bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tepotinib in Asian patients with advanced NSCLC with MET exon 14 (METex14) skipping.
Authors: Kato Terufumi , Yang James Chih-Hsin , Ahn Myung-Ju , Sakai Hiroshi , Morise Masahiro , Chen Yuh-Min , Han Ji-Youn , Yang Jin-Ji , Zhao Jun , Huang Jason , Berghoff Karin , Bruns Rolf , Vioix Helene , Otto Gordon , Le Xiuning , Paik Paul K. 
Published: June 2022

9120 Background: Tepotinib is a highly selective, potent MET inhibitor approved in several Asian countries for the treatment of advanced METex14 skipping NSCLC. In VISION (n=275; data cut-off: Feb 1, 2021), tepotinib had an objective response rate (ORR) of 49.1% (95% CI: 43.0, 55.2) by independent review (IRC), with a median (m) DOR of 13.8 months (9.9, 19.4) across treatment lines. Here, we report outcomes in Asian pts. Methods: Pts with advanced METex14 skipping NSCLC, detected by liquid (L+) or tissue (T+) biopsy, received tepotinib 500 mg (450 mg active moiety) QD. Primary endpoint was objective response by IRC. Efficacy was assessed in 79 Asian pts with ≥3 months’ follow-up, and safety was assessed in 88 Asian pts who received tepotinib by data cut-off (Feb 1, 2021). Only pts enrolled in Asia were assessed for HRQoL. Results: In 79 Asian pts assessed for efficacy (38% female, 42% smoking history, 34% treatment-naïve [1L] and 82% adenocarcinoma), ORR was 54.4% (42.8, 65.7), mDOR was 18.5 months (8.3, ne), mPFS was 12.1 months (6.9, ne) and mOS was 20.4 months (19.1, ne). ORR was 66.7% (46.0, 83.5) in 1L pts (n=27), and 48.1% (34.0, 62.4) in previously treated pts (n=52). Meaningful activity was observed irrespective of METex14 skipping detection method (Table). In pts analyzed for HRQoL (n=73), mean change from baseline for EORTC QLQ-C30 GHS (3.94), EQ-5D-5L VAS (0.83), and EORTC QLQ-LC13 for cough (-6.59), dyspnea (-1.26), and chest pain (-6.14) symptom scores, demonstrated stability in QoL. In 88 Asian pts analyzed for safety, the most common adverse events (AEs) were peripheral edema, increased blood creatinine, and diarrhea. 29.5% of pts had Grade ≥3 treatment-related (TR) AEs. TRAEs led to dose reductions in 29.5%, temporary interruption in 43.2%, and permanent discontinuation in 14.8% of pts. Conclusions: In VISION, tepotinib showed robust and durable clinical activity in Asian pts with METex14 skipping NSCLC. TRAEs were manageable, with few leading to treatment discontinuation. Currently, VISION has enrolled 106 Asian pts with METex14 skipping NSCLC; analysis in this population is ongoing. Clinical trial information: NCT02864992. [Table: see text]
Characterization of MET exon 14 skipping alterations (METex14) in non–small cell lung cancer (NSCLC) using whole transcriptome sequencing (WTS).
Authors: Kim So Yeon , Bohlman Stephen , Yin Jun , Cheng Haiying , Walker Phillip , Dacic Sanja , Kim Chul , Khan Hina , Liu Stephen V. , Ma Patrick C. , Nagasaka Misako , Reckamp Karen L. , Abraham Jim , Uprety Dipesh , Halmos Balazs 
Published: June 2022

9122 Background: Multiple DNA alterations in exon 14 splice sites have been identified in NSCLC and result in skipping of the juxtamembrane domain Cbl-E3 ubiquitin ligase binding region, leading to increased MET stability and oncogenesis. The effects of these alterations on transcriptome-level have not been fully characterized. We present the largest cohort study of METex14 using WTS and identify key cellular pathways associated with invasion and metastases in METex14. Methods: 17,666 NSCLC tumor samples underwent genomic profiling at Caris Life Sciences. Analyses included next generation sequencing of DNA (592 Gene Panel, NextSeq, whole exome sequencing, NovaSeq) and RNA (NovaSeq, WTS). METex14 was captured via WTS. ssGSEA analysis was used to evaluate pathway enrichment. Wilcoxon, Fisher’s exact were used for statistical significance (p without and q values with multiple comparison correction). Results: 440 patients (2.5%) with METex14 were identified. METex14 patients were of older age, female gender, and enriched in sarcomatoid histology (Table 1). The most common alterations were point mutations (51.5%) and deletions (17.3%) at donor splice sites. Splice site alterations except point mutations at splice acceptor site translated to increased mRNA expression compared to wild-type MET (WT). MET amplification translated to higher mRNA expression compared to METex14 and WT with synergistic expression when co-altered with METex14 (q<0.05). The most common co-alterations were amplifications of MDM2 (18.5% vs. 1.8% WT), HMGA2 (13.7% vs 0.9% WT), and CDK4 (10.4% vs 1.4% WT) (q < 0.05). METex14 were mutually exclusive to mutations in KRAS and EGFR. High PD-L1 (22c3) > 50% (53% vs. 27.6% WT, q<0.001) and lower TMB (4 mut/Mb vs. 7 mut/Mb WT, p<0.001) were observed with METex14 and pathways associated with skipping variants included IFNγ signaling, angiogenesis, and apical junction pathways on univariate analysis (q<0.05). Conclusions: We present the largest WTS analysis of METex14. Splicing alterations and MET co-amplification translated to higher and synergistic MET expression at transcriptome level, respectively. Association with upregulated angiogenic and apical junction pathways support preclinical observation of vascular and cytoskeletal remodeling as potential mechanisms of invasion and metastases in MET ex14 NSCLC.[Table: see text]
Impact of cancer susceptibility gene (CSG) mutations in advanced NSCLC (aNSCLC).
Authors: Klingberg Danielle , Dalrymple Janene , Zaheed Milita , Lewis Craig R. , John Tom , Lee Chee Khoon 
Published: June 2022

9131 Background: Next generation sequencing (NGS) is used widely to identify somatic oncogenic driver mutations in aNSCLC to guide treatment. Comprehensive profiling has led to identification of multiple gene mutations of unclear significance, including germline genes associated with cancer risk, termed CSG. Using data from two randomized trials comparing atezolizumab to docetaxel, we investigated the prognostic and predictive values of CSG in aNSCLC. Methods: We used publicly available data from the OAK (NCT02008227) and POPLAR (NCT01903993) trials. At baseline, plasma was analyzed for cfDNA using FoundationOne CDx NGS assay. We defined CSGs as pathogenic variants of APC, BAP1, BRCA1/2, BRIP1, CDH1, CDKN2A, CHEK2, FH, FLCN, MEN1, MET, MSH2/6, MLH1, PMS2, PALB2, PTCH1, PTEN, RAD51, RB1, SDHB, SMARCA4, STK11, TSC1/2 and VHL. Cox models with treatment covariate, CSG status (mutant [mt] vs wild-type [wt]) and their interaction was used to assess the predictive value by treatment of CSG mt for overall survival (OS) and progression free survival (PFS) using univariate and multivariate models. Similar analysis was performed for objective response rate (ORR). Results: Of 1137 patients, 853 with sufficient tumor content formed the analysis population. In total, 295 (35%) had a known/likely pathogenic CSG mt. The variant allele frequencies (vAF) of CSG mt ≥30%, 10-30%, and <10% were 8% (N=23), 25% (N=73), and 67% (N=199) respectively. Patients with CSG mt were more likely to be smokers (89% vs 81%, P=0.005), had squamous tumors (37% vs 26%, P=0.001) with higher blood-based tumor mutation burden (mean 13.8 vs 10.2 per megabase, P<0.001). CSG mt was not predictive of greater OS benefit with atezolizumab over docetaxel (Table). CSG mt was associated with 35% increase risk of death in univariable analysis (HR 1.35, 95% CI 1.15-1.59). CSG mt was associated with inferior OS in multivariable analysis adjusting for performance status, smoking status, tumor histology, age, sex and number of organ sites of metastasis (HR 1.26, 95% CI 1.07-1.48). Conclusions: Plasma CSG mt is an independent poor prognostic factor in two large aNSCLC clinical trial datasets. Majority of vAF of CSG were low, suggesting that very few were potentially germline in origin, but dedicated sequencing for confirmation will be required. If confirmed, CSG status could be used as a stratification factor in future aNSCLC trials. [Table: see text]
Effectiveness of nationwide insurance coverage for next-generation sequencing in advanced non–small cell lung cancer: A real-world data study.
Authors: Kang Dong-Won , Park Sun-Kyeong , Yu Ye Lee , Lee Dae Ho , Kang Sokbom 
Published: June 2022

9134 Background: Next-generation sequencing (NGS) has been covered by Korean national health insurance since March 2017 for patients with advanced non-small cell lung cancer (NSCLC). We explored the clinical and socioeconomic impact of NGS compared with that of a single gene test (SGT) alone. Methods: From the nationwide database, we identified patients who 1) are diagnosed with advanced NSCLC classified as a distant disease using Summary Stage between March 1, 2017, and December 31, 2018; 2) had NGS or SGT within 2 months after diagnosis of advanced NSCLC. Patients with squamous cell carcinoma were excluded. We conducted multivariate logistic regression to identify factors (e.g., age, sex, Charlson comorbidity index, insurance type, year of diagnosis, and region and type of hospital with the initial diagnosis) affecting the performance of NGS. Further, we divided the cohort into subgroups based on whether patients received treatment targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations (group A) or not (group B). We conducted 1:5 propensity score matching for each group to minimize the impact of confounding factors. The median overall survival and the adjusted hazard ratio (aHR) for death were estimated using the Kaplan-Meier method and the Cox proportional hazard model, respectively. We calculated the total medical cost, and per patient per year (PPPY) cost adjusted for the survival period. Results: Among 10,247 patients with advanced NSCLC, 768 patients were identified as group A and 1,596 as group B after matching. Old age, low household income, and rural region were factors negatively impacting on having NGS tests. In Group A, we did not find a significant difference in survival outcome between the NGS cohort and the SGT cohort (median survival 31.6 vs. 27.5 months, P =.331; aHR 0.80, P =.204). In contrast, significantly favorable survival was observed for the NGS group in Group B (median survival 14.1 vs. 9.5 months, P =.023; aHR 0.80, P =.009). Although the total medical cost was higher in the NGS group ($39,145) than the SGT group ($36,207) for Group B, the PPPY cost was lower in the NGS group ($57,502 and $63,293, respectively). Conclusions: Socioeconomic factors hampering the implementation of NGS were identified. Lowering the barrier by covering the NGS cost publicly in a specific clinical setting may have survival and cost-benefit in patients with advanced NSCLC.
Multifocal bronchial neuroendocrine tumor (bNET): A new clinical entity.
Authors: Perera Nirosha D. , Jazieh Khalid , Chen Size , Wampfler Jason A. , Reungwetwattana Thanyanan , Johnson Tucker F. , Roden Anja , Yang Ping , Wigle Dennis A. , Molina Julian R. 
Published: June 2022

9135 Background: Bronchial carcinoid (BC) is often categorized into multifocal (MBC) or solitary (SBC). MBC, excluding tumorlet and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, is considered a relatively uncommon subgroup of BC, with much of the MBC literature stemming from case reports/small series. Our study analyzes MBC among a large cohort of 569 patients with BC and argues for change to the current clinical understanding of MBC. We suggest using the term bronchial neuroendocrine tumor (bNET) to more accurately represent its cells of origin and move away from “carcinoid” (historically meaning “carcinoma-like”) and the outdated associated connotation that carcinoids all have a similar, benign clinical and biological behavior. Methods: Using the Mayo Clinic Epidemiology and Genetics of Lung Cancer Database with Institutional Review Board approval, we retrospectively reviewed 569 patients with bNET (204 males, 365 females) presenting to Mayo Clinic Rochester between 1/1997-12/2012. We used univariate and multivariate Cox regression analyses to evaluate factors affecting overall survival. Results: 80 patients (of 569, 14.1%) were diagnosed with multifocal (MbNET) and 489 with solitary (SbNET). Two-sided Fisher’s exact tests found that older age, female gender, never having smoked cigarettes, and tumorlets were associated with MbNET diagnosis. Family lung cancer history, histopathologic grading (pathology: typical vs. atypical), Ki67, and presence of syndromes (carcinoid, Cushing, and MEN1 syndromes) were similar between MbNET and SbNET groups. Most MbNET cases were stage III-IV at the time of diagnosis, while the majority of SbNET cases were stage I. 5-year OS (83%) and 5-year PFS (75%) of MbNET patients were higher than those of their SbNET counterparts (74% and 68%, respectively). Metastasis status was an independent prognostic factor of poor OS in SbNET (P<0.001) but not in MbNET (P=0.71)(Table). Conclusions: Clinical, radiologic, and histopathologic characteristics and prognostic factors differed between SbNET and MbNET. MbNET arose as a new entity often with advanced stage disease, but good prognosis, which does not follow the NSCLC TNM staging system as in the 2009 NCCN guidelines (used during this study) or the updated 2021 NCCN guidelines which continue to stage lung carcinoid similarly to NSCLC. It may be beneficial to consider multifocal lung carcinoid instead as multifocal bNET, a new clinical entity, warranting a novel staging approach that more accurately reflects prognosis.[Table: see text]
Navtemadlin (KRT-232) activity after failure of anti-PD-1/L1 therapy in patients (pts) with TP53WT Merkel cell carcinoma (MCC).
Authors: Wong Michael K.K. , Burgess Melissa Amber , Chandra Sunandana , Schadendorf Dirk , Silk Ann W. , Olszanski Anthony J. , Grob Jean-Jacques , Jang Sekwon , Grewal Jaspreet Singh , Lewis Karl D. , Fecher Leslie Anne , Rabinowits Guilherme , Lebbe Celeste , Shen Annalise , Chan Tiffanie , McGreivy Jesse S. , Rothbaum Wayne P. , Hanna Glenn J. , Kelly Ciara Marie 
Published: June 2022

9506 Background: MCC is a rare, aggressive, neuroendocrine skin cancer with a high risk of recurrence and metastases. A median survival of about 4 mo for pts with metastatic MCC who failed anti-PD-1/L1 therapy highlights an urgent need for novel therapies. In TP53WT MCC, oncoproteins from the Merkel cell polyomavirus (MCPyV) inhibit p53 tumor suppressor functions by activating murine double minute 2 (MDM2). Navtemadlin is a potent, selective, orally available MDM2 inhibitor that overcomes MDM2 dysregulation by restoring p53 activity and inducing apoptosis of TP53WT tumors. Methods: The dose-finding, phase 1b/2 KRT-232-103 study (NCT03787602) evaluated navtemadlin in adult TP53WT MCC pts who failed anti-PD-1/L1 therapy. Pts were randomly assigned to oral navtemadlin once daily in 21- or 28-day cycles: 240 mg 7 days (D) on/14D off or 5D on/23D off, 180 mg 5D on/23 D off or 7D on/21D off, or 120 mg 7D on/14D off, until disease progression or unacceptable toxicity. The primary endpoint was Recommended Phase 2 Dose (RP2D); objective response rate (ORR) was assessed per RECIST v1.1. Results: As of Nov 30, 2021, 31 pts were enrolled with median age 66 y (range, 25-82); 52% had visceral disease and 71% had received ≥2 lines of prior therapy. Baseline tumor profiling of available samples showed low tumor mutation burden, MCPyV-positivity, and nonamplified MDM2 gene in 100%, 92%, and 100% of pts, respectively. Treatment-emergent adverse events (TEAEs) were observed in 100% (68% grade 3/4) of pts. The most common Grade 3/4 TEAEs were hematologic: 32% anemia, 32% lymphopenia, and 19% thrombocytopenia. Navtemadlin doses ≤180 mg were well tolerated with fewer dose reductions and longer treatment durations; subsequently the 240 mg arms were closed to further enrollment. Evaluable pts receiving 180 mg 5D on/23D off showed a 25% confirmed ORR, a 38% unconfirmed + confirmed ORR, and a 63% disease control rate (Table); median duration of response was not reached (range, 6-16.2+ mo) and median time to treatment response was 4.1 mo (range, 1.2-7). Notably, one responder, following a prolonged partial response, achieved complete metabolic remission by PET/CT after 2 y on treatment. The 120 mg arm was closed due to a low response rate. The 180 mg dose has been selected for further evaluation. Conclusions: Navtemadlin is the first targeted agent to show promising single-agent activity in heavily pretreated MCC pts who failed anti-PD-1/L1 therapy. This study demonstrates that upregulation of the p53 pathway is a viable therapeutic strategy in MCC. Clinical trial information: NCT03787602. [Table: see text]
Characterization of patients with metastatic melanoma that relapses following complete metabolic response from anti–PD-1 therapy.
Authors: Ma Vincent T , Agrawal Yash Neeraj , Fecher Leslie Anne , Lao Christopher D. 
Published: June 2022

9530 Background: Treatment with PD-1 inhibitor-based therapy has significantly improved survival in patients with metastatic melanoma over the past decade. Many of these patients achieve complete metabolic response (CMR) by FDG-PET/CT and electively stop treatment. However, the outcomes of patients who relapse after CMR remain uncertain. In this study, we attempt to further characterize metastatic melanoma patients who relapsed following elective discontinuation of anti-PD-1 based therapy due to CMR. Methods: We performed a single-center, retrospective analysis on a cohort of patients with metastatic or unresectable melanoma from 2012 to 2021 who were treated with anti-PD-1 monotherapy (pembrolizumab or nivolumab) or combination ipilimumab/nivolumab (I/N), with or without local therapies (surgery or radiation therapy). Patients who achieved a CMR from treatment were identified. CMR was defined as no evidence of metabolically active disease on full-body 18F-FDG-PET/CT and no evidence of new intracranial metastasis on MRI brain. Multiple clinical variables and survival outcomes were assessed. Results: Among 386 advanced stage melanoma patients analyzed, 87 achieved a CMR followed by elective treatment cessation with a median anti-PD-1 therapy duration of 10.4 months. 19/87 patients had brain metastasis at baseline. 17/87 patients had disease relapse with a median time to relapse from CMR of 12.1 months. Of those 17 patients, 8 received I/N, 9 received anti-PD-1 monotherapy, and 2 required local therapies to obtain CMR. 7/17 patients were able to achieve CMR again following resumption of anti-PD-1 monotherapy (n = 6) and BRAF/MEK targeted therapy (n = 1). 10/17 patients relapsed in the brain with 7 of those patients having no history of brain metastasis at baseline. Median overall survival after relapse from CMR was 34.1 months. The most common cause of death following relapse from CMR was brain metastasis progression (n = 5). Conclusions: A small proportion of metastatic melanoma patients who achieve complete metabolic (CMR) following treatment with anti-PD-1 therapy develop disease relapse. We found that relapse in the brain is common, regardless of baseline involvement at time of therapy, and is a common cause of mortality suggesting the importance of intracranial surveillance following treatment cessation. Ongoing studies are warranted to identify clinicopathologic factors that predict relapse to better inform patients and providers who elect to stop anti-PD-1 therapy.
Progression and mortality post-immunotherapy discontinuation among patients with BRAFV600-mutant (BRAF+) metastatic melanoma.
Authors: Chandra Sunandana , Hall Evan Thomas , Ling You-Li , Tang Jackson , Shah Rohan , Truong Thach-Giao 
Published: June 2022

9531 Background: Immunotherapy (IO) is commonly used to treat BRAF+ metastatic melanoma (MM) patients in the first line (1L) setting and has demonstrated durable outcomes in clinical trials. However, most patients discontinue IO therapy for toxicity, disease progression, or other reasons. To date, no multi-center or nationwide US-based study has examined treatment patterns and outcomes for patients with BRAF+ MM post discontinuation of 1L IO. The aim of this study is to describe real-world treatment patterns and outcomes among patients who discontinued 1L IO. Methods: This retrospective cohort study used the Novartis BRAF+ meLanoma patients ObsErvational (NOBLE) database, the harmonized customized data from Flatiron and ConcertAI. Patients were ≥18 years old, had a diagnosis of BRAF+ MM, were treated with pembrolizumab, nivolumab, or ipilimumab + nivolumab on or after 9/1/2014, and then discontinued 1L therapy. Reason for discontinuation was extracted from medical records. Descriptive statistics were used to describe baseline characteristics and treatment patterns. Kaplan–Meier curves were used to analyze time to progression or death (TTPD) and time to death (TTD). Results: Of the 898 included patients (mean age: 61 years; male: 65%); 46% initiated ipilimumab + nivolumab, 24% nivolumab, and 30% pembrolizumab. The most common reasons for 1L discontinuation were toxicity (26%) and progression (25%). Medical records noted 5.3% completed therapy on discontinuation and 34.5% provided no reason of discontinuation with median duration of therapy (MDOT) of 379 and 138 days respectively. At 6 months, 34 % (n = 303) remain on IL IO. MDOT for patients who discontinued IO due to toxicity and those who discontinued due to progression were 54 and 63.5 days respectively. Patients who discontinued due to toxicity had a median time of 142 days to next treatment. TTPD was best for patients who discontinued therapy due to completion or toxicity (6-month progression rate: 13% and 20%). Patients who discontinued due to progression did especially poorly (6-month progression rate: 59%). About 33% of patients (n = 296) needed second line (2L) therapy, and the majority (80.7%) received combination BRAF+ targeted therapy. Overall, 38% and 50% of patients died post IO discontinuation for any reason at 1 and 2 years, respectively. 31% of patients had brain metastases and a greater proportion (56%) died within a 2-year period compared with those without brain metastases (56% vs 49%, p = 0.0036). Conclusions: IO, although effective, is not curative for all patients. A significant number of patients discontinue therapy due to progression. Patients with BRAF+ MM who progress early on 1L IO therapy have a high risk of death and should be considered for other therapy options, including targeted therapy.