bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dacomitinib for patients with non-small cell lung cancer harboring uncommon epidermal growth factor receptor mutations: Do mutation patterns matter?
Authors: Li Hong-Shuai , Lei Siyu , Xu Haiyan , Xing Puyuan , Yan Xiang , Wang Yan 
Published: June 2023

9106 Background: Previous evidence has revealed the potential efficacy of dacomitinib in patients with advanced non-small cell lung cancer (NSCLC) carrying uncommon epidermal growth factor receptor ( EGFR) mutations, but it remains unknown whether there are differences in its efficacy for different combination patterns of these uncommon mutations. Methods: The AFANDA cohort, an ambispective cohort including 121 NSCLC patients with uncommon EGFR mutations admitted from two tertiary hospitals in China, was employed for exploration. Meanwhile, a cohort of 63 patients with common mutations was included for comparison. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed between groups. Results: A total of 133 patients with advanced or recurrent NSCLC that received dacomitinib were eligible for analysis. Baseline characteristics were balanced between subgroups. A significant difference was observed between patients with common mutations (C group, n = 63), common mutation plus uncommon mutations (C+U group, n = 24), and uncommon mutations (U group, n = 46) regarding to PFS (mPFS: 7.07, 8.17, and 11.97 months; p = 0.026). Moreover, the highest ORR and DCR of the U group were observed among subgroups, although the differences were not statistically significant (ORR, 40.4%, 40.9%, and 61.4%; p = 0.085; DCR, 78.9%, 72.7%, 90.9%; p = 0.134). Furthermore, the multivariate analysis revealed that the mutation pattern was an independent prognostic indicator of PFS ( p = 0.049), with the C+U group having the highest risk of progression (HR [hazard ratio]: 1.438, 95% CI [confidence interval]: 0.818-2.528) while the U group having the lowest one (HR: 0.666, 95% CI: 0.409-1.084). For toxicity analysis, no significant difference was observed regarding grade 3-4 AEs among subgroups (12.7%, 8.3%, 13.0%; p = 0.827). The drug resistance analysis did not reveal a significant difference concerning the secondary T790M mutation rate (26.3%, 0%, 13.3%; p = 0.331). Conclusions: Dacomitinib demonstrated different therapeutic efficacy for patients with NSCLC harboring different combination patterns of uncommon EGFR mutation, which should be considered in clinical trials' design and clinical application. [Table: see text]
Association between real-world, upfront, next-generation sequencing and overall survival (OS) in advanced non–small-cell lung cancer (aNSCLC) in the United States.
Authors: Levy Benjamin Philip , Nguyen Danny , Shih Yu-Hsuan , Gorritz Magdaliz , Cai Beilei , Caro Nydia , Yasuda Marie , Gu Yifan , Chen Chi-Chang , Pretre Vincent , Saliba Teddy Rassem 
Published: June 2023

9117 Background: Multiple biomarker testing strategies exist as the treatments of aNSCLC rapidly evolve. While upfront NGS is considered optimal, this practice has not been universally adopted. Surprisingly, the impact of NGS vs non-NGS approaches on OS is unclear, with the largest study to date demonstrating lack of benefit. We aim to identify the genomic testing strategy associated with the most optimal OS in aNSCLC using data from a large, contemporary electronic health record (EHR) database. Methods: This retrospective study used Flatiron EHR data. Patients diagnosed with aNSCLC between 11 Apr 2019 and 31 Dec 2021 who received systemic therapy were identified and followed from the date of diagnosis to 31 May 2022 or death. Testing methods reported within the patient’s chart were extracted. Methods assessed included NGS (defined as any test type with ‘NGS’ as test name) and non-NGS (defined as PCR, FISH, IHC, and other sequencing methods not containing ‘NGS’). Upfront testing was defined as tests received on or prior to the date of initiation of first-line (1L) therapy. Kaplan-Meier analyses were used to estimate and compare real-world overall survival (rwOS) by testing strategies. Among those with actionable genetic mutations, we also explored rwOS by timing of targeted therapy (TT) initiation. Results: Of a total 13,139 patients, mean age was 69, 49% female, 64% white, 33% Medicare insured, and 88% treated in community setting only. Median follow up time was 9 months. The percentage of patients with upfront NGS increased from 29% in 2019 to 66% in 2022. Median OS (mOS) was longest in patients with upfront NGS compared to those with upfront non-NGS genomic tests (p < 0.05), those with NGS after 1L (p < 0.05), and those with no NGS test ever (p < 0.05) (see table). 19% of patients with upfront NGS vs. 15% of those with upfront non-NGS received TT in 1L; 23% of patients with NGS vs. 19% of those with upfront non-NGS received TT at any line of therapy. In patients with actionable genetic mutations, mOS decreased with later initiation of TT; mOS was not reached (NR) (34.6 – NR) in patients who initiated TT in 1L, 34.7 (29.1 – NR) months in those with 2L TT, and 24.3 (20.3 – 30.1) months in those who initiated TT in 3L. Conclusions: This is the first and largest study to demonstrate that upfront NGS testing leads to better OS when compared to upfront non-NGS genomic testing, later NGS, or no-NGS in aNSCLC. In line with these results, we also found an OS benefit associated with earlier TT initiation. These results highlight the significant impact of upfront NGS testing and underscore for the need for both education and wider accessibility of NGS testing. [Table: see text]
FDA analysis of toxicity profiles of oral TKIs recently approved for non-small cell lung cancer based on receipt of prior immune checkpoint inhibitor therapy.
Authors: Liu Yufan , Duke Elizabeth , Drezner Nicole Lauren , Singh Harpreet , Kluetz Paul , Pazdur Richard , Larkins Erin A. 
Published: June 2023

9119 Background: Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 are standard front-line therapy for advanced non-small cell lung cancer (NSCLC). Molecularly targeted tyrosine kinase inhibitors (TKIs) are standard of care for subsets of oncogene-driven NSCLC. Published literature suggests the possibility of increased toxicity in patients who receive ICIs followed by EGFR or ALK TKI treatment. However, the toxicity profile in patients who receive ICIs followed by TKIs with other genomic targets has not been well described. Methods: Marketing applications for TKIs in patients with NSCLC submitted to the Office of Oncologic Diseases between Jan 2019 to Dec 2022 were reviewed. Datasets were analyzed for demographics, treatment-emergent adverse events (TEAE), and prior anti-cancer therapies for TKI-treated patients in the primary efficacy population. Drug classes for which < 5% of patients received prior ICI were excluded. Grade 3-4 TEAE, serious adverse events (SAE), discontinuation TEAE and TEAE of interest (hepatotoxicity, rash, and interstitial lung disease [ILD]) were summarized. Results: 9 applications were identified and 2 were excluded. The remaining applications involved TKIs targeting EGFR exon 20 insertion, KRAS G12C, MET exon 14 skipping, and RET fusion alterations. Analyses included 867 patients; 61% received prior ICI therapy. Patient characteristics and results of analyses are presented in the table. In our pooled analysis, the incidence of Grade 3-4 AEs, SAEs, and hepatotoxicity were slightly higher in the prior ICI group, while the incidence of discontinuation TEAE, ILD, and rash were similar between groups. Analysis for hepatotoxicity was limited to reported AEs (did not include analysis of laboratory data). Review of toxicity data across individual drug classes did not show major differences compared to the overall results. Conclusions: Our analysis of safety data for newer TKIs with varied genomic targets does not appear to show excessive toxicity in patients with NSCLC who received prior ICI compared to those who did not. In future clinical trials evaluating TKIs in this population, inclusion of patients who have received prior ICI therapy should be considered when appropriate. [Table: see text]
Phase II randomized trial of first-line pembrolizumab and vorinostat in patients with metastatic NSCLC (mNSCLC): Final results.
Authors: Saltos Andreas Nicholas , Tanvetyanon Tawee , Creelan Ben C. , Shafique Michael Rahman , Antonia Scott Joseph , Haura Eric B. , Zheng Hong , Yu Xiaoqing , Saller James Joseph , Viracacha Sebastian , Thapa Ram , Boyle Theresa A. , Chen Dung-Tsa , Beg Amer A , Gray Jhanelle Elaine 
Published: June 2023

9125 Background: Histone deacetylase inhibitors enhance tumor immunogenicity through various mechanisms including induced expression of MHC and T cell chemokines. A previous phase I trial demonstrated the combination of pembrolizumab (P) with vorinostat (V) in advanced/metastatic (m)NSCLC was well tolerated with signals of activity in ICI-pretreated pts. To further investigate the combination, we conducted a first-line, phase II trial. Methods: Pts with treatment-naïve mNSCLC and tumor PD-L1 expression ≥ 1% were eligible. Pts were randomized, open-label, 1:1 to receive P 200 mg IV q3 wk as monotherapy [Arm A] vs P 200 mg IV q3 wk plus V 400 mg PO daily [Arm B]. The primary endpoint was overall response rate (ORR). Secondary endpoints included DOR, PFS and OS. Tumor biopsies were collected both pre- and on-treatment (day 15-21) for exploratory correlative analysis including gene expression and changes in the tumor microenvironment. Results: Between 7/2017 – 2/2022, 86 pts were enrolled, with 83 pts evaluable for response (40 in Arm A and 43 in Arm B). Median age was 69 (range 44 - 87), 47% female, and ECOG PS 0/1 in 9%/91%. PD-L1 TPS was ≥50% in 20/40 (50%) of pts in Arm A, and in 23/46 (50%) of pts in Arm B. The most common TRAEs in Arm A included diarrhea (15%) and fatigue (10%). 3 pts in Arm A experienced grade ≥ 3 irAEs (including 1 each of grade 3 hepatitis, pneumonitis, and rash). The most common TRAEs in Arm B included fatigue (41%), nausea (44%), diarrhea (35%) and increased creatinine (33%). 3 pts in Arm B experienced grade ≥ 3 irAE (2 grade 3 pneumonitis and 1 grade 4 myopericarditis). In Arm B, 22/45 (49%) of pts had a dose-reduction in vorinostat, most commonly due to grade 2-3 fatigue or nausea. Efficacy results by intention-to-treat are summarized in the Table below. For evaluable patients only, ORR was 44% in Arm B (19/43) and 28% in Arm A (11/40) (p=0.18). RNA-sequencing of a subset of patients showed a significant increase in interferon-γ pathway activity in both Arms. However, between the two Arms, interferon-γ pathway activity was enhanced to greater extent in Arm B, which may have contributed the higher overall response rate. Conclusions: To our knowledge, this is the first randomized trial investigating the combination of HDAC inhibition and anti-PD1 therapy in NSCLC. Although the combination arm had a numerically higher ORR compared to P monotherapy, the result did not meet the primary endpoint for significance. While there were no new safety signals with the combination therapy, reduction or interruption in V dose occurred frequently, which may have contributed to lack of survival differences between arms. Clinical trial information: NCT02638090 . [Table: see text]
Clinical and genomic landscape of EGFR-mutant lung cancers (LCs) with squamous and adenosquamous differentiation.
Authors: Elkrief Arielle , Falcon Christina J. , Richards Allison L. , Dymun Alexandria , Paik Paul K. , Aly Rania G. , Rekhtman Natasha , Rudin Charles M. , Quintanal-Villalonga Alvaro , Yu Helena Alexandra 
Published: June 2023

9129 Background: Outcomes to first-line therapy with osimertinib in patients (pts) with EGFR-mutant (EGFR+) squamous (sq) or adenosquamous (adenosq) LC have not been well described. Pts also undergo adenocarcinoma to squamous transformation (transformed) after treatment with EGFR tyrosine kinase inhibitor (TKI). The clinical and genomic characteristics of pts with EGFR+ sq and adenosq LC are largely unknown. Methods: We clinically and genomically characterized all pts with EGFR+ LC with baseline sq or adenosq histology and transformed histology at Memorial Sloan Kettering Cancer Center. Next-generation sequencing was performed with the MSK-IMPACT. We compared clinical outcomes (time to discontinuation (TTD), overall survival (OS), and post-progression survival after osimertinib discontinuation (PPS)) among the different cohorts. Results: A total of 51 pts were identified: 14 with baseline sq/adenosq treated with first-line (1L) osimertinib; 8 transformed cases post 1L osimertinib; 13 with baseline sq/adenosq treated with early generation TKI; 3 transformed cases post early generation TKI; the remainder of pts had early-stage EGFR+LC with baseline sq/adenosq. Median age was 63, and 57% were female. Eighteen (35%) were former or current smokers. Among pts with baseline sq/adenosq histology who were treated with 1L osimertinib, median TTD was 11.1 months (95%CI 7.7, not reached (NR)), and median OS was 24.3 months (95%CI 11.1 months, NR). Compared to a non-overlapping time-matched cohort with baseline adenocarcinoma treated with 1L osimertinib (N = 55), TTD was numerically shorter in the sq/adenosq cohort (11 vs. 17 months, HR 1.8, p = 0.076), and median OS was significantly shorter (24 vs. 33 months, HR 2.64, p = 0.03). PPS was shortest in baseline sq/adenosq (5 months, HR 2.94, p = 0.023), but similar in transformed (11 months, HR 0.89, p = 0.8) compared to adeno (11 months). The sq/adenosq cohort had significantly higher proportion of L858R EGFR (48% vs 31% p < 0.001) and atypical EGFR mutations at baseline (17% vs 7.3%, p < 0.001) compared to the adenocarcinoma cohort. PIK3CA mutations were enriched at baseline in the sq/adenosq cohort. In the transformed cases, RB1 alterations were present in 13% at baseline. There was a similar distribution of type of EGFR mutations in the non-overlapping pts in the AACR GENIE EGFR+ LC cohort with sq/adenosq histology (N = 4, 50% L858R, 25% atypical). Conclusions: Pts with EGFR+ sq/adenosq LCs exhibit inferior TTD and OS with 1L osimertinib compared to adenocarcinoma controls. Sq/adenosq LCs appear to be molecularly distinct with enrichment in EGFR L858R and atypical EGFR mutations. Transcriptomic profiling of a subset of samples will be presented. Our findings highlight the need for novel therapeutic strategies among pts in this high-risk subgroup.
Artificial intelligence algorithm developed to predict immune checkpoint inhibitors efficacy in non–small-cell lung cancer.
Authors: Rakaee Mehrdad , Tafavvoghi Masoud , Adib Elio , Ricciuti Biagio , Alessi Joao Victor Machado , Cortellini Alessio , Fulgenzi Claudia A.M. , Møllersen Kajsa , Bongo Lars Ailo , Hashemi Sayed MS , Houda Ilias , Busund Lill-Tove Rasmussen , Donnem Tom , Bahce Idris , Pinato David J. James , Sholl Lynette M. , Awad Mark M. , Kwiatkowski David J. 
Published: June 2023

9132 Background: Many non-small cell lung cancer (NSCLC) patients with high PD-L1 IHC expression and/or high TMB level do not respond to immune-check point inhibitors (ICIs). Discovery of novel predictive biomarkers for ICI response in NSCLC continues to be a critical unmet medical need, given the expense, potential toxicity, and therapeutic delay due to ICI treatment without benefit. Methods: We developed a supervised deep learning algorithm (Deep-IO) to predict therapeutic response to ICIs in NSCLC patients from standard histology whole slide hematoxylin and eosin (H&E) images, which was trained based on ICI objective response rate. We utilized a convolutional neural network (CNN) implemented in Pytorch. The efficiency of the Deep-IO was evaluated through classification performance metrics and the area under the receiver operating characteristic curve (AUROC). The algorithm was trained and tested on 85218 tiles (size: 512x512 pixels) in 446 advanced stage NSCLC patients from the Dana Farber Cancer Institute (DFCI), all treated with ICI monotherapy. Results: The objective response rate, comprising complete and partial response, was 26% (n = 114) in the overall cohort. The DFCI patient cohort was randomly split into a training set (N=379, 85%) and a test set (N=67, 15%). The classifier’s predicted class (responder vs non-responder) probabilities at the tiles level were averaged for each patient. Quantitative evaluation of whole section test dataset shows that the developed model achieves the accuracy of 0.72, weighted average (WAVG) precision of 0.77, WAVG recall of 0.72 and WAVG F-score of 0.74 on classifying ICI non-responders from responders. Comparing with PD-L1 expression (TPS%) and TMB (mu/Mb), Deep-IO had superior predictive power for ICI response (AUROC=0.75) in the test set. The combined Deep-IO+PD-L1 scores resulted in a significantly greater AUROC value of 0.82 compared to single tests and a 32% improvement in specificity (0.88 vs. 0.56) compared to PD-L1 evaluation alone (Table). Conclusions: This proof-of-concept study shows that an artificial intelligence–powered H&E image classifier can predict ICI effectiveness in NSCLC. Deep-IO outperformed both established predictive biomarkers. We will assess Deep-IO in additional external NSCLC data sets for validation and confirmation. [Table: see text]
Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma: 2-year results from RELATIVITY-047.
Authors: Tawbi Hussein A. , Hodi F. Stephen , Lipson Evan J. , Schadendorf Dirk , Ascierto Paolo Antonio , Matamala Luis , Gutiérrez Erika Castillo , Rutkowski Piotr , Gogas Helen , Lao Christopher D. , Janoski De Menezes Juliana , Dalle Stéphane , Arance Ana Maria , Grob Jean-Jacques , Ratto Barbara , Rodriguez Saima , Xu Yuanfang , Dolfi Sonia , Long Georgina V. 
Published: June 2023

9502 Background: In RELATIVITY-047 (NCT03470922), NIVO + RELA demonstrated a statistically significant progression-free survival (PFS) benefit vs NIVO; there was an observed improvement in overall survival (OS) although it was not statistically significant. The combination also had a descriptively higher confirmed objective response rate (ORR) assessed by blinded independent central review (BICR) vs NIVO. Here we report updated descriptive analyses (efficacy, safety, and secondary analyses) with longer (~ 2 years) follow-up. Methods: Patients were randomized 1:1 to receive NIVO 480 mg + RELA 160 mg fixed-dose combination or NIVO 480 mg every 4 weeks, as previously described. Primary endpoint of PFS per RECIST v1.1 was assessed by BICR; secondary endpoints included OS and ORR per BICR. Exploratory analyses were performed for melanoma-specific survival (MSS; defined as death due to melanoma, with censoring of deaths due to other causes) and efficacy outcomes on subsequent systemic therapy. Results: Patients received NIVO + RELA (n = 355) or NIVO (n = 359). Median follow-up was 25.3 months in this updated analysis (minimum follow-up, 21.0 months). NIVO + RELA continued to show a benefit over NIVO for PFS, OS and ORR (Table). A similar improvement was also observed in MSS. NIVO + RELA was generally favored over NIVO across key subgroups (consistent with previous reports). Subsequent systemic therapy was received by 131 (36.9%) and 136 (37.9%) patients in the NIVO + RELA and NIVO arms, respectively. Treatment-related adverse events (TRAEs; any grade) leading to treatment discontinuation were observed in 61 (17.2%) and 31 (8.6%) patients on NIVO + RELA and NIVO, respectively. Grade 3–4 TRAEs were observed in 78 (22.0%) patients on NIVO + RELA and 43 (12.0%) patients on NIVO. In total, there were 6 treatment-related deaths (NIVO + RELA, n = 4; NIVO, n = 2); no new treatment-related deaths have been reported since the last analysis. Conclusions: With 12.3 months of additional follow-up, a consistent benefit was observed with NIVO + RELA vs NIVO for PFS, OS and ORR in the ITT population, as well as in key patient subgroups. MSS was longer with NIVO + RELA compared with NIVO. The safety profile of NIVO + RELA remained consistent with previous reports, with no new or unexpected safety signals. Efficacy outcomes on subsequent systemic therapy (by type of subsequent therapy, including PD-L1/CTLA-4) will be presented. Clinical trial information: NCT03470922 . [Table: see text]
Association of biomarkers (BMs) with efficacy of adjuvant nivolumab (NIVO) vs placebo (PBO) in patients with resected stage IIB/C melanoma (CA209-76K).
Authors: Long Georgina V. , Kirkwood John M. M. , Hoeller Christoph , Grob Jean-Jacques , Weber Jeffrey S. , Taube Janis M. , Mohr Peter , Van Akkooi Alexander Christopher Jonathan , Loquai Carmen , Dutriaux Caroline , Chiarion-Sileni Vanna , Tenney Daniel J. , Dolfi Sonia , Tang Hao , Ritchings Corey , Lobo Maurice , Campigotto Federico , Wang Wenjia , Gastman Brian , Del Vecchio Michele 
Published: June 2023

9504 Background: Adjuvant NIVO significantly prolonged recurrence-free survival (RFS) over PBO in stage IIB/C melanoma in the randomized, phase III Checkmate 76K trial (HR; 95% CI: 0.42 [0.30–0.59]). For the first time, select BMs and their association with RFS were analyzed in early-stage melanoma treated with an anti-PD-1 agent. Methods: Baseline primary tumor and serum BMs were analyzed, including interferon gamma-related gene expression signature (IFNγ-sig), TMB, BRAF mutation, % intratumoral CD8+ T cells, tumor cell PD-L1 expression, and serum CRP levels. BMs were evaluated as continuous variables (high vs low levels) and dichotomized by median or prespecified cutoffs. HRs were estimated using a Cox proportional hazards model. Results: Analysis of continuous BM levels within treatment arms showed that higher IFNγ-sig, TMB, and % CD8+ T cells, and lower CRP levels were associated with prolonged RFS with NIVO but not PBO. The same trend was observed in the dichotomized analyses. No clear association between PD-L1 expression and RFS was identified in either arm. Benefit of NIVO over PBO was seen across all BM subgroups, including by BRAFV600 mutation status. Patients with higher IFNγ-sig, TMB, and % CD8+ T cells, and lower CRP levels showed numerically greater relative benefit with NIVO, although CIs overlapped (Table). Conclusions: Higher IFNγ-sig, TMB, and % CD8+ T cells, and lower CRP levels were associated with longer RFS with NIVO treatment. No BMs assessed were prognostic for RFS in the PBO arm, in contrast to previous reports in melanoma. Prolonged RFS was seen in patients treated with NIVO over PBO across levels of BMs, and irrespective of BRAF mutational status. Composite analyses of BMs with clinical and histopathologic factors will be evaluated for their potential to optimize risk:benefit stratification for NIVO in this patient population. Clinical trial information: NCT04099251 . [Table: see text]