bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sunvozertinib for the treatment of NSCLC with EGFR Exon20 insertion mutations: The first pivotal study results.
Authors: Wang Mengzhao , Fan Yun , Sun Meili , Wang Yongsheng , Zhao Yanqiu , Jin Bo , Hu Ying , Han Zhigang , Song Xia , Liu Anwen , Tang Kejing , Cuimin Ding , Liang Li , Wu Lin , Gao Junzhen , Wang Jianghong , Cheng Ying , Zhou Jianying , He Yong , Zheng Li 
Published: June 2023

9002 Background: Sunvozertinib(DZD9008) is a rationally designed selective, irreversible EGFR exon20 insertion (exon20ins) inhibitor with wild-type EGFR selectivity. Here we reported the results of WU-KONG6, the first pivotal study of sunvozertinib in previously treated NSCLC patients with EGFR exon20ins. Methods: WU-KONG6 (NCT05712902 and CTR20211009) is a phase II, multi-center pivotal study in NSCLC patients with EGFR exon20ins, whose diseases had progressed on or were after platinum-based chemotherapy. Tumor tissue EGFR exon20ins status was tested by local or central laboratory. The primary and key secondary endpoint were objective response rate (ORR) and duration of response (DoR), respectively, assessed by Blinded Independent Central Review (BICR). Patients received 300 mg sunvozertinib once daily until discontinuation criteria were met. Results: Between July 19, 2021, and May 6, 2022, a total of 104 Chinese patients were enrolled into WU-KONG6 study. The efficacy analysis set included 97 patients, whose EGFR exon20ins status was retrospectively confirmed by a central laboratory. A total of 30 different exon20ins subtypes were enrolled. The median age was 58 years; 59.8% (58/97) were female; 95.9% (93/97) were adenocarcinoma; 95.9% (93/97) had metastatic diseases at study entry; 32% (31/97) had baseline brain metastasis; the median prior lines of therapy were 2. By the data cutoff date (October 17, 2022), the BICR assessed confirmed ORR (cORR) was 60.8% (59/97). In patients with baseline brain metastasis, the cORR was 48.5% (15/31). Anti-tumor efficacy was observed irrespective of age, gender, smoking status, prior lines of therapies, prior onco-immunotherapies, mutation subtypes, and baseline brain metastasis. By the data cut-off date, median follow-up time for responders was 7.1 months, and 64.4% (38/59) of responders were still responding. The longest DoR was > 11 months, and the median DoR has not been reached. The safety analysis set included all enrolled 104 patients. The most common treatment emergent adverse events (TEAEs) were similar as what have been previously reported for sunvozertinib, and also similar as that of other EGFR inhibitors. Majority of the TEAEs were grade 1 or 2, and clinically manageable. Conclusions: The first pivotal study results confirmed sunvozertinib’s superior anti-tumor efficacy than the current available therapy for NSCLC with EGFR exon20ins. The safety profile from WU-KONG6 study was consistent with previously reported findings. The updated data will be presented at the meeting. A multinational phase II pivotal study (WU-KONG1, NCT03974022) with the same study design is ongoing in the USA, Australia, and countries/regions in Asia, Europe and South America. Clinical trial information: NCT05712902 .
Intracranial and systemic efficacy of repotrectinib in advanced ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC) and central nervous system metastases (CNS mets) in the phase 1/2 TRIDENT-1.
Authors: Lin Jessica Jiyeong , Drilon Alexander E. , Cho Byoung Chul , Felip Enriqueta , De Langen Adrianus , Yang Nong , Kim Sang-We , Lu Shun , Kao Steven Chuan-Hao , Velcheti Vamsidhar , MORO SIBILOT Denis Lucien , Solomon Benjamin J. , Dziadziuszko Rafal , Krebs Matthew G , Cheema Parneet Kaur , Dooms Christophe Alfons , Stopatschinskaja Shanna , Trone Denise , Ades Felipe , Camidge D. Ross 
Published: June 2023

9017 Background: Repotrectinib is a next-generation ROS1 and TRK tyrosine kinase inhibitor (TKI) that has demonstrated durable activity with a manageable safety profile in TKI-naïve and TKI-pretreated patients (pts) with advanced ROS1+ NSCLC. We report the first analysis of outcomes on repotrectinib in pts with ROS1+ NSCLC by baseline (BL) CNS met status in the global pivotal phase 1/2 TRIDENT-1 trial (NCT03093116). Methods: Pts with ROS1+ NSCLC were assigned to 4 cohorts by treatment history: ROS1 TKI-naïve, 1 ROS1 TKI and no chemotherapy (chemo), 1 ROS1 TKI and 1 platinum-based chemo, and 2 ROS1 TKIs and no chemo. Treated or untreated asymptomatic CNS mets were permitted. Brain scans were mandated for all pts in phase 2 at screening and at protocol-specified intervals until progression. Endpoints included confirmed objective response rate (cORR) and duration of response (DOR) by blinded independent central review (BICR; RECIST v1.1); intracranial ORR (icORR) in pts with measurable brain mets at BL by BICR per mRECIST v1.1; and safety. Results: In pts with BL measurable CNS mets who were TKI-naïve (n = 8) and in those with 1 TKI and no chemo (n = 12), icORR (95% CI) was 88% (47-100) and 42% (15-72), respectively. At data cutoff (June 20, 2022), 0 of 7 responders in the TKI-naïve cohort and 2 of 5 in the cohort with 1 prior TKI and no chemo had intracranial progression or death; intracranial DOR range was 1.9-14.8+ mo (TKI-naïve) and 3.0-11.1+ mo (1 TKI and no chemo), with 86% and 80% of pts with an intracranial response remaining on treatment, respectively. Median follow-up and systemic response by CNS met status are shown in the Table. In pts with ROS1+ NSCLC with (n = 118) or without (n = 178) CNS mets, most common any-grade neurologic treatment-emergent adverse events were dizziness (57% / 63%), dysgeusia (42% / 53%), paresthesia (32% / 34%), headache (27% / 12%), ataxia (17% / 22%), and memory impairment (14% / 10%). Conclusions: In TRIDENT-1, repotrectinib showed durable clinical activity in ROS1 TKI-naïve and -pretreated pts with or without BL CNS mets, including intracranial responses. Repotrectinib safety profile was similar in pts with ROS1+ NSCLC with or without CNS mets. Clinical trial information: NCT03093116 . [Table: see text]
Real-world testing and treatment patterns among patients with stage IV non-small cell lung cancer: A retrospective observational study.
Authors: Scott Jeffrey A. , Katzen Harvey I. , Lennerz Jochen K , Johnson Melissa Lynne , Gordan Lucio N. , Dumanois Robert H , Quagliata Luca , Ritterhouse Lauren , Cappuzzo Federico , Vasudevan Anupama , Sura Teena , English Sandy , Wang Brandon , Varughese Prateesh , Choksi Rushir J. 
Published: June 2023

9030 Background: Guidelines (NCCN, CAP/IASLC/AMP) recommend clinical molecular testing of patients with advanced NSCLC to inform therapy decisions. We investigated the testing and treatment patterns of patients with stage 4 NSCLC treated in the real-world setting. Methods: This retrospective observational study included de-identified stage 4 NSCLC patients from the Integra Connect PrecisionQ database (ICD) enriched with information obtained by curation. Patients with a positive mutation for EGFR, ALK, ROS1, BRAF, MET, RET, HER2, or NTRK and who initiated treatment for stage 4 NSCLC between 01/01/2018 and 12/31/2021 were included with follow-up through 05/31/2022. Also included were demographics, ECOG score, time of ordering test, and date of death. Genomic test data were classified by method and type of test. Overall survival (OS) was calculated using Kaplan-Meier curves and data are presented using descriptive statistics. Results: Of 5195 patients in the ICD with stage 4 NSCLC, 3532 patients initiated first line of therapy (LOT1), and 2899 had somatic molecular testing ordered, specifically via tissue-based next-generation sequencing (NGS, 30%), plasma-based NGS (26%), or non-NGS methods (44%). A total of 934 patients tested positive for a driver mutation at any time during the study observation period, and 671 patients (72%) had test results available before initiating treatment. Of those treated after receiving biomarker results, 407 (61%) initiated treatment with a tyrosine kinase inhibitor (TKI), 43 (6%) with chemotherapy (chemo), 156 (23%) with chemo + immuno-oncology (IO), and 65 (10%) with IO. The median OS (95% confidence interval [CI]) was 24.46 (21.90-29.18) months for patients treated with TKI and 14.2 (11.6-16.5) months for patients treated without TKI (unadjusted hazard ratio [95% CI], 1.56 [1.26, 1.92]; P < 0.001). Conclusions: Among patients with stage 4 NSCLC treated in the real-world setting, patients treated with TKI after receiving test results had better overall survival than patients treated without TKI. While subject to the limitations of a retrospective observational real-world data study, this study suggests that, with regard to utilizing genomic testing and appropriate selection of targeted treatment, adherence to treatment guidelines may improve patient outcomes. As new targeted agents continue to emerge in NSCLC, these data encourage utilization of genomic testing data to guide treatment selection. We acknowledge the significant contributions of our dear friend, Dr. Robert E. Smith, whose cheerful enthusiasm and deep expertise were a driving force of this work.
The effect of ctDNA tumor fraction (TF) on overall survival and concordance between tissue genomics and ctDNA in Lung-MAP.
Authors: Mack Philip C. , Redman Mary Weber , Kozono David E. , Callis Sam , Tukachinsky Hanna , Tolba Khaled A. , Neal Joel W. , Waqar Saiama Naheed , Dragnev Konstantin H. , Aggarwal Charu , Hirsch Fred R. , Patel Jyoti D. , Herbst Roy S. , Chiang Anne C. , Reckamp Karen L. , Kelly Karen , Borghaei Hossein , Gray Jhanelle Elaine , Gandara David R. 
Published: June 2023

9035 Background: Discordance in genomic profiling between tumor tissue and ctDNA can occur due to inter-patient variability in shed tumor DNA, and intra-patient variability in sources of cell-free DNA (tumor heterogeneity, metastatic variants, CHIP). TF is an aneuploidy-based estimation of tumor-specific DNA in circulation. We evaluated the impact of TF levels on overall survival (OS), mutation concordance and tumor mutation burden in tissue (tTMB) and ctDNA (bTMB) in the LUNGMAP screening study. Methods: Eligible advanced NSCLC pts had blood drawn ≤30 days of fresh tissue biopsy with no intervening therapies. Genomic profiling was done by FoundationOne CDx and FoundationOne Liquid CDx. ctDNA TF was quantified via aneuploidy using deviations in genome-wide SNP coverage or somatic allele frequencies if under aneuploidy LoD. High TF was defined as ≥10%. Concordance among driver genes, cancer genes of interest (CGoI: T P53, PIK3CA, STK11, KEAP1, RB1, PTEN, ATM, BRCA1/2), and variant subtype were assessed by the percentage positive agreement (PPA) and positive predictive value (PPV) with 95% confidence intervals (CI). OS by TF used a Cox model and log-rank test. PPA and TF among CGoIs was compared with a Wilcoxon test. Correlation between tTMB and bTMB used Lin’s coefficient (LC). Results: 167 pts met inclusion criteria; 161 had TF data with 51 (32%) ≥10% (high TF). High TF was associated with worse OS (HR: 2.06 [1.43-2.95], p<0.001). The PPA and PPV ranged from 50%-100% and 60%-100%, respectively for driver genes. The PPA was numerically larger for high versus low TF for most drivers (p=0.18) and significantly larger for all mutations and SNVs combined (Table). For CGoI, the distribution of PPA differed between high and low TF (p=0.03). The median PPA for CGoI (25th%ile,75th%ile) was 56% (50,87) for low TF and 100% (100,100) for high TF. PPV for CGoI did not differ by TF (p=0.20). High TF was associated with higher levels of TMB and bTMB (p<0.01 for both). TMB LC (CI) for low and high TF were 0.46 (0.27,0.61) and 0.69 (0.53,0.81). Conclusions: High TF was associated with worse OS, better PPA among CGoI, and better LC for t/bTMB. TF may improve the clinical utility of mutations detected by liquid biopsies and should be reported and considered in interpreting these results. [Table: see text]
Uncommon EGFR mutations conducted with osimertinib in patients with NSCLC (UNICORN): A phase 2 study.
Authors: Okuma Yusuke , Kubota Kaoru , Shimokawa Mototsugu , Hashimoto Kana , Kawashima Yosuke , Sakamoto Tomohiro , Wakui Hiroshi , Murakami Shuji , Okishio Kyoichi , Hayashihara Kenji , Ohe Yuichiro 
Published: June 2023

9045 Background: Non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutation (uC- EGFRm), excluding exon 20 insertion, is a heterogenous rare fraction consisting of 10% of all EGFR mutations. Key drugs for metastatic NSCLC (mNSCLC) uC- EGFRm are limited, with only afatinib being FDA approved. Data on the efficacy of osimertinib for previously untreated metastatic patients (pts) harboring uC- EGFRm NSCLC is limited. Methods: UNICORN study for previously untreated mNSCLC pts harboring uC- EGFRm, excluding exon 20 insertion mutation, evaluating osimertinib with a dose of 80 mg QD orally is a multicenter, open-label, single-arm phase 2 study. The primary endpoint was the overall response rate (ORR) evaluated by central review according to the Response Evaluation Criteria in Solid Tumors (version 1.1), and key secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety. Results: Between March 2020 to May 2022, a total of 42 pts were registered. Among the eligible 40 pts, 45.0% were female; the median age was 72 years (range 39-88); 42.5% were never smokers or light smokers; 92.5% were adenocarcinomas, solitary uC- EGFRm/compound mutation ratio was 57.5%/42.5%. The most common mutations were G719X (50.0%), followed by S768I (25.0%), L861Q (20.0%), and others, including compound mutation data. The ORR was 55.0 % (90% confidence interval [CI]; 40.9-68.5), the DCR was 90.0 % (95% CI; 76.3-97.2), the mPFS was 9.4 months (95% CI; 3.7-15.2) after a median follow-up of 27.0 months, the mOS was not reached (NR) (95% CI, 19.23- NR), and the mDoR 22.7 months (95% CI; 9.43-NR). In solitary and compound mutations with uC- EGFR m NSCLC, ORR was 52.2%/58.8%, mPFS was 5.4 months/11.4 months, mOS 23.0 months/NR, and mDoR was 22.7 months/NR, respectively. Safety was similar to previous reports and Grade 3/4 AEs were reported in 8 of 36 pts (27.5%) and 12.5% of pts developed pneumonitis. All of the AEs were manageable and there were no treatment-related deaths. Conclusions: Osimertinib in mNSCLC pts harboring uC- EGFRm other than exon 20 insertions showed clinical activity with manageable toxicities. These results suggest that osimertinib can be considered as a treatment option for this specific population. Clinical trial registration: jRCTs071200002. The study was funded by AstraZeneca. Clinical trial information: jRCTs071200002 .
Safety and efficacy of immune checkpoint inhibitors in patients with cancer and pre-existing autoimmune disease: A systematic review and meta-analysis in non-small cell lung cancer.
Authors: Aung Wint Yan , Lee Chung-Shien , Morales Jaclyn , Kohn Nina , Rahman Husneara , Seetharamu Nagashree 
Published: June 2023

9053 Background: Cancer patients with pre-existing autoimmune diseases (AID) have been traditionally excluded from clinical trials of immune checkpoint inhibitors (ICI) due to concerns for immune activation leading to toxicity. As indications for ICI expand, there is a need for robust data on safety and efficacy of ICI in cancer patients with AID. Existing studies examined a heterogenous group of cancers and do not include a comparison to cancer patients without pre-existing AID. Therefore, data are lacking concerning how safety and efficacy of ICI in this group of patients may differ from the general population and whether the results are generalizable to non-small cell lung cancer (NSCLC). Methods: We searched for studies consisting of NSCLC, AID, ICI, treatment response, and adverse events using database-controlled vocabulary terms. We systematically searched Medline (PubMed), EMBASE, Scopus, CINAHL, and Web of Science. We selected studies that included NSCLC and excluded abstracts, case reports, review articles, and articles lacking outcomes or populations of interest. Three authors (WA, CL, NS) independently reviewed all abstracts to determine study eligibility and quality. Study quality was assessed using the Newcastle-Ottawa Scale. Study data were pooled using random-effects meta-analysis. Results: Data were extracted from 24 cohort studies, consisting of 10,924 cancer patients, of which 4353 were NSCLC patients. Studies examined a broad spectrum of AID consisting of 1157 patients, of which 291 were NSCLC patients. Pooled analysis revealed an AID flare incidence of 36% (95%CI 27%-46%) in all cancers and 23% (95%CI 9%-40%) in NSCLC. Tests of subgroup difference revealed no significant difference in AID flares by organ system in all cancers and NSCLC (p = 0.602 and p = 0.19, respectively). Pre-existing AID was associated with a higher risk of de novo iRAE in all cancer patients (RR 1.38, 95%CI 1.16-1.65) and in NSCLC patients (RR 1.51, 95%CI 1.12-2.03). There was no difference in de novo grade 3-4 iRAE and tumor response between cancer patients with and without AID. However, in NSCLC patients, pre-existing AID was associated with a 2-fold increased risk of de novo grade 3-4 iRAE (RR 1.95, 95%CI 1.01-3.75) but also better tumor response in achieving a complete or partial response (RR 1.56, 95%CI 1.19-2.04). Conclusions: Pre-existing AID confers an increased risk of toxicity during ICI therapy. NSCLC patients with AID are at a higher risk of de novo grade 3-4 iRAE but are also more likely to achieve treatment response than those without AID. Multidisciplinary collaboration is paramount when considering ICI therapy in this patient population with careful calculation of risk and benefit as well as close monitoring for toxicity.
Phase II trial of lazertinib in patients with epidermal growth factor receptor (EGFR) mutation-positive (M+), metastatic non-small cell lung cancer (NSCLC) with asymptomatic or mild symptomatic brain metastases after failure of EGFR tyrosine kinase inhibitor (TKI) (KCSG LU20-15).
Authors: Hong Min Hee , Choi Yoon Ji , Ahn Hee Kyung , Keam Bhumsuk , Kim Yu Jung , Kim Ju Won , Kim Hye Ryun , Kang Jin-Hyoung 
Published: June 2023

9054 Background: Central nervous system (CNS) metastases occur not infrequently, ultimately devastating consequences in advanced EGFR M+ NSCLC. Lazertinib, a 3rd-generation (G) EGFR-TKI, has shown potent antitumor activity in EGFR-mutant NSCLC. We conducted a phase II single-arm study of lazertinib in EGFR M+ NSCLC patients (pts) having CNS metastases to evaluate its CNS activity. Methods: The patients exhibiting CNS progression upon 1st or 2nd-G EGFR-TKIs with least one measurable CNS lesion were enrolled. The primary endpoint was intracranial objective response rate (iORR) in evaluable for response set (ERS). Secondary endpoints included iORR without T790M mutation, overall ORR (oORR), disease control rate (DCR), intracranial progression-free survival (iPFS) in ERS. Overall survival (OS) and safety analyses were performed in pts who received at least one dose of lazertinib. Cerebrospinal fluid (CSF) penetration was measured as exploratory biomarker study. Results: Of 40 pts enrolled, 38 were evaluable for tumor response. Nineteen pts harbored exon 19 deletion and 21 pts for exon 21 L858R and 30% of pts had radiologic evidence of leptomeningeal carcinomatosis (LM) with 2 cytological confirmed cases. Forty-five percent of pts received afatinib as first line treatment, followed by 42.5% of gefitinib and 12.5% of erlotinib. Baseline plasma samples of all the 40 patients obtained for liquid-based next-generation sequencing (Guardant360) and T790M was found in 5 pts prior to lazertinib treatment. iORR was 57.9% (22/38). iORR with T790M-negative, oORR, and DCR were 54.5%, 39.5%, and 97.4%, respectively. With median follow-up of 13.6 months, median iPFS and OS were not reached. Treatment-related adverse events (TRAEs) emerged in 85.0% of pts with most common TRAEs being skin rash (50.0%) and paresthesia (42.5%). Grade 3 or 4 TRAEs were reported in 10.0%. The CSF penetration rates of lazertinib and its metabolite (YH26334) were 46.2% and 33.1%, respectively in paired CSF and plasma samples, suggesting high CNS penetration efficacy. Conclusions: Lazertinib has substantial CNS activity regardless of T790M status against the progression of intracranial metastases ± LM during the treatment of 1st or 2nd-G EGFR-TKIs in metastatic EGFR M+ NSCLC pts. These results suggest that using lazertinib instead of brain local treatment would be a potential strategy in EGFR M+ NSCLC, who progressed on CNS metastases after prior EGFR-TKI. Clinical trial information: NCT05326425 . [Table: see text]
Impact of first-line immunotherapy on survival and intracranial outcomes from a real-world cohort of patients with non-small cell lung cancer with brain metastases at diagnosis.
Authors: Nigen Benoît , Mathiot Laurent , Goronflot Thomas , Herbreteau Guillaume , Sagan Christine , Raimbourg Judith , Bennouna Jaafar , Thillays Francois , Pons-Tostivint Elvire 
Published: June 2023

9058 Background: Although brain metastases (BM) at diagnosis are common in non-squamous NSCLC patients (ns-NSCLC), they have been mostly excluded from randomized trials. The aim of this retrospective study was to evaluate real-word outcomes of frontline immune checkpoint inhibitor (ICI) in these patients. Methods: We conducted a retrospective study to assess the intracranial and overall efficacy of first-line ICI-based therapy compared to chemotherapy (CT) in ns-NSCLC patients diagnosed with BM, showing no targetable alterations. Patients were divided according to systemic therapy: CT, ICI, or CT-ICI respectively. Primary endpoint was overall survival (OS), compared using Kaplan-Meier and Cox methodology. Secondary endpoint was intracranial progression free survival (icPFS). Results: Between 01-2018 and 05-2021, 118 newly diagnosed ns-NSCLC patients with BM were included (52 CT, 38 ICI and 28 CT-ICI). Median follow-up was 30.0 months [95% CI: 25.9-36.0]. Intracranial radiotherapy was delivered for 75.0%, 68.4% and 67.9% of patients for CT, ICI and CT-ICI groups (p = 0.805) respectively. OS rates at 24 months were respectively 25.3% (95% CI: 15.7-40.9), 44.6% (95% CI: 30.8-64.7) and 50.5% (95% CI: 34.3-74.4) in CT, ICI and CT-ICI groups (p = 0.048). Twelve-month icPFS was respectively 17.0% (95% CI: 9-32), 47% (95% CI: 33-66) and 45% (95% CI: 30-69) in CT, ICI and CT-ICI groups . After adjustment, ICI and CT-ICI were associated with a better OS compared to CT (HR = 0.46, 95%CI: 0.23-0.89, p = 0.021 and HR = 0.52, 95%CI: 0.27-1.01, p = 0.054 respectively). ICI and CT-ICI were associated with a significant reduction in the risk of intracranial progression by 54% (HR = 0.46, 95%CI: 0.25–0.84, p = 0.0123) and 59% (HR = 0.41, 95%CI: 0.23–0.77, p = 0.0050) compared to CT. Stereotactic radiosurgery was associated with an increased icPFS compared to systemic therapy alone (HR = 0.51, 95% CI: 0.29 – 0.92, p = 0.0247), whereas whole-brain was not (p = 0.096). Conclusions: Real-life ns-NSCLC patients with BM at diagnosis treated frontline with ICI presented OS and icPFS benefit compared to CT alone. A prospective assessment of the ideal type and sequence of systemic and local therapy should be conducted.