiotherapy (NR) as part of the first course of treatment. As per Table, we ran 8 KM models to generate median OS (mOS) data across stratifications for age (<70 vs. ≥70), CDS (0-1 vs. 2-3), tumor histology (adenocarcinoma vs. squamous), and use of immunotherapy (yes vs. no). We provide a ranked order of these 3 cohorts by mOS (‘survival sequence’, or ‘SS’), as well as differences in mOS (‘ΔmOS’) between NR and WBRT – the two cohorts most comparable in life expectancy. Results: A total of n=38,119 patients were included in this study. Most received WBRT (n=18,052, 47.4%), n=6,562 (17.2%) received SRS, while n=13,505 (35.4%) did not receive brain radiation as part of their first course of treatment. In all subgroups, patients treated with SRS for brain metastasis had the highest mOS. Survival for those receiving WBRT was better or comparable (difference in mOS <0.5 months) to those that did not receive radiotherapy, except in patients aged ≥70 (SS: NR > WBRT; KM p-value <0.05; ΔmOS of 1.6 months), those with Charlson-Deyo comorbidity scores of 2-3 (SS: NR > WBRT; KM p-value <0.05; ΔmOS: 0.6 months), those with squamous carcinoma (SS: NR > WBRT; KM p-value <0.05; ΔmOS: 0.7 months), and those already receiving immunotherapy (SS: NR > WBRT; KM p-value <0.05; ΔmOS: 0.6 months). Conclusions: SRS for de novo brain metastases is associated with improved OS in mNSCLC. In contrast, the burden of WBRT may outweigh the survival benefit it affords in patients ≥70, and those with comorbidities. Squamous cell carcinomas may be associated with more radio-resistance than adenocarcinomas to WBRT. Finally, as previously described in melanoma, the survival benefit afforded by brain radiotherapy may be lower in patients on immunotherapy.[Table: see text]
Effects of baseline lactate dehydrogenase (LDH), interferon gamma (IFN-g) expression, and tumor mutational burden (TMB) on treatment response to first-line atezolizumab (A) + vemurafenib (V) and cobimetinib (C) in BRAFV600 mutation–positive advanced melanoma.
Authors: Robert Caroline , Lewis Karl D. , Ascierto Paolo Antonio , Munhoz Rodrigo Ramella , Liszkay Gabriella , de la Cruz-Merino Luis , Olah Judit , Queirolo Paola , Mackiewicz Jacek , Caro Ivor , Shah Kalpit , Forbes Harper , Li Haocheng , Hertig Christian , Yan Yibing , Mckenna Edward Francis , Gutzmer Ralf , McArthur Grant A. 
Published: June 2021

9523 Background: The phase 3 IMspire150 study showed that first-line A+V+C improved investigator-assessed PFS vs placebo (P)+V+C in BRAFV600E/K mutation–positive advanced melanoma (hazard ratio 0.78; P=.0249). Prior biomarker analyses showed that IFN-g or TMB > 10 mut/Mb were associated with greater PFS benefits with A+V+C (Lewis et al. J ImmunoTher Cancer 2020;8:A188-A189). We further evaluated the association of these biomarkers with outcomes. Methods: Exploratory recursive partitioning analysis (RPA) was used to model associations between PFS and age ( < 65 vs ≥65 y), Eastern Cooperative Oncology Group performance status (0 vs 1), liver metastases (yes vs no), metastatic sites (≤3 vs > 3), sum of longest tumor diameters ( < 44 mm vs ≥44 mm), baseline LDH (normal [n] vs elevated [e]), TMB ( < 10 vs ≥10 mut/Mb), PD-L1 (negative vs positive), and IFN-g (high [h; > Quartile 3; Q3] vs intermediate [ > Q1 and ≤Q3] vs low [≤Q1]). Time-to-event analyses were summarized using Kaplan-Meier estimates. Results: The RPA analysis included 208/256 (81.3%) patients (pts) from the A+V+C arm of IMspire150 for whom LDH, TMB, IFN-g, and PD-L1 data were available. RPA showed that LDH was associated with PFS. In pts treated with A+V+C and n-LDH, h-IFN-g signature was associated with longer PFS and higher rates of objective response (OR) and complete response (CR) vs low/intermediate (l/i) IFN-g (2-y PFS: 59% vs 38%; ORR: 77% vs 69%; CR: 38% vs 15%, respectively); TMB ≥10 mut/Mb was associated with more favorable outcomes in pts with e-LDH (Table). In contrast, neither IFN-g nor TMB discriminated PFS outcomes in n-LDH or e-LDH pt subgroups receiving P+V+C. Pts with e-LDH and TMB < 10 mut/Mb had poor PFS outcomes, with 2-y PFS rates of 9% and 3% and lower rates of OR (51% and 62%) and CR (5% and 9%) in the A+V+C and P+V+C arms, respectively. Similar trends were observed for duration of response (DOR), and for the subset of pts with BRAFV600E mutation–positive melanoma. A+V+C improved PFS vs P+V+C across all subgroups with the exception of e-LDH and TMB < 10. Conclusions: IFN-g and TMB discriminated PFS benefit in pts receiving A+V+C but not for those receiving P+V+C. Durable responses were observed for pts treated with A+V+C in the n-LDH + h-IFNg subgroups.[Table: see text]
Clinical characteristics of SF3B1 mutant (mut) uveal melanoma (UM) and response to immune checkpoint inhibition (ICI).
Authors: Grimes Joe , Shoushtari Alexander Noor , Orloff Marlana , Khan Shaheer , Chiuzan Cody , Hsiao Susan Jean , McDonnell Diana , Marr Brian P. , Carvajal Richard D. 
Published: June 2021

9535 Background: Metastatic UM is associated with a median overall survival (OS) < 1 year (yr) and overall response rate (RR) to ICI < 18%. SF3B1 mut UM represent a clinically unique subset of UM, distinct from BAP1 mut disease, characterized by aberrant spliceosome machinery which may result in increased neoantigen presentation, increased immunogenicity, and sensitivity to ICI. To assess these hypotheses, we performed a multicenter retrospective analysis to assess the natural history and response to ICI in patients (pts) with SF3B1 mut UM. Methods: Patients were identified from institutional databases and the AACR Project GENIE Consortium. Data collected included: baseline and recurrent disease characteristics, molecular characteristics, treatments received, treatment response, and vital status. Efficacy endpoints included investigator assessed RECIST RR and OS. Results: 58 pts with deleterious SF3B1 mutations were identified: 56 R625; 1 D781G; 1 G742D. Median age at diagnosis (dx) was 52 (range, 14-87). 50% were female. 49 pts developed distant metastases. The median time from initial dx to metastasis was 6.1 years (yrs; range, 0.9 to 26.7). Initial metastatic sites (n = 48) were: liver-only (52%); non-liver-only (29%); mixed liver and non-liver disease (19%). The most common initial metastatic sites were: liver (71%), lung (29%), soft tissue (13%), lymph node (8%), and bone (4%). The median OS for all pts from time of metastasis was 3.9 years (95% confidence interval (CI), 2.3-6.2) with OS for pts with non-liver only disease at 6.2 yrs vs those with liver-only or mixed disease at 3.4 yrs (hazard ratio = 2.12, p = 0.14). 1-year OS rate from time of metastasis was 94% (95% CI, 0.86-0.99). 34 pts received ICI for metastatic disease at which time 27% had received a prior systemic therapy (median, 0; range, 0-3) and 35% had received a prior hepatic regional therapy (median, 0; range, 0-6). 15 pts received single-agent anti-PD1; 4 received ipilimumab alone; 15 received dual ICI. 10 pts received ICI with concurrent hepatic regional tx. Best response among 33 evaluable pts were: 9% partial response; 39% stable disease; 52% progressive disease. Median OS from ICI initiation was 20.2 months (95% CI, 13.1-27.4). 1-year OS from ICI initiation was 74% (95% CI, 0.59-0.90). Conclusions: SF3B1 mut UM is characterized by later development of metastases, more common involvement of extrahepatic sites, and longer OS when compared with historical datasets of molecularly unselected UM. Although a modest RR to ICI was observed, the median OS and 1-year survival rate post-ICI are numerically superior to historical controls. Given the more indolent course of SF3B1 mut UM, stratification by SF3B1 status should be included in future clinical trials.
The risk and tropism of central nervous system metastases (CNS) in patients with stage II cutaneous melanoma.
Authors: Johannet Paul , Kim Min Jae , Call Melissa , Gulati Nicholas , Zhong Judy , Mehnert Janice M. , Osman Iman 
Published: June 2021

9551 Background: Recent data suggest that patients with stage III melanoma are at high enough risk for developing CNS metastases to consider routine surveillance neuroimaging (Journal of Clinical Oncology; PMID: 31990608). Given that a subset of stage II patients have a worse prognosis than stage III patients, we investigated the risk of developing brain metastases in stage II disease and compared it to the risk in stage III disease. Methods: We studied a cohort of prospectively enrolled melanoma patients who had protocol driven follow-up at New York University (NYU) Langone Health. We investigated both the incidence and time to development of CNS metastases, and explored whether the frequency of CNS metastases as a first isolated site of distant disease varies among the different stages. Results: The study cohort included a total of 1,102 patients (stage II: n = 619 with median follow-up 56.5 months; stage III: n = 483 with median follow-up 40.9 months). 85/619 (14%) stage II and 91/483 (19%) stage III patients developed CNS metastases (p = 0.03). The estimated 5-year cumulative incidence was 9% in stage IIA, 14% in stage IIB, and 29% in stage IIC patients (p = 0.0001). It was 10% in stage IIIA, 32% in stage IIIB, 23% in stage IIIC, and 49% in stage IIID (p = 0.0001). The CNS was the site of first metastasis for 32/154 (21%) stage II patients who developed distant disease compared to 28/214 (13%) stage III patients (p = 0.06). Conclusions: A subset of stage II patients are at an elevated risk for developing CNS metastases within 5 years of their initial diagnosis, which is comparable to that seen in stage III patients. The frequency of the CNS as a first site of metastasis in stage II melanoma suggests a propensity for brain tropism that cannot only be explained by a generalized pro-metastatic phenotype. Surveillance strategies that incorporate serial neuroimaging should be considered for these individuals.
Pyrexia-related outcomes upon application of an adapted pyrexia management algorithm in patients (pts) with BRAF V600: Mutant unresectable or metastatic melanoma treated with dabrafenib plus trametinib (DabTram) in the COMBI-i trial.
Authors: Ascierto Paolo Antonio , Robert Caroline , Nathan Paul D. , Dummer Reinhard , Tawbi Hussein Abdul-Hassan , Flaherty Keith T. , Ribas Antoni , Schadendorf Dirk , Green Steven , Sandalic Lali , Lau Mike R. , Romero Tonatiuh , Long Georgina V. 
Published: June 2021

9560 Background: First-line DabTram has shown long-term efficacy in pts with BRAF V600–mutant unresectable or metastatic melanoma in the Phase III COMBI-d and COMBI-v trials. Data from the Phase III COMBI-i trial comparing spartalizumab plus DabTram vs placebo plus DabTram (pbo-DabTram) demonstrated efficacy in the pbo-DabTram arm, consistent with historical data. Pyrexia (single preferred term [PT]) is the most common adverse event (AE) reported with DabTram (pooled COMBI-d [data cutoff: Jan 12, 2015] and COMBI-v [data cutoff: Apr 17, 2014]: any grade, 54.2%; grade ≥ 3, 5.4%; serious pyrexia AEs leading to hospitalization, 11.8%). A new pyrexia management algorithm was implemented in the COMBI-i trial to improve pyrexia-related outcomes. We report pyrexia-related outcomes in pts treated with pbo-DabTram in the control arm of COMBI-i part 3. Methods: COMBI-i (NCT02967692) part 3 is a double-blind, Phase III trial in which pts with previously untreated BRAF V600–mutant unresectable or metastatic melanoma were randomized 1:1 to receive spartalizumab (400 mg intravenously every 4 weeks) plus Dab (150 mg orally twice daily) and Tram (2 mg orally once daily) vs pbo-DabTram. In the adapted pyrexia management algorithm, both Dab and Tram are interrupted promptly at the first symptom of pyrexia or its associated prodrome (ie, chills, rigors, night sweats, or influenza-like symptoms). Treatment at the same dose level is restarted upon the improvement of symptoms if pts are symptom free for ≥ 24 hours. Pyrexia incidence rates presented are for the single PT of pyrexia. Results: At data cutoff (July 1, 2020), median follow-up was 27.2 mo for all pts enrolled in COMBI-i part 3 (N = 532). In the DabTram control arm, 52.7% (139/264) and 3.0% (8/264) of pts had any-grade and grade ≥ 3 pyrexia, respectively. Serious pyrexia AEs were reported in 6.1% (16/264), which led to hospitalization in 5.3% (14/264). Pyrexia led to dose interruption of both Dab and Tram in 39.0% (103/264), with 1.5% (4/264) permanently discontinuing both agents. Median relative dose intensity was 97.8% for Dab and 97.7% for Tram. Conclusions: Pyrexia-related outcomes, including grade ≥ 3 pyrexia (3.0% vs 5.4%) and serious pyrexia AEs leading to hospitalization (5.3% vs 11.8%), were improved in pts treated with DabTram in COMBI-i part 3 compared with historical data from COMBI-d/v. The adapted algorithm offers a simplified approach for managing pyrexia, thereby reducing the incidence of severe pyrexia while maintaining consistent efficacy with DabTram. Clinical trial information: NCT02967692.
Tumor PD-L1 expression and gene panel mutational profile as outcome predictors of PD-1-based checkpoint inhibition therapy in metastatic melanoma: A prospective multicenter DeCOG study.
Authors: Ugurel Selma , Griewank Klaus , Horn Susanne , Herbst Rudolf , Terheyden Patrick , Utikal Jochen , Pföhler Claudia , Ulrich Jens , Kreuter Alexander , Mohr Peter , Gutzmer Ralf , Meier Friedegund Elke , Dippel Edgar , Sucker Antje , Placke Jan-Malte , Hadaschik Eva , Becker Jürgen C. , Weichenthal Michael , Schadendorf Dirk ,   Dermatologic Oncology Group (DeCOG)
Published: June 2021

9568 Background: PD-1 checkpoint inhibition (CPI) has recently advanced to one of the most effective treatment strategies in melanoma. However, since a considerable proportion of patients shows upfront therapy resistance, baseline predictive biomarkers of therapy outcome are needed. Methods: This prospective multicenter study included metastatic melanoma patients whose formalin-fixed paraffin-embedded tumor tissue samples taken prior to the start of a systemic non-adjuvant therapy of any line were analyzed for PD-L1 expression on tumor cells by immunohistochemistry (clone 28-8, DAKO) and for COSMIC-annotated oncogenic mutations by 29-gene panel sequencing (MiSeq, Illumina). Clinical baseline and follow-up data were collected within the DeCOG multicenter skin cancer registry ADOREG. Results: From 09/2015 until 10/2020, 706 enrolled patients from 15 centers were evaluable for the endpoints best overall response (BOR), progression-free (PFS) and overall survival (OS). Thereof, 540 patients received PD-1-based CPI as first systemic treatment after tumor tissue analysis. 197/540 patients tested positive for PD-L1 (cut-off = 5%) in pre-treatment tumors, and revealed a favourable BOR (objective response 34.4% versus 19.1%; p < 0.0001), PFS (median 10.4 versus 4.2 months; p < 0.0001) and OS (median 45.1 versus 18.8 months; p = 0.001) compared to patients with PD-L1 negative tumors. 47/540 patients presented oncogenic mutations of three or more genes in pre-treatment tumors, and revealed a favourable BOR (objective response 46.8% versus 32.1%; p = 0.041), PFS (median 15.1 versus 6.1 months; p = 0.008) and OS (median not reached versus 25.2 months; p = 0.027) compared to patients whose tumors showed mutations in two or less genes. Multivariable Cox regression including sex, primary site, non-adjuvant systemic pre-treatment, serum LDH, and ECOG performance state demonstrated tumor PD-L1 expression and gene panel mutational profile as independent predictors of survival upon treatment with PD-1-based CPI. In contrast, in 106/706 patients treated with BRAF/MEK inhibitors as first systemic treatment after tumor tissue analysis, no association was found between tumor PD-L1 expression or gene panel mutational profile and therapy outcome. Conclusions: PD-L1 expression quantification and gene panel mutational profiling provide useful outcome predictors of PD-1-based CPI therapy in metastatic melanoma patients.
Granulomatous and sarcoid-like immune related adverse events (irAEs) in melanoma patients following CTLA4 blockade adjuvant therapy: An analysis of 1670 high-risk patients.
Authors: Noor Arish , Yassine Ibrahim , Lee Sandra J. , Othus Megan , Moon James , Kirkwood John M. , Sondak Vernon K. , Ribas Antoni , Grossmann Kenneth F. , Tarhini Ahmad A. 
Published: June 2021

9582 Background: Granulomatous and sarcoid-like lesions (GSL) affecting the skin, lungs, thoracic lymph nodes, eyes and other organs following treatment with immune checkpoint inhibitors (ICIs) have been described in sporadic reports in the literature but the true incidence is unknown. Methods: We sought to estimate the incidence of GSL in the context of prospectively conducted ECOG-ACRIN E1609 phase III adjuvant trial in high-risk resected melanoma (N=1670 patients) testing ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus high-dose interferon-α (HDI). Descriptive statistics were used to calculate the incidence. Results: Among 1670 total patients treated with ICIs or with HDI in E1609, 1034 were treated with ipilimumab and 636 with HDI. Six GSL cases were reported among 1670 total patients treated with ipilimumab or with HDI as summarized in the table along with the corresponding CTCAE grades. More cases were observed with ipi10, followed by ipi3 and HDI, respectively. Organs involved included skin and subcutaneous tissue (granuloma annulare, granulomatous dermatitis), eye (ocular sarcoidosis), lymph nodes (noncaseating granulomatous lymphadenitis), lung and mediastinal lymph nodes (sarcoidosis, granulomatous inflammation). Conclusions: The incidence of granulomatous and sarcoid-like lesions (GSL) with adjuvant ipilimumab therapy in high-risk melanoma is rare. Reported cases ranged in grade from 1-3 and appeared manageable. Since most cases are asymptomatic, it is possible that GSLs are under-recognized and therefore, under-reported. A larger analysis including patients treated with anti-PD1 antibodies is currently underway. Clinical trial information: NCT01274338. [Table: see text]