bluuebunny/crossref_metadata_2025 huggingface dataset:
Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic non–small cell lung cancer (mNSCLC): Treatment (tx) beyond progressive disease (PD) in platinum-pretreated patients (pts) with and without intracranial PD.
Authors: Janne Pasi A. , Ramalingam Suresh S. , Yang James Chih-Hsin , Riely Gregory J. , Bunn Veronica , Jin Shu , Zhou Caicun , Camidge D. Ross
Published: June 2022

9099

Background: Mobocertinib is a potent, irreversible, oral tyrosine kinase inhibitor selectively targeting EGFR ex20ins in NSCLC. Mobocertinib demonstrated clinical efficacy in 114 platinum-pretreated pts (PPP) with EGFR ex20ins+ mNSCLC in a phase 1/2 study. Methods: In this study (NCT02716116), pts with ECOG status 0–1 and ≥1 prior therapy line for locally advanced/metastatic EGFR ex20ins+ NSCLC received mobocertinib 160 mg QD. Pts were allowed to continue tx beyond PD at the discretion of the investigator (INV) if evidence of clinical benefit existed. We present data on continuation of mobocertinib tx beyond PD in the PPP cohort by site of first PD (brain vs extracranial). Results: At the November 1, 2020, data cutoff, among PPP (n=114; median age 60 y, 66% female, 60% Asian), 59% had ≥2 prior systemic anticancer lines; 35% had baseline brain metastases (Zhou C, et al. JAMA Oncol. 2021;7(12):e214761. doi:10.1001/jamaoncol.2021). Confirmed objective response rate (cORR) per independent review committee (IRC) was 28%; median duration of response was 17.5 mo. IRC-assessed cORR was 34% among PPP with no baseline brain metastases versus 18% among PPP with baseline brain metastases (Zhou C, et al. JAMA Oncol. 2021;7(12):e214761. doi:10.1001/jamaoncol.2021); median progression-free survival was 9.2 and 3.7 mo, respectively. Per INV assessment, 64 pts had PD. Duration of mobocertinib tx beyond PD is summarized in the Table. Among pts with first site of PD in brain per INV (n=21), 17 (81%) pts remained on mobocertinib tx beyond PD; 7 (33%) received radiotherapy to brain and remained on mobocertinib tx, of whom 3 pts remained on mobocertinib tx for ≥6 mo and 1 pt for ≥12 mo. Among pts with first site of PD outside the brain per INV (n=43), 28 (65%) pts continued tx beyond PD and 4 (9%) pts remained on mobocertinib tx for ≥6 mo. Conclusions: These results suggest that mobocertinib may have limited intracranial activity given the high frequency of first PD in brain (25%) and numerically lower IRC-assessed cORR in pts with baseline brain metastases. Per INV assessment, pts may derive ongoing systemic benefit from mobocertinib. Duration of time to next progression based on local therapy continues to be investigated. Clinical trial information: NCT02716116. [Table: see text]
Central nervous system efficacy of furmonertinib versus gefitinib in patients with non–small cell lung cancer with epidermal growth factor receptor mutations: Results from FURLONG study.
Authors: Chen Gongyan , Wang Xiang , Liu Yunpeng , Wu Lin , Hao Yanrong , Liu Chunling , Zhu Shuyang , Zhang Xiaodong , Li Yuping , Liu Jiwei , Cao Lejie , Cheng Ying , Zhao Hui , Zhang Shucai , Zang Aimin , Cui Jiuwei , Feng Jian , Liu Fei , Gu Chuan , Shi Yuankai
Published: June 2022

9101

Background: Furmonertinib (AST2818) is a third-generation epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitor (TKI) with central nervous system (CNS) penetration. Here we report the CNS response to furmonertinib versus gefitinib as first-line therapy in EGFR-mutated non-small cell lung cancer (NSCLC) patients in the FURLONG study. Methods: FURLONG was a randomized, double-blind, multi-center phase III study. Patients were randomized 1:1 to receive first-line furmonertinib 80mg/d or gefitinib 250mg/d. Brain scan was mandatory at screening. Patients with asymptomatic CNS metastases who did not require steroid treatment for 28 days or more were enrolled. A pre-planned CNS efficacy analysis was done using RECIST v1.1 in patients with measurable or non-measurable CNS lesions (cFAS) and patients with only measurable CNS lesions (cEFR). Results: Of 358 enrolled patients in the FURLONG study, 133 (37%) patients were defined as cFAS and 60 (17%) were defined as cEFR according to baseline brain scan judged by a blinded independent review committee (IRC). At the cut-off date of Sep 15, 2021, CNS progression-free survival (PFS) assessed by IRC in the cFAS population was significantly longer in the furmonertinib group than in the gefitinib group (20.8 vs 9.8 months, HR 0.40 [95% 0.23-0.71]; p = 0.0011). CNS PFS rate at 6, 12, 18 months were 91%, 77%, 63% in the furmonertinib group, and 76%, 46%, 34% in the gefitinib group. In the cEFR set, confirmed CNS objective response rate was 91% in patients with furmonertinib and 65% in patients with gefitinib (p = 0.0277), and CNS disease control rate were 100% vs 84% (p = 0.9420), respectively. The mean best percentage change in the sum of target CNS lesion size from baseline in cEFR was -61.8% in the furmonertinib group versus -38.7% in the gefitinib group (p = 0.0011). Conclusions: Furmonertinib showed CNS efficacy as first-line therapy in EGFR-mutated NSCLC patients with CNS lesions. Patients treated with furmonertinib had a reduced risk of CNS progression or death, a higher CNS ORR and a deeper CNS response compared with gefitinib. Clinical trial information: NCT03787992.
Afatinib (Afa) + bevacizumab (Bev) versus afatinib alone as first-line treatment of patients with EGFR-mutated advanced non-squamous NSCLC: Primary analysis of the multicenter, randomized, phase II study—AfaBev-CS study.
Authors: Ishikawa Nobuhisa , Ninomiya Takashi , Kozuki Toshiyuki , Kuyama Shoichi , Inoue Koji , Yokoyama Toshihide , Kanaji Nobuhiro , Yasugi Masayuki , Shibayama Takuo , Aoe Keisuke , Ochi Nobuaki , Fujitaka Kazunori , Kodani Masahiro , Ueda Yutaka , Watanabe Kazuhiko , Bessho Akihiro , Sugimoto Keisuke , Oze Isao , Kiura Katsuyuki
Published: June 2022

9112

Background: Adding Bev to erlotinib prolonged PFS in NEJ026 and CTONG1509 trials, but limited data are available adding Bev to a second-generation EGFR-tyrosine kinase inhibitor. AfaBev-CS is a Japanese no-profit, randomized, open-label, multicenter phase II trial of Afa plus Bev vs Afa alone as first-line treatment for EGFR-mutated advanced NSCLC. Methods: This study enrolled untreated pts of advanced non-squamous NSCLC harboring EGFR sensitizing mutation (Del19 or L858R) and without symptomatic brain metastases. 100 eligible pts were randomized in a 1:1 ratio to receive either Afa (30 mg, daily) plus Bev (15 mg/kg, every 3 weeks) (AfaBev arm) or Afa (40 mg, daily) monotherapy (Afa arm), and stratified according to stage, EGFR mutation status and institution. The primary endpoint was PFS and the secondary endpoints were OS, tumor response and time to treatment failure. The sample size was set in terms of feasibility. The power is greater than 50% under the assumptions of a median PFS of 12 months for the Afa arm and HR of 0.6 for the AfaBev arm, with an accrual of 2.5 years and a minimum planned follow-up period of 2 years with the type 1 error of 0.05 (two-sided). Results: Between August 2017 and September 2019, 100 pts were enrolled (each arm, 50 pts). At a median follow-up of 31.3 months for all randomized pts, total 69 events occurred. Median PFS was 16.3 months for AfaBev arm and 16.1 months for Afa arm, with a hazard ratio (HR) of 0.865 (95%CI, 0.539 – 1.388; loglank p = 0.5476). In subgroup analysis, pts < 70 years old (HR 0.347) and pts with brain metastasis (HR 0.353) showed better trend of PFS in AfaBev arm. On the other hand, pts ≥ 70 years old (HR 1.738) and pts without brain metastasis (HR 1.196) did not show better trend in AfaBev arm. In terms of OS, result was immature because number of events was still small. Objective response rate was 77.6% in AfaBev arm and 72.0% in Afa arm. Severe adverse events were observed in 11 pts for each arm. Grade 3 or more diarrhea, hypertension, rash acneiform, paronychia and stomatitis were frequently observed in AfaBev arm. Pneumonitis was not observed for AfaBev arm and observed in 3 (6.0%) for Afa arm, and grade 3 in one patient. Conclusions: This study failed to show the efficacy of AfaBev arm for improving PFS in untreated pts with EGFR mutated non-squamous NSCLC. In pts < 70 years old, Afa plus Bev might be promising. Clinical trial information: jRCTs061180006.
Updated study results of pelcitoclax (APG-1252) in combination with osimertinib in patients (pts) with EGFR-mutant non–small cell lung cancer (NSCLC).
Authors: Zhang Li , Zhao Hongyun , Zhao Yanqiu , Cheng Ying , Cui Jiuwei , Ma Yuxiang , Yang Chen , Zhang Jie , Xu Liang , Yu Juan , Men Lichuang , LIANG ZHIYAN , Yang Dajun , Zhai Yifan
Published: June 2022

9116

Background: Investigational agent pelcitoclax is a dual BCL-2/BCL-xL inhibitor, which enhanced antitumor effects of osimertinib in preclinical models. A report presented at International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer demonstrated that the combination of pelcitoclax and osimertinib at the recommended phase 2 dose (RP2D) was safe, and preliminary efficacy was observed in some patients whose disease failed prior osimertinib or other third-generation EGFR-TKI treatments. Here, we further provide safety and efficacy results of this combination therapy. Methods: After RP2D was determined to be pelcitoclax 160 mg per week plus osimertinib 80 mg QD, pts were enrolled into 3 expansion cohorts of 20 pts each: Cohort 1 (EC-1) included those with disease resistant to third-generation EGFR-TKIs; Cohort 2 (EC-2) included those with osimertinib-naïve, EGFR-sensitive or T790M-positive mutations; and Cohort 3 (EC-3) included those with the EGFR exon 20 insertion mutation. Results: At the data cutoff date of January 6, 2022, 61 pts (median age, 56 years [69% female]) had been treated with pelcitoclax plus osimertinib. Among them, 13 were in dose escalation cohorts, 20 in EC-1, 20 in EC-2, and 8 in EC-3. Sixteen pts in EC-2 were EGFR-TKI naïve, and 4 were T790M positive with prior TKI treatment. All pts in EC-2 experienced treatment-related adverse events (TRAEs) but only 4 (20%) had grade ≥ 3. Common TRAEs included increased aspartate aminotransferase (90%) and alanine aminotransferase (85%) levels, reduced platelets (40%), diarrhea (40%), and increased lipase (35%). Among 20 evaluable pts, 17 PRs (85%) were observed and 16 (80%) confirmed. The median (range) time to response was 1.4 (1.2-7.0) months, and the median duration of response (DOR) was not reached. The DOR rate at 9 months after first response was 71.4% (95% CI 25.8-92.0). Seven pts had brain metastases at baseline in EC-2; 2 CRs and 3 PRs were observed intracranially. Conclusions: Osimertinib in combination with targeted therapies has been of clinical interest to improve the outcomes of patients with EGFR-mutant NSCLC. Pelcitoclax plus osimertinib was well tolerated and showed comparable efficacy in TKI-naïve pts. Further randomized control trials are warranted to elucidate the role of pelcitoclax when combined with osimertinib. Clinical trial information: NCT04001777.
Analysis of MET exon 14skippingmutations in non–small cell lung cancer (NSCLC) by histology and specific mutation.
Authors: Marks Jennifer Aline , Yin Jun , Halmos Balazs , Bazhenova Lyudmila , Ramalingam Suresh S. , Marmarelis Melina Elpi , Xiu Joanne , Walker Phillip , Oberley Matthew James , Ma Patrick C. , Liu Stephen V.
Published: June 2022

9119

Background: MET exon 14 skipping mutations (METex14) join a growing list of viable therapeutic targets in advanced NSCLC. Several unique features distinguish METex14 from other established targets. METex14 has been characterized as a tumor-agnostic genomic alteration, though most frequently reported in lung adenocarcinoma. However, METex14 represents a family of mutations (mt), not a single alteration, and there is notable heterogeneity in histology. The degree and significance of heterogeneity within METex14 have not been well characterized. Methods: NSCLC tissue samples were analyzed with DNA-based next-generation sequencing (NGS; 592 genes, NextSeq) or whole-exome sequencing (NovaSeq), RNA-based whole transcriptome sequencing (WTS, NovaSeq), and immunohistochemistry (IHC) at Caris Life Sciences (Phoenix, AZ). PD-L1 expression utilized the 22C3 clone (Dako); TMB-high was defined as ≥ 10 mt/Mb. Wilcoxon or Fisher’s exact were used to determine statistical significance (p without and q with multi comparison correction). Immune cell fraction (QuanTiseq) and pathway analysis (ssGSEA) were informed by WTS analysis. Results: A total of 440 METex14 cases were identified: 49 (11.1%) with squamous histology, 381 (86.6%) with non-squamous histology, and 10 (0.2%) with adenosquamous histology. A total of 147 distinct METex14 mutations were detected. The most common METex14 mutations were D1028H (8.4%), D1028N (7.0%), c.3082+2T > C (5.7%), D1028Y (5.2%), and c.3082+1G > A (4.5%). Co-mutations in TP53 were common (43.9%) but varied by specific METex14 mutation; TP53 co-mutations were observed in 53.9% of c.3082+3A > T but only 21.1% of c.3082+1G > T. Among all METex14 cases, 8.6% were TMB-high, but this varied by specific mutation with a median TMB of 2 mt/Mb in MET c.3082+2T > A and a median of 7 mt/Mb in MET c.3082+1G > C (q < 0.05). PD-L1 expression ≥ 1% was present in 82.2% of METex14 samples but also varied by specific METex14 mutation with a median PD-L1 tumor proportion score (TPS) of 97.5% in MET c.3082+1G > C and a median TPS of 0% in MET c.3082+3A > G (q < 0.05). Co-mutations varied by histology: in squamous METex14, 90.4% had TP53 mt (p < 0.001), 17.9% had KMT2D mt (p < 0.05), and 10.7% had PIK3CA mt (p < 0.05), while in non-squamous METex14, 60.7% had TP53 mt, 2.7% had KMT2D mt, and 4.3% had PIK3CA mt. Survival was numerically shorter in squamous METex14 NSCLC compared to non-squamous (HR 1.22, p = 0.47, mOS 336 vs.1106 days). Conclusions: There is significant heterogeneity within METex14 NSCLC with differences in co-mutations, TMB, and PD-L1 expression noted among different METex14 mutations. While METex14 is detected in both squamous and non-squamous NSCLC, there are differences in enrichment of oncogenic pathways. The clinical impact of these differences warrants further investigation.
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.
Real-world evaluation of the association between baseline metastatic patterns and clinical outcomes among patients with BRAF-positive metastatic melanoma.
Authors: Eroglu Zeynep , Chandra Sunandana , Buchbinder Elizabeth Iannotti , Ling You-Li , Tang Jackson , Shah Rohan , Truong Thach-Giao
Published: June 2022

9532

Background: While immunotherapy (IO) and BRAF-targeted therapy (TT) have benefit in BRAFV600 mutant (BRAF+) metastatic melanoma (MM), there is a paucity of real-world data on the impact of systemic therapy choice on outcomes based on key characteristics such as site and number of baseline metastases. Patients with >1 baseline site and certain sites of metastases are also underrepresented or excluded in clinical trials. The aim of this study was to evaluate the association between these characteristics and survival among BRAF+ MM patients. Methods: This was a retrospective cohort study using the Novartis BRAF+ meLanoma patients ObsErvational (NOBLE) dataset – harmonized customized data from Flatiron and ConcertAI. It included patients ≥18 years, who received treatment with a first-line (1L) IO (anti-PD-1 mono or combination therapy ipilimumab + nivolumab) or TT (any BRAF/MEK-inhibitors) after 1/1/2014. Progression free survival (PFS) and overall survival (OS) for IO and TT were analyzed according to number (1, 2, 3+ sites) and location (brain, lung, liver, bone) of baseline metastasis. Treatment sequence from 1L to 2L (i.e. IO/TT vs TT/IO) were also compared for PFS and OS outcomes. Results: A total of 1,961 patients were included, with 620 patients (32%) on IO monotherapy, 501 patients (26%) on IO combo therapy, and 840 patients (43%) on TT in the 1L. When adjusted for sex, age, ECOG, and Charlson Comorbidity Index, there was no difference in PFS or OS between 1L IO mono, IO combo and TT therapies in patients who had 1, 2, or 3+ baseline metastases. For patients who had either baseline brain, liver, lung, or bone metastasis, there was no difference in PFS and OS between IO mono, IO combo, and TT combo therapies. Of the 521 patients included in the sequencing analysis (only patients who received 2L therapy), 239 patients (46%) had 1L IO/2L TT. There was no difference in PFS or OS between treatment sequences for patients with any number or location of baseline metastasis. Conclusions: In this real-world retrospective cohort study, there is no difference in survival between 1L TT and IO for BRAF+ MM patients. Outcomes are comparable regardless of number and location of metastases, including brain metastasis. Whether switching from 1L TT to IO before progression may account for differences compared to trial data will be explored further.[Table: see text]
The prognostic impact of immune-related adverse events in real-world patients with metastatic melanoma treated with single-agent and combination immune checkpoint blockade.
Authors: Watson Alexander , Goutam Siddhartha , Stukalin Igor , Ewanchuk Benjamin , Sander Michael , Meyers Daniel E. , Pabani Aliyah , Cheung Winson Y. , Heng Daniel Yick Chin , Cheng Tina , Monzon Jose Gerard , Navani Vishal
Published: June 2022

9542

Background: Immune checkpoint blockade (ICB) has revolutionized the treatment of metastatic melanoma (MM). Immune-related Adverse Events (irAEs) associated with ICB have been shown to correlate positively with survival outcomes across solid tumours. In MM, conclusions on the impact of irAE severity have been conflicting, and combination ICB therapy experience is limited to smaller cohorts. We sought to clarify these relationships using the Alberta Immunotherapy Database (AID). Methods: The AID provides a multi-centre, province-wide observational cohort comprising consecutive patients treated with ICB. We included adult patients with MM, treated with ICB (single agent nivolumab or pembrolizumab, or combination ipilimumab and nivolumab) at any line of therapy, agnostic to site of origin, from August 2013 to May 2020, with analysis in December 2021. The primary endpoint of interest was the identification of a relationship between development of irAEs and subsequent overall survival (OS, defined from time of ICB initiation). To minimize immortal time bias from poor prognosis patients who may have died prior to the development of irAEs, patients who died before 12 weeks were excluded from OS and time-to-next-treatment (TTNT) analysis. Adjusted Cox regression analyses were performed to determine the association of variables with OS. Results: Of 492 MM patients receiving ICB, 124 received combination ICB, 198 developed an irAE and 67 required hospitalization for an irAE. irAEs were more common in patients < 50 years old (p = 0.02), with ECOG 0 (p < 0.001) and normal albumin (p = 0.002). Median time to irAE development (2.6 months) and frequency of individual irAEs were consistent with the published literature. In the overall population, patients who experienced an irAE had longer median OS (56.3 vs 18.5mo, p < 0.0001), and TTNT (49.6 vs 12.9mo, p < 0.0001). This remained consistent in combination ICB-treated patients (median OS 56.3 vs 19mo, p < 0.0001). Patients hospitalized for an irAE had improved OS and TTNT over patients requiring only outpatient treatment (median OS NR vs 27.9mo, p = 0.0039), while ICB re-challenge after an irAE also improved OS (56.3 vs 31.5mo, p = 0.0093). Development of an irAE retained independent association with OS after adjusted multivariable regression (HR 0.376, p < 0.001). Conclusions: These data support the association of irAEs and improved survival outcomes in MM, including those patients treated with combination ICB. Among patients with irAE, hospitalization for irAE, and ICB re-challenge post-irAE, were further associated with improved outcomes.
Metabolic complete responses (mCR) in patients with metastatic uveal melanoma (mUM) treated with image-guided injection (IGI) of PV-10.
Authors: McVay Krysta , Sheth Rahul , Murthy Ravi , Gombos Dan S. , Carter Brett W. , Bhosale Priya , Tahon Nourel hoda , Balmes Gener C , Coz Ysabell M , Washington Edwina , Rodrigues Dominic , Wachter Eric Andrew , Patel Sapna Pradyuman
Published: June 2022

9543

Background: Traditional CT imaging can underestimate the degree of anti-cancer treatment effect due to reliance on morphological changes of visualized tumors. In contrast, PET imaging offers information on metabolic activity using a positron emitting radiolabeled agent (e.g. FDG) but is less sensitive to changes in tumor size. FDG-PET images acquired, co-registered, and superimposed on CT images (PET-CT) allow spatial detection of anti-cancer activity. Moreoever, FDG-PET-CT can provide information regarding anti-tumor immune responses in patients receiving immunotherapy. Rose bengal (PV-10) is a small molecule autolytic immunotherapy in development for metastatic disease. When administered by intralesional injection, PV-10 can produce immunogenic cell death and a T-cell mediated immune response against treatment-refractory and immunologically-cold tumors. Herein, we report the FDG-PET-CT imaging responses of 7 metastatic uveal melanoma (mUM) patients who received percutaneous image-guided injection (IGI) of PV-10 into hepatic tumors. Methods: The Phase 1 study is evaluating safety, tolerability, and efficacy of intralesional PV-10 in hepatic tumors. PV-10 is administered percutaneously via IGI into designated tumors ≤4.9 cm in diameter. Response is assessed at Day 28, then every 3 months, using CT/MRI or PET-CT. Patients with multiple tumors may receive further IGI of PV-10 after Day 28. Results: To date, 25 mUM patients with liver metastases have been treated; 16 patients received standard of care immune checkpoint inhibitor (ICI) during or post PV-10 treatment. Seven subjects had FDG-PET-CT imaging during the study (baseline 1, follow-up 6). Two follow-up FDG-PET-CTs were performed 1 and 3 years after PV-10 injection with intervening ICI, and another was 1.5 years after PV-10, without any follow-on treatment. Four patients experienced mCR in all metastatic sites, including extrahepatic metastasis. Conclusions: FDG-PET-CT shows that PV-10 is capable of inducing mCR in injected (adscopal) and non-injected (abscopal) lesions. This pattern of response is suggestive of immunogenic cell death in mUM patients with liver metastases. Clinical trial information: NCT00986661.
Better (a little) late than never: The impact of steroidal treatment initiation timing on the outcome of patients with melanoma treated with immunotherapy.
Authors: Asher Nethanel , Bar-Hai Neta , Ben-betzalel Guy , Stoff Ronen , Grynberg Shirly , Schachter Jacob , Shapira-Frommer Ronnie
Published: June 2022

9544

Background: The immune-system manipulation by immune-checkpoint inhibitors (ICI) has led to unprecedented clinical advances in melanoma. The management of the consequent immune-related adverse events (irAEs) is based mostly on steroids and other immune-modulators. Methods: A real world single-site cohort of metastatic melanoma patients who were treated with immunotherapy as first line between 2014 and 2020. This study explores the effect of dose, timing, and duration of steroid exposure on treatment efficacy. Results: Four hundred and forty patients were treated with either anti PD-1 (n = 285, 65%) or combination of anti PD-1 and ipilimumab ICI (n = 112, 25%), or ipilimumab alone (n = 43, 10%). The median age was 68 years [12-99y], and 57% were male. Any-grade irAEs were seen in 71% of the patients, and 49% were exposed to steroids. The median steroid dose was 0.75mg/kg prednisolone equivalent [0.03- 80mg/kg], the median duration of steroidal treatment was 11.2 weeks [0.1-316w] and the median time to onset of steroids was 7.6 weeks [0-193w]. Both experiencing irAEs, and the associated steroid exposure were associated with a significant progression free survival (PFS) benefit [HR 0.47, p < 0.001; 95%CI 0.39-0.6 and HR 0.77, p = 0.026; 95%CI 0.60-0.97, respectively], regardless of dose and duration. Notably, within those who were exposed to steroids, an earlier onset of < 4 weeks from immunotherapy initiation was significantly associated with a shorter PFS [HR = 3.5, p < 0.001 (95%CI 2.32-5.45)]. This observation resulted significant also on multivariable analysis including other prognostic variables – ECOG PS, M-stage, LDH and protocol. Conclusions: Steroidal treatment during the immunotherapy priming phase (first 4 weeks) might have a deleterious effect on its’ efficacy and should be explored in larger prospective cohorts.