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  • 1
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    Online Resource
    Impact of rapid multigene assays with short turnaround time (TAT) on the development of precision medicine for non-small cell lung cancer (NSCLC).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 9094-9094
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 9094-9094
    Abstract: 9094 Background: A variety of oncogene drivers have been identified in NSCLC and molecularly-stratified precision medicine has led to improved survival in advanced NSCLC. Next-generation sequencing (NGS)-based testing is utilized to detect actionable gene alterations; however, the TAT of NGS is often too long to translate into clinical decision making. Thus, rapid multi-gene testing alternatives are needed. Methods: A lung cancer genomic screening project (LC-SCRUM-Asia) capturing clinical outcome was established in 2013 to identify patients with oncogene drivers and to support the development of novel targeted therapies. Since February 2013 to May 2019 (LC-SCRUM-Asia 1st-phase), single gene testing and/or a targeted NGS assay, Oncomine Comprehensive Assay (OCA), were used for the genomic screening. Since June 2019 to December 2020 (2nd-phase), a multi-gene PCR assay (Amoy 9-in-1 test) and a rapid NGS assay (Genexus/Oncomine Precision Assay [OPA]) were also implemented as rapid multi-gene testing. Results: A total of 10667 Japanese NSCLC patients, including 6826 in the 1st-phas e and 3841 in the 2nd-phase, were enrolled in the LC-SCRUM-Asia. Success rate for OCA: 93%, for 9-in-1 test: 98%, for Genexus/OPA: 96%. Median TAT for OCA: 21 days, for 9-in-1 test: 3 days, for Genexus/OPA: 4 days. The frequencies of genetic alterations detected in the 1st-/2nd-phase were EGFR: 17/24%, KRAS: 15/16%, HER2 ex20ins: 4/3%, ALK fusions: 3/3%, RET fusions: 3/2%, ROS1 fusions: 3/2%, MET ex14skip: 2/2%, BRAF V600E: 1/1%, NRG1 fusions: 0/0.2% and NTRK3 fusions: 0.05/0.04%. Overall percent agreement of 9-in-1 test compared with OCA for EGFR/KRAS/HER2/BRAF/MET/ALK/ROS1/RET/NTRK3 alterations was 98%, and that of OPA compared with OCA was 95%. The rate of patients who received targeted therapies as 1st-line treatment was significantly elevated in the 2nd-phase compared with the 1st-phase (510/3841 [13%] vs. 567/6826 [8%] , p 〈 0.001). Through the genomic screening, 1410 (37%) and 1269 (18%) candidate patients for clinical trials of KRAS, HER2, BRAF, MET, ALK, ROS1, RET or TRK-targeted drugs were identified in the 2nd-phase and in the 1st-phase, respectively. The rate of patients who were actually enrolled into the genotype-matched clinical trials were also significantly higher in the 2nd-phase than in the 1st-phase (222 [6%] vs. 186 [3%] , p 〈 0.001). In 1st-line treatments for advanced NSCLC patients, the median progression-free survival was 8.5 months (95% CI, 7.7−9.4) in the 2nd-phase (n = 1839) versus 6.1 months (95% CI, 5.9−6.3) in the 1st-phase (n = 4262) (p 〈 0.001). Conclusions: Both the 9-in-1 test and Genexus/OPA had short TATs (3−4 days), high success rates (96−98%) and good concordance (95−98%) compared with another NGS assay (OCA). These rapid multi-gene assays highly contributed to enabling precision medicine and the development of targeted therapies for advanced NSCLC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.9094
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 2
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    Optimal next-generation sequencing (NGS) panel for estimating tumor mutation burden (TMB) and its clinical implication for non-small cell lung cancer (NSCLC).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 9097-9097
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 9097-9097
    Abstract: 9097 Background: TMB estimation using targeted NGS panels is widely performed in clinical practice. The objective of this study was to determine the optimal NGS panel for estimating TMB and to evaluate its clinical implications for NSCLC. Methods: Two NGS panels, Oncomine Tumor Mutation Load Assay (OMLA) and FoundationOne (F1), were compared to select the most accurate TMB prediction panel. From February 2017 to May 2018, 350 lung cancer patients were analyzed by whole-exome sequencing (WES), and the concordance rate of OMLA and F1 to WES was examined. In addition, its clinical utility as a biomarker for immune checkpoint inhibitors (ICIs) was evaluated in our international genome screening network (LC-SCRUM-Asia). From June 2019 to December 2020, 3141 patients with NSCLC from 185 institutions were enrolled, and genomic analysis was successful. The clinico-genomic database of LC-SCRUM-Asia was used for this analysis. Results: The linear correlation with WES was 0.80 for OMLA and 0.78 for F1. This indicated that OMLA was more strongly correlated with WES. The cutoff value of F1 was 10 mut/Mb, which corresponded to 9 mut/Mb (OMLA) and 194 mutations (WES). The sensitivity of the OMLA for WES was 79%, and the specificity was 85%. Meanwhile, the sensitivity of the F1 was 74%, and the specificity was 80%. OMLA more accurately predicted TMB, and its clinical utility was evaluated. 3141 NSCLC patients, consisting of 2282 adenocarcinomas, 593 squamous cell carcinomas, and 266 others, were analyzed for TMB, estimated using OMLA. The median number of mutations was 4.2 mut/Mb (range, 0-718.4/Mb). High TMB (≥9 mut/Mb) was observed in 17.2% (393/2282) of adenocarcinoma cases and 25.8% (153/593) in squamous cell carcinoma cases. 778 patients were treated with ICI or ICI plus chemotherapy as the first-line treatment. Patients’ characteristics were as follows: male/female; 595/183, median age (range); 67 (25-90), stage II/III/VI/recurrence; 11/90/649/28, TMB high/low; 177/601, ICI/ICI plus chemotherapy; 114/664. The progression-free survival (PFS) was significantly longer in patients with high TMB than in those with low TMB (median PFS, 7.5 vs. 5.9 months, p = 0.0314). The overall survival (OS) was significantly longer in patients with high TMB than in those with low TMB (median OS, 27.4 vs. 20.4 months, p = 0.006). Conclusions: The TMB estimated by OMLA correlated more strongly with the WES-derived TMB comparing with F1. TMB estimated by OMLA was correlated with PFS and OS in NSCLC patients treated with ICIs. Prospective clinical trials are needed to determine whether TMB estimated by OMLA is a biomarker for ICI.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.9097
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    A nation-wide genomic screening project for further development of targeted therapies in treatment-refractory non–small-cell lung cancer (LC-SCRUM-TRY).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 9097-9097
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 9097-9097
    Abstract: 9097 Background: Targeted therapies based on oncogenic drivers demonstrate dramatic and durable response in patients with non-small cell lung cancer (NSCLC). However, acquired resistance inevitably develop by diverse genomic resistance mechanisms. Genotype-matched targeted therapies to overcome treatment-resistance have not been established, except osimertinib against EGFR T790M mutation. Methods: We established a nation-wide genomic screening project in treatment-resistant NSCLC (LC-SCRUM-TRY; UMIN000041957) in September 2020 to identify the genetic resistant alterations, and to promote clinical therapeutic development. Enrolled patients have been screened for genetic alterations using a rapid next-generation sequencing (NGS) system, Oncomine Precision Assay (OPA) for tissue samples, and Guardant 360 (G360) or OPA for plasma samples. MET amplification was also evaluated by FISH for NSCLC post EGFR-TKI treatment. Results: As of January 2023, 129 institutions in Japan were participating, and 1252 patients had been enrolled. Sample types were tissue (84%), and plasma (16%), respectively. Turn-around-time (median [interquartile range]) of OPA and G360 was 5 (4-6), and 9 (8-10.5) days, respectively. Of these, a total of 711 (57%) were already identified to have oncogenic driver at enrollment ( EGFR, 556 [43%] ; ALK, 70 [6%]; RET, 22 [2%] ; ROS1, 21 [2%]; KRAS, 15 [1%] ; ERBB2 exon 20 insertion [ex20ins], 8 [0.6%] ; MET exon 14 skipping [ex14skip], 8 [0.6%] ; BRAF V600E, 7 [0.6%]; NTRK3, 2 [0.2%] ; others, 2 [0.2%]). Of 556 EGFR-mutated NSCLC, 537 (97%) were enrolled post EGFR-TKIs. EGFR mutation subtypes were exon 19 deletion (52%), L858R (41%), ex20ins (1%), others (6%), respectively. Of 537 EGFR-TKI resistant tumors, 326 (40%) had at least one genetic alteration related with drug resistance, including EGFR alterations (amplification [13%] , C797S [4%], A750P [3%] , E709X [2%], L792X [1%] , L718Q [1%]), MET amp (16%), and other driver mutation/rearrangement (8%). Through this screening, 37 (7%) of patients resistant to EGFR-TKI were enrolled into clinical trials, with 16/102 (16%) patients with targetable alterations ( MET amp or EGFR C797S). In addition, of 541 NSCLC without oncogenic drivers at enrollment, 116 (21%) were identified to have actionable oncogenic drivers with FDA-approved drug (KRAS G12C, 23 [4%] ; ERBB2 ex20ins, 23 [4%]; RET, 13 [2%] ; MET ex14skip, 13 [2%]; EGFR except ex20ins, [4%] ; EGFR ex20ins, 10[2%]; ALK, 6 [1%] ; ROS1, 5 [1%]). Conclusions: LC-SCRUM-TRY contributes to the clinical development of precision medicine to overcome drug resistance, especially for EGFR-mutated NSCLC resistant to EGFR-TKI. This screening platform also help to practice precision medicine for patients initially diagnosed as driver-negative. Clinical trial information: UMIN000041957 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.9097
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
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    Co-occurring gene alterations associated with efficacy of osimertinib in EGFR-mutated lung cancer: Based on a large-scale genomic screening project (LC-SCRUM-Asia).
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 9103-9103
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 9103-9103
    Abstract: 9103 Background: Osimertinib is a standard drug for first-line treatment of patients with advanced non–small cell lung cancer (NSCLC) harboring EGFR mutations (mt). While tumor mutational burden (TMB)-high and co-occurring genetic alterations (alt) have been reported to be negatively associated with the efficacy of other EGFR-TKIs, the impact of co-occurring genetic alt with EGFR major mt on the efficacy of osimertinib remains unclear. Methods: In a multi-institutional genomic screening project (LC-SCRUM-Asia), we have analyzed lung cancer patients for genomic alt by a targeted next-generation sequencing (NGS) system, Oncomine Comprehensive Assay and Genexus/OPA. We retrospectively evaluated the association between the genomic profile and efficacy of first-line osimertinib for EGFR-mutated NSCLC based on the LC-SCRUM-Asia database. Results: Between March 2015 and January 2022, 12,705 NSCLC patients were enrolled in the LC-SCRUM-Asia database, and EGFR mt was detected in 2,232 patients. Of these, 324 patients, including 171 with ex19del (53%) and 153 with L858R (47%), received first-line treatment with osimertinib. The patient characteristics were as follows: median age, 69 years (range 31-97); females, 64%; never-smokers, 57%; adenocarcinoma, 97%; and performance status 0-1, 99%. The frequency of compound EGFR mt and TMB were higher in the L858R (LR) group than in the ex19del (Ex19) group (compound mt (%), 12 vs. 4; mean TMB (mt/Mb), 3.4 vs. 2.5). There were no differences in the frequencies of other co-occurring genetic alt between the two groups. Higher TMB, alt of genes encoding receptor tyrosine kinase (RTK), including FGFR1, RET, MET etc., and amp of cell-cycle related genes were significantly associated with shorter progression-free survival (PFS) in the entire group (median PFS: TMB 〉 3 vs. ≤3 mt/Mb = 11.4 vs. 17.1 months; p = 0.023; RTK gene alt+ vs. alt- = 9.7 vs. 15.2 months; p = 0.014; cell-cycle gene amp+ vs. amp- = 10.6 vs. 15.6 months, p = 0.001). EGFR subgroup analysis showed that a higher TMB was significantly associated with a shorter PFS in the LR group ( 〉 3 vs. ≤3 mt/Mb = 10.0 vs. 17.1 months, p 〈 0.001), but not in the Ex19 group. On the other hand, alt of genes encoding RTK and amp of cell-cycle related genes were significantly associated with a shorter PFS in the Ex19 group (RTK gene alt+ vs. alt- = 8.4 vs. 17.8 months, p = 0.008; cell-cycle gene amp+ vs. amp- = 10.6 vs. 17.5 months, p = 0.003), but not in the LR group. Multivariate analysis identified RTK gene alt in the Ex19 group and higher TMB in the LR group as being independently associated with a shorter PFS. Conclusions: First-line osimertinib treatment was less effective in NSCLC patients harboring Ex19 with other RTK gene alt or LR with a higher TMB, indicating that co-occurring genetic alt affecting the efficacy of osimertinib differ between NSCLC patients harboring Ex19 and LR.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.9103
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 5
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    Online Resource
    MO45-1 Osimertinib vs. erlotinib + bevacizumab or ramucirumab for EGFR mutated NSCLC; a retrospective study from LC-SCRUM-Asia
    Elsevier BV ; 2022
    In:  Annals of Oncology Vol. 33 ( 2022-07), p. S510-
    Details
    In: Annals of Oncology, Elsevier BV, Vol. 33 ( 2022-07), p. S510-
    Type of Medium: Online Resource
    ISSN: 0923-7534
    URL: Article
    DOI: 10.1016/j.annonc.2022.05.214
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2003498-2
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  • 6
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    A Large-Scale Prospective Concordance Study of Plasma- and Tissue-Based Next-Generation Targeted Sequencing for Advanced Non–Small Cell Lung Cancer (LC-SCRUM-Liquid)
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 8 ( 2023-04-14), p. 1506-1514
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 8 ( 2023-04-14), p. 1506-1514
    Abstract: We evaluated plasma cell-free DNA (cfDNA) and tissue-based sequencing concordance for comprehensive oncogenic driver detection in non–small cell lung cancer (NSCLC) using a large-scale prospective screening cohort (LC-SCRUM-Liquid). Experimental Design: Blood samples were prospectively collected within 4 weeks of corresponding tumor tissue sampling from patients with advanced NSCLC to investigate plasma cfDNA sequencing concordance for alterations in 8 oncogenes (EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1) compared with tissue-based next-generation targeted sequencing. Results: Paired blood and tissue samples were obtained in 1,062/1,112 enrolled patients with NSCLC. Oncogenic alteration was detected by plasma cfDNA sequencing and tissue assay in 455 (42.8%) and 537 (50.5%) patients, respectively. The positive percent agreement of plasma cfDNA sequencing compared with tissue DNA and RNA assays were 77% (EGFR, 78%; KRAS, 75%; BRAF, 85%; HER2, 72%) and 47% (ALK, 46%; RET, 57%; ROS1, 18%; MET, 66%), respectively. Oncogenic drivers were positive for plasma cfDNA and negative for tissue due to unsuccessful genomic analysis from poor-quality tissue samples (70%), and were negative for plasma cfDNA and positive for tissue due to low sensitivity of cfDNA analysis (61%). In patients with positive oncogenic drivers by plasma cfDNA sequencing but negative by tissue assay, the response rate of genotype-matched therapy was 85% and median progression-free survival was 12.7 months. Conclusions: Plasma cfDNA sequencing in patients with advanced NSCLC showed relatively high sensitivity for detecting gene mutations but low sensitivity for gene fusions and MET exon 14 skipping. This may be an alternative only when tissue assay is unavailable due to insufficient DNA and RNA. See related commentary by Jacobsen Skanderup et al., p. 1381
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-1749
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 7
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    The CLIP1–LTK fusion is an oncogenic driver in non‐small‐cell lung cancer
    Springer Science and Business Media LLC ; 2021
    In:  Nature Vol. 600, No. 7888 ( 2021-12-09), p. 319-323
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 600, No. 7888 ( 2021-12-09), p. 319-323
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-021-04135-5
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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