bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of concomitant NSAID and immunotherapy on outcomes in patients with non-small cell lung cancer: Analysis of the National Veterans Health Administration Database.
Authors: Moghanaki Drew , Stokes William A. , Behera Madhusmita , Jiang Renjian , Gutman David , Giuste Felipe , Burns Abigail , Sebastian Nikhil , Ramalingam Selvi , Sukhatme Vidula , Lowe Michael C. , Ramalingam Suresh S. , Sukhatme Vikas 
Published: June 2021

9107 Background: Preclinical data suggests the efficacy of immune checkpoint inhibitors (ICI) may be enhanced with concomitant nonsteroidal anti-inflammatory (NSAID) medications. Real-world evidence to support investigating this hypothesis in prospective randomized trials are needed. Methods: A retrospective cohort study queried the VA Corporate Data Warehouse (VA-CDW) to identify patients diagnosed with NSCLC who were treated with ICI between 2010-18. Exposure to concomitant NSAID was determined whenever NSAID prescriptions were released from the VA pharmacy within 90 days of the first ICI infusion. Chi-square and ANOVA tests were used to compare baseline characteristics. The outcome of overall survival (OS) was measured from the start of ICI. Cox proportional hazard regression was used to adjust for demographic, clinical, tumor, and treatment characteristics. Results: The study cohort consisted of 3,415 patients with NSCLC treated with ICI, and 2,336 (64%) were exposed to concomitant NSAID. The median age was 69, male 97%, race: white 73%, black 21%, and 66% lived in urban areas. Most patients were initially diagnosed with stage III or IV disease (68%); tumor histology: adenocarcinoma 48% and squamous cell 38%. Comorbidity counts were 0 in 40%, 1-3 in 30%, and 4+ in 30%. Chemotherapy was delivered before ICI in 54% and concurrently with ICI in 31%. The most commonly used NSAIDs were aspirin (35%), ketorolac (11%), and ibuprofen (7%); 44% were exposed to more than one NSAID. With a median follow-up of 8 months, exposure to concomitant NSAIDs was associated with a longer OS (HR = 0.90; 0.83-0.98, p = 0.01) after adjusting for all available potential confounders on multivariable analyses. Longer OS persisted following propensity score matching (HR = 0.89; 0.82-0.97 p = 0.007). Other factors significant for OS on multivariable testing included use of chemotherapy after ICI (HR = 0.53 [0.40-0.69], p < 0.001), concurrent chemotherapy during ICI (HR = 0.68 [0.62-0.74], p < 0.001), younger age, black race, female gender, and adenocarcinoma histology. Among the various NSAIDs analyzed on the multivariable analyses, only diclofenac approached statistical significance (HR = 0.78 [0.59-1.03], p = 0.08). Limiting the comparison to patients exposed to diclofenac (n = 101) versus no NSAIDs (n = 1,298), the comparison demonstrated a similar trend for OS (HR = 0.79 [0.60-1.04], p = 0.094), although the association was attenuated after propensity-score matching (HR = 0.90 [0.63-1.29], p = 0.57). Conclusions: This retrospective cohort study of Veterans with NSCLC who were treated with ICI identified that concomitant receipt of NSAIDs is associated with longer OS.
Genomic landscape of non-small cell lung cancer (NSCLC) with methylthioadenosine phosphorylase (MTAP) deletion.
Authors: Graziano Stephen L. , Pavlick Dean C. , Sokol Ethan , Ramkissoon Shakti H. , Severson Eric Allan , Huang Richard S.P. , Mata Douglas A. , Decker Brennan , McGregor Kimberly , Danziger Natalie , Ross Jeffrey S. 
Published: June 2021

9116 Background: NSCLC remains a major cause of cancer-associated mortality despite major advancements in treatments. In addition to immune checkpoint inhibitors (ICPI), new strategies for clinically advanced NSCLC now include the development of new synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of tumor cell genomic loss of MTAP. Methods: 29,379 advanced/metastatic NSCLC cases underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 tumor cell expression was determined by DAKO 22C3 immunohistochemistry (IHC); low positive was a tumor proportion score (TPS) 1-49% and high positive was a TPS ≥50%. Results: 3,928 NSCLC exhibited MTAP homozygous loss. Cases had the following subtypes: adenocarcinoma (59%), squamous cell ca (22%), NSCLC NOS (16%), and large cell neuroendocrine, sarcomatoid, adenosquamous ca (all 1%). GA/tumor were similar when CDKN2A/B losses associated with 9p21 co-deletion with MTAP loss are excluded. Significant differences in currently targetable GA included KRAS G12C higher in MTAP-intact NSCLC (P =.0003) and EGFR short variant mutations higher in MTAP-deleted NSCLC (P <.0001). MTAP-intact NSCLC had higher frequencies of GAs in TP53 (P <.0001) and RB1 and a lower frequency of SMARCA4 (P <.0001). GAs frequencies in ERBB2, MET, ALK, ROS1 and NTRK1 were similar. Biomarkers for potential ICPI efficacy were higher in MTAP-intact including TMB ≥10mut/Mb (P =.0002) and low and high PD-L1 IHC staining (P =.01). Biomarkers potentially predictive of ICPI resistance ( STK11 and KEAP1) were similar in both groups. Conclusions: MTAP loss occurs in 13% of NSCLC, supporting the development of novel targeted therapies designed to exploit PRMT5 hyper-dependence in these tumors. MTAP loss in NSCLC is accompanied by differences in targeted and ICPI options for these patients which may impact future combination strategies. Further study of anti-PRMT5 drugs that are enabled by MTAP loss in NSCLC appears warranted.[Table: see text]
Five-year overall survival (OS) in COLUMBUS: A randomized phase 3 trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients (pts) with BRAF V600-mutant melanoma.
Authors: Dummer Reinhard , Flaherty Keith , Robert Caroline , Arance Ana Maria , de Groot Jan Willem , Garbe Claus , Gogas Helen , Gutzmer Ralf , Krajsová Ivana , Liszkay Gabriella , Loquai Carmen , Mandalà Mario , Schadendorf Dirk , Yamazaki Naoya , Pickard Michael D. , Zohren Fabian , Edwards Michelle L. , Ascierto Paolo Antonio 
Published: June 2021

9507 Background: Combined BRAF/MEK inhibitor therapy has demonstrated benefits on progression-free survival (PFS) and OS and is standard of care for the treatment of advanced BRAF V600-mutant melanoma. Here we report a 5-year update from the COLUMBUS trial. Methods: In Part 1 of COLUMBUS, 577 pts with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomized 1:1:1 to encorafenib 450 mg QD + binimetinib 45 mg BID (COMBO450), encorafenib 300 mg QD (ENCO300), or vemurafenib 960 mg BID (VEM). An updated analysis including PFS, OS, objective response rate (ORR; by blinded independent central review), and safety was conducted after minimum follow-up of 65.2 months (mo). Data are as is; study is ongoing. Results: At data cut-off (Sep 15, 2020), there were 131 (68%), 117 (60%), and 145 (76%) deaths in the COMBO450, ENCO300, and VEM treatment arms, respectively. The median OS (95% CI) and 5-year OS rate (95% CI) with COMBO450 were 33.6 (24.4–39.2) mo and 34.7% (28.0–41.5), respectively (median follow-up: 70.4 mo). The 5-year OS rate (95% CI) in COMBO450 pts who had normal lactate dehydrogenase (LDH) levels at baseline was 45.1% (36.5–53.2). Median OS and 5-year OS rates for ENCO300 and VEM, as well as for pts with normal and high LDH levels and > 3 organs involved at baseline, are shown in the table. For COMBO450, ENCO300, and VEM, the 5-year PFS rate was 22.9%, 19.3%, and 10.2%; ORR (95% CI) was 64.1% (56.8–70.8), 51.5% (44.3–58.8), and 40.8% (33.8–48.2); and the median duration of response (DOR) was 18.6, 15.5, and 12.3 mo, respectively. Safety results were consistent with the known tolerability profile of COMBO450. Additional efficacy and updated safety analyses will be presented. Following study drug discontinuation, the most common subsequent treatment in all arms was checkpoint inhibitors. Conclusions: Updated OS and DOR results with COMBO450 demonstrate continued long-term benefits in pts with BRAF V600-mutant melanoma. Clinical trial information: NCT01909453. [Table: see text]
Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets).
Authors: Long Georgina V. , Atkinson Victoria , Lo Serigne , Guminski Alexander David , Sandhu Shahneen Kaur , Brown Michael Paul , Gonzalez Maria , Scolyer Richard A. , Emmett Louise , McArthur Grant A. , Menzies Alexander M. 
Published: June 2021

9508 Background: Preliminary data from the ABC (76 pts) and CheckMate 204 (94 pts) trials showed that nivo and nivo+ipi have activity in active melanoma brain metastases, with durable responses in a subset of pts. Here, we report updated 5-yr data from all pts enrolled on the ABC trial (NCT02374242). Methods: This open-label ph2 trial enrolled 3 cohorts of pts with active melanoma brain mets naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014-Apr 2017. Pts with asymptomatic brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3Wx4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets i) that failed local therapy, ii) with neuro symptoms and/or iii) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥wk12. Key secondary endpoints were IC PFS, overall PFS, OS, & safety. Results: A total of 76 pts (med f/u 54 mo) were enrolled; median age 59y, 78% male. For cohorts A, B and C: elevated LDH 51%, 58% and 19%; V600BRAF 54%, 56% and 81%; prior BRAFi 23%, 24%, 75%. Efficacy and toxicity are shown in the table. There were no treatment-related deaths. 1/17 deaths in cohort A & 4/16 in cohort B were due to IC progression only. Conclusions: Nivo monotherapy and ipi+nivo are active in melanoma brain mets, with durable responses in the majority of patients who received ipi+nivo upfront. A study of upfront ipi+nivo+/-SRS is underway (NCT03340129). Clinical trial information: NCT02374242. [Table: see text]
Discrepancies in response and immune-related adverse events (irAE) of anti-PD-1 monotherapy between races and primary sites in patients (pts) with advanced nonacral cutaneous melanoma (NACM).
Authors: Bai Xue , Shoushtari Alexander Noor , Betof Warner Allison , Quach Henry , Cann Christopher G , Zhang Michael , Pallan Lalit , Harvey Catriona , Si Lu , Tang Bixia , Cui Chuanliang , Kim Michelle S. , Sharova Tatyana , Flaherty Keith , Long Georgina V. , Menzies Alexander M. , Sullivan Ryan J. , Boland Genevieve Marie , Johnson Douglas Buckner , Guo Jun ,   MGH Melanoma Clinical Research Team
Published: June 2021

9530 Background: Ultraviolet (UV)-induced high tumor mutation burden (TMB) of NACM is associated with response to anti-PD-1 monotherapy (aPD-1). Anatomic location of the primary lesion (reflecting UV exposure) and race (reflecting eumelanin level) may serve as surrogates for TMB and be associated with varying response and irAE patterns. Methods: Pts with advanced NACM receiving aPD-1 between 2009-2019 were retrospectively analyzed from 5 institutions in the US, Australia and China. Best response, survival (PFS and OS), and organ/system-specific irAEs were compared by race (Caucasian [C] vs non-Caucasian [NC]) and primary anatomic site. Results: Among 697 patients, 616 were C, 81 were NC. Complete response rate (CRR) was 24.8% (95%CI, 21.4-28.4) and 2.6% (95%CI, 0.3-9.1) and ORR was 54.9% (95%CI, 50.9-58.9) and 15.6% (95%CI, 8.3-25.6) in C and NC, respectively (both P<.001). Median PFS was 16.5 (95%CI, 12.0-23.1) and 5.2 (95%CI, 3.6-7.6) months, median OS was 60.5 (95%CI, 49.9-not reached [NR]) and 29.2 (95%CI, 17.9-NR) months, in C and NC, respectively (P<.001 and =.04). In multivariate analyses, C had significantly higher CRR (OR 13.4, 95%CI 3.1-57.4), ORR (OR 10.6, 95%CI 4.6-24.5), and longer PFS (HR 0.5, 95%CI 0.4-0.7) than NC. Compared to a head primary site, NACM from less UV-exposed regions had significantly lower CRR (upper trunk, OR 0.6, 95%CI 0.4-0.96; lower limb, OR 0.5, 95%CI 0.2-0.9), ORR (lower limb, OR 0.6, 95%CI 0.3-0.9) and poorer PFS (perineum/buttock, HR 2.1, 95%CI 1.2-3.5; lower limb, HR 1.6, 95%CI 1.2-2.2) and OS (perineum/buttock, HR 3.8, 95%CI 2.2-6.8; lower limb, HR 1.7, 95%CI 1.2-2.4). Overall irAE incidence was similar between C and NC but irAE subtypes varied. C had significantly higher incidence of GI (12.2%, 95%CI 9.5-15.3% vs 1.2%, 95%CI, 0.03-6.7%, P=.001), respiratory (10.3%, 95%CI 7.8-13.2% vs 0, P<.001) and grade 3/4 (15.4%, 95%CI 12.4-18.8% vs 6.2%, 95%CI 2.0-13.8%, P=.03) irAEs; and lower incidence of endocrine (13.8%, 95%CI 10.9-17.0% vs 32.1%, 95%CI 22.2-43.4%, P<.001) and liver (4.8%, 95%CI 3.2-7.1% vs 13.6%, 95%CI, 7.0-23.0%, P=.005) irAEs. IrAEs did not vary by primary NACM site. Conclusions: Race and primary site are independently correlated with distinct response and survival outcomes in pts with advanced NACM receiving aPD-1. IrAE subtypes vary by race although overall irAE incidence does not.
Survival outcomes associated with fewer combination ipilimumab/nivolumab doses in advanced-stage melanoma.
Authors: Ma Vincent T , Sun Yilun , Sitto Merna , Waninger Jessica , Fecher Leslie Anne , Green Michael , Lao Christopher D. 
Published: June 2021

9549 Background: Standard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma. While many patients receive less than 4 doses due to treatment-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and if fewer doses of I/N can achieve similar survival outcomes. Methods: We performed a single-center, retrospective analysis on a cohort of patients with metastatic or unresectable melanoma from 2012 to 2020 who were treated with standard I/N. Cox regression of progression free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response assessment after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging or physical examination. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 3 or 4 vs 1 or 2 doses of I/N adjusted by age, gender, pre-treatment LDH level, BRAF mutation status, primary melanoma site, time to initial assessment, brain metastasis, and liver metastasis. Results: 199 patients were identified and considered evaluable in our study. Median follow up was 28.8 months. Patients with CBR after 1 dose of I/N had improved PFS (HR: 0.23, 95% CI 0.14-0.39; p<0.001) and OS (HR: 0.19, 95% CI 0.10-0.38; p<0.001) compared to progressive disease (PD) [Table]. Patients with CBR (vs PD) after 2 doses of I/N also had improved PFS (HR: 0.17, 95% CI 0.11-0.26; p<0.001) and OS (HR: 0.13, 95% CI 0.07-0.23; p<0.001) [Table]. The survival risk comparing 3 or 4 vs 1 or 2 doses of I/N were HR 0.82 (95% CI 0.45-1.53; p=0.540) for PFS and HR 0.56 (95% CI 0.24-1.30; p=0.175) for OS. Conclusions: Clinical benefit response (CBR) after 1 or 2 doses of I/N may be predictive of long-term survival in advanced stage melanoma. Patients who have CBR after 1 or 2 doses of I/N may achieve a similar survival benefit with fewer doses of I/N. Longer follow up and prospective studies are warranted to validate our findings.[Table: see text]
Treatment outcomes in patients (pts) with melanoma brain metastases (MBM) treated with systemic therapy: A systematic literature review (SLR) and meta-analysis.
Authors: Tawbi Hussein Abdul-Hassan , Long Georgina V. , Meyer Nicolas , Breznen Boris , Vyas Charmy , Leung Lisa , Moshyk Andriy , Pushkarna Divya , Thakkar Pratik K. , Fazeli Mir Sohail , KOTAPATI SRIVIDYA , Schadendorf Dirk 
Published: June 2021

9561 Background: The introduction of immunotherapy and targeted therapy has revolutionized the treatment landscape for metastatic melanoma. However, clinical trial data in pts with MBM are scarce; here we summarize the available clinical evidence. Methods: An SLR was conducted by searching EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials databases through November 13, 2020. When available, Kaplan-Meier (K-M) curves for overall survival (OS) were digitized and converted to pseudo-individual pt data using the Guyot algorithm. A meta-analysis of the pooled K-M curves was performed for selected interventions, including immunotherapies and targeted therapies. Median OS was calculated either through the meta-analysis of K-M curves or as a weighted average of median OS (table). When interventions were reported in only 1 study, the value reported was used instead of the weighted average and compared qualitatively with the other results. Results for treatment modalities other than systemic agents will also be presented. Results: The SLR included 70 publications that evaluated systemic therapies in pts with MBM for qualitative evidence synthesis: 12 pertaining to 7 randomized controlled trials, 55 pertaining to 46 single-arm studies, and 3 involving nonrandomized comparative studies. The pt population was highly heterogeneous with respect to prior therapies, pt characteristics, and neurological symptoms. For the meta-analysis, a total of 25 K-M curves from 12 studies representing 6 interventions and 1043 pts were digitized. Based on the pooled K-M curves, median OS was numerically longer with nivolumab plus ipilimumab (NIVO + IPI; 28.3 mo; 95% CI, 19.7-31.9) than with the other interventions (range 5.7-11.8 mo; table). Similar OS benefit was also observed with NIVO + IPI when the weighted average of the median was used (in a long-term study, median OS was 29.2 mo) compared with the other interventions. Conclusions: Given the lack of comparative clinical trial data in pts with MBM, there remains an unmet need to determine the best approach to treat these pts. This analysis suggested a clinical advantage with NIVO + IPI compared with other systemic agents analyzed. The heterogeneity of the available data added uncertainty to our treatment assessments. Therefore, these findings warrant further research into the best approach to improve outcomes in pts with MBM.[Table: see text]
Health-related quality of life (HRQoL) in patients (pts) with locally advanced basal cell carcinoma (laBCC) treated with cemiplimab: Analysis of a phase II, open-label clinical trial.
Authors: Stratigos Alexander J. , Chen Chieh-I , Ivanescu Cristina , Lewis Karl D. , Peris Ketty , Bechter Oliver Edgar , Harnett James , Mastey Vera , Reaney Matthew , Daskalopoulou Christina , LaFontaine Patrick R. , Konidaris Gerasimos , Bury Denise , Yoo Suk Young , Mohan Kosalai Kal , Coates Ebony , Bowler Timothy Geoffrey , Fury Matthew G. , Sekulic Aleksandar 
Published: June 2021

9566 Background: Cemiplimab-rwlc is the first immunotherapy to receive approval in the US, fully for pts with laBCC and accelerated for metastatic BCC, post hedgehog inhibitors or for whom hedgehog inhibitors are not appropriate. Cemiplimab resulted in clinically meaningful anti-tumor activity in pts with laBCC who progressed on or were intolerant to hedgehog inhibitor therapy (NCT03132636). This analysis evaluated HRQoL in these pts. Methods: Adults with laBCC and ECOG performance status ≤1 (n=84) received IV cemiplimab 350 mg Q3W for up to 9 treatment cycles. At baseline (BL) and day 1 of each cycle (C), pts completed EORTC QLQ-C30 and SKINDEX-16 questionnaires that assess Global Health Status (GHS)/QoL, functioning, and BCC-related symptoms. Mixed-effects repeated measures (MMRM) models were used to estimate least squares (LS) mean (standard error [SE]) change from BL during treatment (i.e., across C2 to C9); changes ≥|10| points were considered clinically meaningful. Responder analyses were conducted in pts with non-missing data from BL to determine the proportions with clinically meaningful improvement or deterioration, or stability on QLQ-C30 and SKINDEX-16 at C2 and C9; a 10-point threshold was considered meaningful for both instruments. Results: BL scores showed moderate to high levels of functioning and low symptom burden. In MMRM models, overall changes from BL on QLQ-C30 indicated stability for GHS/QoL and all scales except for clinically meaningful worsening of fatigue (LS mean [SE] change 12.5 [3.9]; P<.05). In responder analysis, the majority of pts reported clinically meaningful improvement or stability at C2 and C9 on all QLQ-C30 functioning scales and the key symptom of pain but not fatigue (Table). On SKINDEX-16, MMRM models showed clinically meaningful improvement on the emotional subscale (LS mean [SE] change –13.2 [3.9]; P<.05) and stability on the symptom and functional subscales. Responder analysis showed clinically meaningful improvements or stability across the SKINDEX-16 subscales in approximately 80% of pts at C2, and 70–80% of pts at C9. Conclusions: In laBCC pts treated with cemiplimab, the majority reported clinically meaningful improvement or stability in GHS/QoL and functional status while maintaining a low symptom burden except for fatigue. Clinical trial information: NCT03132636. [Table: see text]