bims-preonc Biomed News
on Precision oncology
Issue of 2024‒10‒13
twelve papers selected by
Ankita Daiya, OneCell Diagnostics Inc.
  1. Real-world pan-tumor comprehensive genomic profiling sample adequacy and success rates in tissue and liquid specimens.
  2. Analytical and clinical validation of a NGS panel in detecting targetable variants from ctDNA of metastatic NSCLC patients.
  3. Discerning the impact of ctDNA detection on patient decision-making in early-stage breast cancer.
  4. Clinical trial design for novel targeted agents in neuro-oncology.
  5. A novel liquid biopsy assay for detection of ERBB2 (HER2) amplification in circulating tumor cells (CTCs).
  6. -New frontiers in domain-inspired radiomics and radiogenomics: increasing role of molecular diagnostics in CNS tumor classification and grading following WHO CNS-5 updates.
  7. Evaluation of blood MSI burden dynamics to trace immune checkpoint inhibitor therapy efficacy through the course of treatment.
  8. Characterization of somatic mutations in sporadic uveal melanoma and uveal melanoma in patients with germline BAP1 pathogenic variants.
  9. Single-Hit and Multi-hit PIK3CA Short Variant Genomic Alterations in Clinically Advanced Prostate Cancer: A Genomic Landscape Study.
  10. Circulating tumor DNA predicts recurrence and survival in patients with resectable gastric and gastroesophageal junction cancer.
  11. Dissecting the Clinical Characteristics and Treatment Outcomes Correlates of KRAS G12C-Mutated Non-Small Cell Lung Cancer.
  12. Updated overall survival and ctDNA analysis in patients with EGFR T790M-positive advanced non-small cell lung cancer treated with lazertinib in the phase 1/2 LASER201 study.
  1. Oncologist. 2024 Oct 04. pii: oyae258. [Epub ahead of print]
    Real-world pan-tumor comprehensive genomic profiling sample adequacy and success rates in tissue and liquid specimens.
    Douglas I Lin, Lincoln W Pasquina, Estefany Mavares, Julia A Elvin, Richard S P Huang.
      Real-world success rate of liquid and tissue-based comprehensive genomic profiling (CGP) is unknown. We analyzed real-world pan-tumor cohorts that underwent CGP during clinical care via FoundationOne CDx (F1CDx) and FoundationOne Liquid CDx (F1LCDx) to determine tissue and liquid sample adequacy based on tumor type. Pan-tumor presequencing adequacy was high (>90%) by both tissue-based F1CDx (median: 92.3%; range: 88.2%-96.9%) and liquid-based F1LCDx (median: 94.8%; range: 86.6%-96.7%). Similarly, postsequencing analysis revealed that most tissue and liquid samples yielded successful sequencing results with a median sequencing success rate of 97.9% and 98.1% for F1CDx and F1LCDx, respectively. One exception is central nervous system (CNS) tumors, for which F1CDx had dramatically higher sample sufficiency (96.9%) and postsequencing success rate (97.0%) compared with F1LCDx (86.6% and 92.9%, respectively). The pan-tumor median sample-to-success rate was 90.4% (range: 84.8%-94.4%) for F1CDx. The equivalent rate for F1LCDx was slightly higher at 93.2% (range: 80.4%-95.7%). Conversely, when examining the prevalence of F1LCDx results with high tumor fraction (TF≥1%), the sample-to-high TF results rate was dramatically lower (median: 37.7%, range: 2.1% [CNS tumors]-46.0%). In conclusion, except in CNS tumors or when accounting for liquid TF, success rates of F1CDx and F1LCDx are equivalently high. These results may guide informed decision on when to pursue tissue vs liquid testing of patients with cancer.
    Keywords:  FoundationOne CDx; FoundationOne Liquid CDx; success rates
    DOI:  https://doi.org/10.1093/oncolo/oyae258
  2. Cancer Med. 2024 Oct;13(19): e70078
    Analytical and clinical validation of a NGS panel in detecting targetable variants from ctDNA of metastatic NSCLC patients.
    Feifei Fan, Guozhong Jiang, Juan Lv, Hongmin Wang, Wenjie Li, Chenglin Liu, Yu Zhao, Zhou Zhang, Haiwei Du, Zhihong Zhang, Xiangnan Li, Wen-Cai Li.
      BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for noninvasive cancer diagnostics, particularly in the context of metastatic non-small-cell lung cancer (NSCLC). Detecting targetable variants through ctDNA analysis offers the potential to guide treatment decisions, especially in cases where tissue samples are insufficient or unavailable.METHOD: In this study, we developed and validated a next-generation sequencing panel targeting 101 cancer-related genes (101-test) to detect somatic variants in ctDNA from a large cohort of Chinese patients with metastatic NSCLC. The performance of the 101-test was assessed by evaluating its limit of detection (LOD), accuracy, and precision in identifying molecular variants. Additionally, the concordance between ctDNA and tissue samples for detecting targetable variants was analyzed in 904 patients.
    RESULTS: The 101-test demonstrated a LOD of 0.38% for single-nucleotide variants (SNVs), 0.33% for insertions and deletions (InDels), and 0.33% for fusions. Sensitivity was 98.3% for SNVs, 100% for InDels, and 100% for fusions when compared to digital droplet PCR (ddPCR)/breakpoint PCR reference methods. The by-variant sensitivity for somatic variants was 97.5%, with a specificity of 99.9% between tumor-only and tumor-normal analyses. In a real-world cohort, the concordance between ctDNA and tissue samples for identifying targetable variants was 72.2% (457/633). Notably, the EGFR S768I variant, recently recommended by clinical guidelines, achieved an 80% concordance rate. Furthermore, 4.3% of patients (27/633) with targetable variants were identified exclusively through ctDNA testing.
    CONCLUSION: The ctDNA-based 101-test is a highly sensitive and specific tool for detecting targetable variants in metastatic NSCLC, particularly in cases with insufficient tissue samples. The findings support the use of ctDNA testing as a reliable and complementary method to traditional tissue-based molecular analysis, enhancing the precision of treatment strategies for NSCLC patients.
    Keywords:  circulating tumor DNA; concordance; next‐generation sequencing; targetable variants; tissue sample
    DOI:  https://doi.org/10.1002/cam4.70078
  3. NPJ Breast Cancer. 2024 Oct 08. 10(1): 89
    Discerning the impact of ctDNA detection on patient decision-making in early-stage breast cancer.
    Tarah J Ballinger, Mary Lou Smith, Elda Railey, Greg Zimet, Bryan P Schneider.
      The impact of knowledge of circulating tumor DNA (ctDNA) status on patient decisions in high-risk triple-negative breast cancer (TNBC) weighing benefit and toxicity is unknown. Here, 286 women with a history of non-metastatic breast cancer who had received chemotherapy completed a survey mimicking scenarios of residual TNBC after chemotherapy and unknown, negative, or positive ctDNA status to determine the shift in the decision to receive adjuvant therapy. Participants were then presented scenarios mimicking possible post-neoadjuvant therapies and rated acceptability. A general linear model with repeated measures determined contributions of risk reduction and toxicity. When the hypothetical risk of recurrence mimicked ctDNA negativity, significantly less participants were accepting of adjuvant capecitabine versus no therapy. When presented with ctDNA positivity and increased recurrence risk, the degree of benefit impacted acceptability more than the toxicity profile. As genomic technology advances and ctDNA assays become commercially available, it is imperative to understand the impact on patient decision-making.
    DOI:  https://doi.org/10.1038/s41523-024-00701-y
  4. J Neurooncol. 2024 Oct 08.
    Clinical trial design for novel targeted agents in neuro-oncology.
    Mary Jane Lim-Fat, Katrina Roberto, Patrick Y Wen.
      Biomarker-based clinical trials investigating targeted treatments for brain tumors have surged due to better access to biomarker testing and a deeper grasp of the molecular basis of tumor development. The design of clinical trials is crucial for evaluating safety, confirming effectiveness, and affirming the clinical advantage of novel agents, with the goal of approval by regulatory authorities to expand patient treatment options. Given some challenges unique to brain tumors, early-stage clinical trials for novel targeted agents must integrate pharmacokinetics and tissue-based pharmacodynamic assessments to establish timely go-no-go decisions for larger studies. Surgical window-of-opportunity trials can allow for the comparison of treated and untreated tumor samples, verifying target engagement and its modulatory effects for evidence of biological activity. Due to the challenges of achieving the required sample sizes to power efficacy analyses, later-stage trials of targeted therapies can include basket trials which test one drug on multiple tumor types, while umbrella trials evaluate several biomarkers within a single histology. Platform trials can also be leveraged to investigate multiple biomarker-driven hypotheses within a unified protocol and can incorporate Bayesian algorithms for adaptive randomization. Selecting appropriate endpoints, such as progression-free survival or overall response rate, is crucial and novel response assessment criteria need to be considered in the context of the tumor and therapy being investigated. Lastly, inclusivity in trials is essential to address health disparities and engage diverse patient populations to ensure real-world impact. Future trials should build upon the knowledge gained from both initial achievements and past setbacks in the field.
    Keywords:  Brain metastasis; Clinical trial; Glioma; Meningioma; Precision oncology; Targeted therapy
    DOI:  https://doi.org/10.1007/s11060-024-04846-5
  5. J Circ Biomark. 2024 Jan-Dec;13:13 27-35
    A novel liquid biopsy assay for detection of ERBB2 (HER2) amplification in circulating tumor cells (CTCs).
    Giuseppe Di Caro, Ernest T Lam, David Bourdon, Martin Blankfard, Nilesh Dharajiya, Megan Slade, Emily Williams, Dong Zhang, Rick Wenstrup, Lee Schwartzberg.
      Purpose: Circulating tumor cell (CTC)-based ERBB2 (HER2) assay is a laboratory test developed by Epic Sciences using single-cell genomics to detect ERBB2 (HER2) amplification in CTCs found in the peripheral blood of metastatic breast cancer (MBC) patients.Patients and methods: Peripheral blood was collected in Streck tubes and centrifugation was used to remove plasma and red blood cells. The remaining nucleated cells were deposited on glass slides, immunofluorescent-stained with proprietary antibodies, scanned by a high-definition digital scanner, and analyzed by a proprietary algorithm. In addition, single-cell genomics was performed on selected CTC. Analytical validation was performed using white blood cells from healthy donors and breast cancer cell lines with known levels of ERBB2 amplification. Clinical concordance was assessed on MBC patients whose blood was tested by the CTC ERBB2 (HER2) assay and those results are compared to results of matched metastatic tissue biopsy (immunohistochemistry [IHC] 3+ or IHC2+/in situ hybridization [ISH+]).
    Results: Epic's ERBB2 (HER2) assay detected 2-fold ERBB2 amplification with 85% sensitivity and 94% specificity. In the clinical concordance study, among the 50% of the cases that had ERBB2 status results from CTCs found to be chromosomally-unstable, the CTC ERBB2 (HER2) assay showed sensitivity of 69% and specificity of 78% when compared to HER2 status by metastatic tissue biopsy.
    Conclusions: The CTC ERBB2 (HER2) assay can consistently detect ERBB2 status in MBC cell lines and in the population of patients with MBC with detectable chromosomally unstable CTCs for whom tissue biopsy is not available or is infeasible.
    Keywords:  Analytical validation; Breast cancer; Circulating tumor cells; Epic CTC platform; HER2; Liquid biopsy
    DOI:  https://doi.org/10.33393/jcb.2024.3046
  6. Cancer Imaging. 2024 Oct 07. 24(1): 133
    -New frontiers in domain-inspired radiomics and radiogenomics: increasing role of molecular diagnostics in CNS tumor classification and grading following WHO CNS-5 updates.
    Gagandeep Singh, Annie Singh, Joseph Bae, Sunil Manjila, Vadim Spektor, Prateek Prasanna, Angela Lignelli.
      Gliomas and Glioblastomas represent a significant portion of central nervous system (CNS) tumors associated with high mortality rates and variable prognosis. In 2021, the World Health Organization (WHO) updated its Glioma classification criteria, most notably incorporating molecular markers including CDKN2A/B homozygous deletion, TERT promoter mutation, EGFR amplification, + 7/-10 chromosome copy number changes, and others into the grading and classification of adult and pediatric Gliomas. The inclusion of these markers and the corresponding introduction of new Glioma subtypes has allowed for more specific tailoring of clinical interventions and has inspired a new wave of Radiogenomic studies seeking to leverage medical imaging information to explore the diagnostic and prognostic implications of these new biomarkers. Radiomics, deep learning, and combined approaches have enabled the development of powerful computational tools for MRI analysis correlating imaging characteristics with various molecular biomarkers integrated into the updated WHO CNS-5 guidelines. Recent studies have leveraged these methods to accurately classify Gliomas in accordance with these updated molecular-based criteria based solely on non-invasive MRI, demonstrating the great promise of Radiogenomic tools. In this review, we explore the relative benefits and drawbacks of these computational frameworks and highlight the technical and clinical innovations presented by recent studies in the landscape of fast evolving molecular-based Glioma subtyping. Furthermore, the potential benefits and challenges of incorporating these tools into routine radiological workflows, aiming to enhance patient care and optimize clinical outcomes in the evolving field of CNS tumor management, have been highlighted.
    Keywords:  CNS-5 classification updates; Deep learning; Glioblastoma; Gliomas; Machine learning; Radiogenomics; Radiomics
    DOI:  https://doi.org/10.1186/s40644-024-00769-6
  7. Sci Rep. 2024 10 08. 14(1): 23454
    Evaluation of blood MSI burden dynamics to trace immune checkpoint inhibitor therapy efficacy through the course of treatment.
    Egor Veselovsky, Alexandra Lebedeva, Olesya Kuznetsova, Daria Kravchuk, Ekaterina Belova, Anastasia Taraskina, Tatiana Grigoreva, Alexandra Kavun, Victoria Yudina, Laima Belyaeva, Vladislav Nikulin, Vladislav Mileyko, Alexey Tryakin, Mikhail Fedyanin, Maxim Ivanov.
      Analysis of serial liquid biopsy (LB) samples has been found to be a promising approach for the monitoring of tumor dynamics in the course of therapy for patients with colorectal cancer (CRC). Currently, somatic mutations are used for tracing the dynamics of the tumor via LB. However, the analysis of the dynamic changes in the molecular signatures such as microsatellite instability (MSI) is not currently used. We hypothesized that changes in blood MSI burden (bMSI) could be registered using serial LB sampling in the course of immune checkpoint inhibitors (ICI), and that its changes could potentially correlate with treatment outcomes. We report the preliminary findings of the observational trial launched to study (NCT06414304) the dynamics of bMSI in 9 MSI-positive CRC patients receiving ICI. NGS-based MSI testing was performed on both pre-treatment FFPE and serial LB samples. For patients who had detectable bMSI burden in any of the LB samples (n = 8, 89%), median bMSI was 1.4% (range, 0.01-40%). Among patients with detectable MSI in available FFPE samples, median MSI burden was 29.3% (range, 10-40%). bMSI detected in baseline LB and FFPE samples were positively correlated (Pearson's R 0.47). Maximal variant allele frequencies of driver mutations observed in LB were also positively correlated with bMSI burden (Pearson's R 0.7). Patients who had clinical benefit had undetectable bMSI burden at follow-up. Our results provide the rationale for further validation of bMSI as a predictive biomarker of ICI in MSI-positive patients.
    Keywords:  Colorectal cancer; Immune checkpoint inhibitors; Immunotherapy; Liquid biopsy; Microsatellite instability; Next-generation sequencing
    DOI:  https://doi.org/10.1038/s41598-024-73952-1
  8. PLoS One. 2024 ;19(10): e0306386
    Characterization of somatic mutations in sporadic uveal melanoma and uveal melanoma in patients with germline BAP1 pathogenic variants.
    Karin A W Wadt, Katja Harbst, Mette M B Sjøl, Frida Rosengren, Christina Westmose Yde, Kristoffer Staal Rohrberg, Marlene Richter Jensen, Steffen Heegaard, Jens Folke Kiilgaard, Anne-Marie Gerdes, Nicholas Hayward, Göran B Jönsson.
      Genetic analyses were conducted on tumor samples from 88 patients with uveal melanoma (UM), 6 of whom carry pathogenic germline variants in BAP1. We assessed the frequency, pattern, and prognostic significance of somatic aberrations, and investigated differences between germline BAP1 variant carriers compared to sporadic cases. The frequency of the main oncogenic driver mutations was not significantly different between these groups. Patients with germline BAP1 variants did not have significantly different overall survival compared to the wildtype or somatic BAP1 mutation groups. Patients with a somatic BAP1 mutation (n = 24) had a significantly worse prognosis compared to wildtype (n = 58). All patients with stage III tumors and a somatic BAP1 mutation (n = 7) developed metastasis, however four of 28 stage I-II tumors without metastasis had somatic BAP1 mutations, with observation time >5 years. The tumor from one germline BAP1 carrier (stage IIIC) with a somatic EIF1AX splice variant, has not developed metastasis within a 22-year observation time.
    DOI:  https://doi.org/10.1371/journal.pone.0306386
  9. Target Oncol. 2024 Oct 05.
    Single-Hit and Multi-hit PIK3CA Short Variant Genomic Alterations in Clinically Advanced Prostate Cancer: A Genomic Landscape Study.
    Michael F Basin, Carla M Miguel, Joseph M Jacob, Hanan Goldberg, Petros Grivas, Philippe E Spiess, Andrea Necchi, Ashish M Kamat, Dean C Pavlick, Richard S P Huang, Douglas I Lin, Natalie Danziger, Ethan S Sokol, Smruthy Sivakumar, Ryon Graf, Liang Cheng, Neil Vasan, Jeffrey Ross, Alina Basnet, Gennady Bratslavsky.
      BACKGROUND: Tumors harboring two or more PIK3CA short variant (SV) ("multi-hit") mutations have been linked to improved outcomes with anti-PIK3CA-targeted therapies in breast cancer. The landscape and clinical implications of multi-hit PIK3CA alterations in clinically advanced prostate cancer (CAPC) remains elusive.OBJECTIVE: To evaluate the genomic landscape of single-hit and multi-hit PIK3CA genomic alterations in CAPC.
    PATIENTS AND METHODS: The Foundation Medicine FoundationCore database was used to identify 19,978 CAPC tumors that underwent hybrid capture-based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA) and determine tumor mutational burden (TMB), microsatellite instability (MSI), genomic ancestry, single-base substitution mutational signatures, and homologous recombination deficiency signature (HRDsig). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3).
    RESULTS: 18,741 (93.8%) tumors were PIK3CA wild type (WT), 1155 (5.8%) featured single PIK3CA SV, and 82 (0.4%) featured multi-hit PIK3CA SVs. Single-hit (6.6 versus 3.8; p < 0.0001) and multi-hit (12.8 versus 3.8; p < 0.0001) featured more driver GA per tumor than PIK3CA WT CAPC, as well as higher prevalence of MMR mutational signature, MSI high status, and TMB levels versus PIK3CA WT (p < 0.0001). Other differences in GA included higher frequencies of GA in BRCA2 in multi-hit versus WT (18.3% versus 8.5%; p = 0.0191), ATM in multi-hit versus WT (13.4% versus 5.6%; p = 0.02) and PTEN in single-hit versus WT (40.2% versus 30.1%; p < 0.0001). Homologous recombination deficiency signatures were higher in PIK3CA WT versus single-hit (11.2% versus 7.6%; p = 0.0002). There were no significant differences in PD-L1 expression among the three groups.
    CONCLUSIONS: Identification of multi-hit PIK3CA GA in CAPC highlights a potentially unique phenotype that may be associated with response to anti-PIK3CA targeted therapy and checkpoint inhibition, supporting relevant clinical trial designs.
    DOI:  https://doi.org/10.1007/s11523-024-01100-w
  10. Gastric Cancer. 2024 Oct 05.
    Circulating tumor DNA predicts recurrence and survival in patients with resectable gastric and gastroesophageal junction cancer.
    Cecilie Riis Iden, Salah Mohammad Mustafa, Nadia Øgaard, Tenna Henriksen, Sarah Østrup Jensen, Lise Barlebo Ahlborn, Kristian Egebjerg, Lene Baeksgaard, Rajendra Singh Garbyal, Mette Kjølhede Nedergaard, Michael Patrick Achiam, Claus Lindbjerg Andersen, Morten Mau-Sørensen.
      BACKGROUND: Gastric and gastroesophageal junction (GEJ) cancer represents a significant global health challenge, with high recurrence rates and poor survival outcomes. This study investigates circulating tumor DNA (ctDNA) as a biomarker for assessing recurrence risk in patients with resectable gastric and GEJ adenocarcinomas (AC).METHODS: Patients with resectable gastric and GEJ AC, undergoing perioperative chemotherapy and surgery, were prospectively enrolled. Serial plasma samples were collected at baseline, after one cycle of chemotherapy, after preoperative chemotherapy, and after surgery. ctDNA was assessed by a ddPCR test (TriMeth), which targets the gastrointestinal cancer-specific methylation patterns of the genes C9orf50, KCNQ5, and CLIP4.
    RESULTS: ctDNA analysis was performed on 229 plasma samples from 86 patients. At baseline, ctDNA was detected in 56% of patients, which decreased to 37% following one cycle of chemotherapy, 25% after preoperative chemotherapy and 15% after surgical resection. The presence of ctDNA after one cycle of chemotherapy was associated with reduced recurrence-free survival (RFS) (HR = 2.54, 95% confidence interval (CI) 1.33-4.85, p = 0.005) and overall survival (OS) (HR = 2.23, 95% CI 1.07-4.62, p = 0.032). Similarly, ctDNA after surgery was associated with significantly shorter RFS (HR = 6.22, 95% CI 2.39-16.2, p < 0.001) and OS (HR = 6.37, 95% CI 2.10-19.3, p = 0.001). Multivariable regression analysis confirmed ctDNA after surgery as an independent prognostic factor (p < 0.001).
    CONCLUSION: ctDNA analysis has the potential to identify patients at elevated risk of recurrence, thus providing personalized treatment strategies for patients with resectable gastric and GEJ cancer. Further validation in larger cohorts and ctDNA-guided interventions are needed for future clinical use.
    Keywords:  Circulating tumor DNA; Curative treatment; DNA methylation; Gastroesophageal cancer; Tumor biomarkers
    DOI:  https://doi.org/10.1007/s10120-024-01556-9
  11. Int J Gen Med. 2024 ;17 4507-4517
    Dissecting the Clinical Characteristics and Treatment Outcomes Correlates of KRAS G12C-Mutated Non-Small Cell Lung Cancer.
    Yawan Jing, Ruixin Cheng, Hao Zeng, Qin Huang, Dongyu He, Jiayi Sun, Panwen Tian, Yalun Li.
      Background: KRAS mutation is one of the most common driver oncogenes in non-small cell lung cancer (NSCLC), and the most common mutation subtype is G12C. However, there is still a lack of efficacy and prognosis data related to immunotherapy, which hinders the promotion of new strategies.Methods: Clinical characteristics and treatment outcomes were collected and analyzed for patients with NSCLC harboring KRAS mutations at West China Hospital of Sichuan University from June 2013 to March 2023.
    Results: Among the 231 patients with KRAS-mutated NSCLC, 29.4% had KRAS G12C mutations. Compared to the KRAS non-G12C NSCLC group, the KRAS G12C NSCLC group had a greater number of pack-years. The programmed death ligand 1 expression and the proportion of patients with a high tumor mutational burden were not significantly different between the two groups. Similar patterns of TP53, STK11, and CDKN2A mutations were observed between KRAS G12C and KRAS non-G12C NSCLC groups. The median progression-free survival (PFS) (8.4 vs 7.0 months, p=0.100) and overall survival (OS) (12.1 vs 18.1 months, p=0.590) were not statistically different between KRAS G12C and KRAS non-G12C. Compared to patients with KRAS G12C NSCLC who did not receive immunotherapy, patients who received immunotherapy had a better objective response rate (46.2% vs 0%, p=0.002), PFS (12.2 vs 7.5 months, p=0.087) and OS (49.9 vs 11.1 months, p=0.12).
    Conclusion: Patients with KRAS G12C were more likely to be smokers. Advanced KRAS G12C NSCLC patients who received immunotherapy had a better ORR than those who did not, suggesting that patients with G12C mutations are more likely to benefit from immunotherapy.
    Keywords:  KRAS G12C mutation; KRAS mutation; immunotherapy; non-small cell lung cancer; overall survival
    DOI:  https://doi.org/10.2147/IJGM.S484435
  12. BMC Med. 2024 Oct 08. 22(1): 428
    Updated overall survival and ctDNA analysis in patients with EGFR T790M-positive advanced non-small cell lung cancer treated with lazertinib in the phase 1/2 LASER201 study.
    Ji-Youn Han, Myung-Ju Ahn, Ki Hyeong Lee, Yun-Gyoo Lee, Dong-Wan Kim, Young Joo Min, Sang-We Kim, Eun Kyung Cho, Joo-Hang Kim, Gyeong-Won Lee, Sung Sook Lee, Na Mi Lee, Hyun Woo Jang, Heewon Han, Hyejoo Park, Jieon Lee, Byoung Chul Cho.
      BACKGROUND: Lazertinib is a potent, irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with significant efficacy in patients with EGFR T790M-mutated non-small cell lung cancer (NSCLC). This is the final overall survival (OS) report from the phase 1/2 LASER201 study in patients with advanced NSCLC with disease progression on or after prior EGFR TKI therapy.METHODS: Eligible patients were aged ≥ 20 years, with advanced EGFR-mutated NSCLC and previous therapy with EGFR TKI. Patients in this integrated analysis received oral lazertinib 240 mg/day. Endpoints included efficacy and safety; exploratory analyses included associations between circulating EGFR-mutant tumor DNA (ctDNA) and efficacy parameters.
    RESULTS: This integrated analysis included 78 patients in Korea who received second- or later-line lazertinib. The median OS was 38.9 months; estimated survival rates at 12, 24, and 36 months were 89.5%, 73.9%, and 52.8%, respectively. The cumulative 12-month incidence of central nervous system progression was 9.4%. EGFR-mutant ctDNA was detected in 46 patients (62.2%) at baseline. The presence of ctDNA at baseline significantly predicted progression-free survival (PFS), disease control rate (DCR), and OS. PFS, response rate, and DCR were significantly associated with EGFR-mutant ctDNA clearance at cycle 3; PFS and OS were significantly associated with ctDNA clearance at cycle 5. The safety profile of lazertinib 240 mg/day was consistent with previous findings.
    CONCLUSIONS: Lazertinib is a promising treatment option for patients with EGFR T790M-positive NSCLC following disease progression on prior EGFR-directed TKIs. Patients in LASER201 experienced prolonged OS, regardless of their EGFR mutation, brain metastases, or prior brain radiation status. Clearance of plasma EGFR mutations after lazertinib was associated with patient outcomes.
    TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03046992.
    Keywords:  Lazertinib; NSCLC; Overall survival; TKI; ctDNA
    DOI:  https://doi.org/10.1186/s12916-024-03620-8
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒05 at 10:20.