Displaying publications 21 - 40 of 41 in total

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  1. Loh TC, Pang YK, Liam CK, Chew MF, Tan JL
    Respirol Case Rep, 2022 Oct;10(10):e01030.
    PMID: 36090023 DOI: 10.1002/rcr2.1030
    Metastatic pulmonary calcification (MPC) is characterized by deposition of calcium in the normal lung parenchyma secondary to elevation of serum calcium. Most patients are asymptomatic and routine chest radiograph is not sensitive to make the diagnosis. Further imaging is needed such as computed tomography (CT) which typically shows small centrilobular nodules in the upper lobes. We report a case of a 30-year-old woman with end stage kidney disease who was diagnosed with pulmonary tuberculosis which was then revised to metastatic pulmonary calcification. The CT thorax feature for this patient was atypical for metastatic pulmonary calcification where it demonstrated tree-in-bud nodules suggestive of infection. The final diagnosis was made based on bronchoalveolar lavage which was culture-negative for Mycobacterium and transbronchial lung biopsy demonstrating calcium deposition in the interstitium.
  2. Ang MY, Dymock D, Tan JL, Thong MH, Tan QK, Wong GJ, et al.
    Genome Announc, 2013;1(6).
    PMID: 24309744 DOI: 10.1128/genomeA.01025-13
    Parvimonas micra is an important oral microbe that has the ability to grow and proliferate within oral biofilms and is involved in periodontal disease, leading to gingival bleeding, gingival recession, alveolar bone loss, and tooth mobility. However, occasionally these normally oral pathogens can cause infections at other sites in the body. We present the genome sequence of Parvimonas micra strain A293, a smooth Parvimonas micra strain isolated from an abdominal abscess from a patient at Barts Hospital, London, United Kingdom.
  3. Ang MY, Dymock D, Tan JL, Thong MH, Tan QK, Wong GJ, et al.
    Genome Announc, 2014;2(1).
    PMID: 24526626 DOI: 10.1128/genomeA.00009-14
    Fusobacterium nucleatum is a bacterial species commonly detected in dental plaque within the human oral cavity, with some strains associated with periodontal disease, one of the most common clinical bacterial infections in the human body. The exact mechanisms of its pathogenesis are still not completely understood. In this study, we present the genome sequence and annotation of F. nucleatum strain W1481, isolated from a periodontal pocket of a dental patient at the University of Bristol, United Kingdom, the 16S rRNA gene sequencing of which showed it to be markedly different from the five previously named subspecies.
  4. Choo SW, Wee WY, Ngeow YF, Mitchell W, Tan JL, Wong GJ, et al.
    Sci Rep, 2014;4:4061.
    PMID: 24515248 DOI: 10.1038/srep04061
    Mycobacterium abscessus (Ma) is an emerging human pathogen that causes both soft tissue infections and systemic disease. We present the first comparative whole-genome study of Ma strains isolated from patients of wide geographical origin. We found a high proportion of accessory strain-specific genes indicating an open, non-conservative pan-genome structure, and clear evidence of rapid phage-mediated evolution. Although we found fewer virulence factors in Ma compared to M. tuberculosis, our data indicated that Ma evolves rapidly and therefore should be monitored closely for the acquisition of more pathogenic traits. This comparative study provides a better understanding of Ma and forms the basis for future functional work on this important pathogen.
  5. Ngeow YF, Leong ML, Wong YL, Wong GJ, Tan JL, Wee WY, et al.
    Genome Announc, 2013;1(4).
    PMID: 23990576 DOI: 10.1128/genomeA.00669-13
    Mycobacterium massiliense is a nontuberculous mycobacterium associated with human infections. We report here the draft genome sequence of M. massiliense strain M159, isolated from the bronchial aspirate of a patient who had a pulmonary infection. This strain showed genotypic and in vitro resistance to a number of tetracyclines and beta-lactam antibiotics.
  6. Poh ME, Liam CK, Mun KS, Chai CS, Wong CK, Tan JL, et al.
    Thorac Cancer, 2019 09;10(9):1841-1845.
    PMID: 31350945 DOI: 10.1111/1759-7714.13156
    Adjuvant chemotherapy has long been indicated to extend survival in completely resected stage IB to IIIA non-small cell lung cancer (NSCLC). However, there is accumulating evidence that chemotherapy or chemoradiotherapy can induce epithelial-to-mesenchymal transition (EMT) in disseminated or circulating NSCLC cells. Here, we describe the first case of EMT as the cause of recurrence and metastasis in a patient with resected stage IIB lung adenosquamous carcinoma after adjuvant chemotherapy. We review the literature and explore the possible mechanisms by which EMT occurs in disseminated tumor cells (DTC) or circulating tumor cells (CTC) in response to adjuvant chemotherapy (cisplatin) as a stressor. We also explore the possible therapeutic strategies to reverse EMT in patients with recurrence. In summary, although adjuvant cisplatin-based chemotherapy in resected NSCLC does extend survival, it may lead to the adverse phenomenon of EMT in disseminated tumor cells (DTC) or circulating tumor cells (CTC) causing recurrence and metastasis.
  7. Oong XY, Ng KT, Tan JL, Chan KG, Kamarulzaman A, Chan YF, et al.
    PLoS One, 2017;12(1):e0170610.
    PMID: 28129386 DOI: 10.1371/journal.pone.0170610
    Reassortment of genetic segments between and within influenza B lineages (Victoria and Yamagata) has been shown to generate novel reassortants with unique genetic characteristics. Based on hemagglutinin (HA) and neuraminidase (NA) genes, recent surveillance study has identified reassortment properties in B/Phuket/3073/2013-like virus, which is currently used in the WHO-recommended influenza vaccine. To understand the potential reassortment patterns for all gene segments, four B/Phuket/3073/2013-like viruses and two unique reassortants (one each from Yamagata and Victoria) detected in Malaysia from 2012-2014 were subjected to whole-genome sequencing. Each gene was phylogenetically classified into lineages, clades and sub-clades. Three B/Phuket/3073/2013-like viruses from Yamagata lineage were found to be intra-clade reassortants, possessing PA and NA genes derived from Stockholm/12-like sub-clade, while the remaining genes from Wisconsin/01-like sub-clade (both sub-clades were within Yamagata Clade 3/Yam-3). However, the other B/Phuket/3073/2013-like virus had NS gene that derived from Stockholm/12-like sub-clade instead of Wisconsin/01-like sub-clade. One inter-clade reassortant had Yamagata Clade 2/Yam-2-derived HA and NP, and its remaining genes were Yam-3-derived. Within Victoria Clade 1/Vic-1 in Victoria lineage, one virus had intra-clade reassortment properties: HA and PB2 from Vic-1B sub-clade, MP and NS from a unique sub-clade "Vic-1C", and the remaining genes from Vic-1A sub-clade. Although random reassortment event may generate unique reassortants, detailed phylogenetic classification of gene segments showed possible genetic linkage between PA and NA genes in B/Phuket/3073/2013-like viruses, which requires further investigation. Understanding on reassortment patterns in influenza B evolution may contribute to future vaccine design.
  8. Tan MC, Ang QX, Yeo YH, San BJ, Ibrahim R, Ng SJ, et al.
    J Innov Card Rhythm Manag, 2024 Mar;15(3):5782-5785.
    PMID: 38584749 DOI: 10.19102/icrm.2024.15035
    Sarcoidosis is a disease that involves multiple organs, including the cardiovascular system. While cardiac sarcoidosis has been increasingly recognized, the impact of sarcoidosis on atrial fibrillation (AF) is not well established. This study aimed to analyze the impact of sarcoidosis on in-hospital outcomes among patients who were admitted for a primary diagnosis of AF. Using the all-payer, nationally representative Nationwide Readmissions Database, our study included patients aged ≥18 years who were admitted for AF between 2017-2020. We stratified the cohort into two groups depending on the presence of sarcoidosis diagnosis. The in-hospital outcomes were assessed between the two groups via propensity score analysis. A total of 1031 (0.27%) AF patients with sarcoidosis and 387,380 (99.73%) AF patients without sarcoidosis were identified in our analysis. Our propensity score analysis of 1031 (50%) patients with AF and sarcoidosis and 1031 (50%) patients with AF but without sarcoidosis revealed comparable outcomes in early mortality (1.55% vs. 1.55%, P = 1.000), prolonged hospital stay (9.51% vs. 9.70%, P = .874), non-home discharge (7.95% vs. 9.89%, P = .108), and 30-day readmission (13.29% vs. 13.69%, P = .797) between the two groups. The cumulative cost of hospitalization was also similar in both groups ($12,632.25 vs. $12,532.63, P = .839). The in-hospital adverse event rates were comparable in both groups. Sarcoidosis is not a risk factor for poorer in-hospital outcomes following AF admission. These findings provide valuable insights into the effectiveness of the current guideline for AF management in patients with concomitant sarcoidosis and AF.
  9. Ngeow YF, Wong YL, Tan JL, Arumugam R, Wong GJ, Ong CS, et al.
    J Bacteriol, 2012 Aug;194(15):4125.
    PMID: 22815444 DOI: 10.1128/JB.00712-12
    Mycobacterium massiliense is a rapidly growing mycobacterial species. The pathogenicity of this subspecies is not well known. We report here the annotated genome sequence of M. massiliense strain M18, which was isolated from a lymph node biopsy specimen from a Malaysian patient suspected of having tuberculous cervical lymphadenitis.
  10. Tan MC, Yeo YH, Tham JW, Tan JL, Fong HK, Tan BE, et al.
    Int J Heart Fail, 2024 Apr;6(2):76-81.
    PMID: 38694934 DOI: 10.36628/ijhf.2023.0020
    BACKGROUND AND OBJECTIVES: Real-world clinical data, outside of clinical trials and expert centers, on adverse events related to the use of SyncCardia total artificial heart (TAH) remain limited. We aim to analyze adverse events related to the use of SynCardia TAH reported to the Food and Drug Administration (FDA)'s Manufacturers and User Defined Experience (MAUDE) database.

    METHODS: We reviewed the FDA's MAUDE database for any adverse events involving the use of SynCardia TAH from 1/01/2012 to 9/30/2020. All the events were independently reviewed by three physicians.

    RESULTS: A total of 1,512 adverse events were identified in 453 "injury and death" reports in the MAUDE database. The most common adverse events reported were infection (20.2%) and device malfunction (20.1%). These were followed by bleeding events (16.5%), respiratory failure (10.1%), cerebrovascular accident (CVA)/other neurological dysfunction (8.7%), renal dysfunction (7.5%), hepatic dysfunction (2.2%), thromboembolic events (1.8%), pericardial effusion (1.8%), and hemolysis (1%). Death was reported in 49.4% of all the reported cases (n=224/453). The most common cause of death was multiorgan failure (n=73, 32.6%), followed by CVA/other non-specific neurological dysfunction (n=44, 19.7%), sepsis (n=24, 10.7%), withdrawal of support (n=20, 8.9%), device malfunction (n=11, 4.9%), bleeding (n=7, 3.1%), respiratory failure (n=7, 3.1%), gastrointestinal disorder (n=6, 2.7%), and cardiomyopathy (n=3, 1.3%).

    CONCLUSIONS: Infection was the most common adverse event following the implantation of TAH. Most of the deaths reported were due to multiorgan failure. Early recognition and management of any possible adverse events after the TAH implantation are essential to improve the procedural outcome and patient survival.

  11. Tan MC, Tan JL, Lee WJ, Srivathsan K, Sorajja D, El Masry H, et al.
    J Arrhythm, 2023 Oct;39(5):784-789.
    PMID: 37799789 DOI: 10.1002/joa3.12898
    BACKGROUND: Real-world clinical data on the adverse events related to the use of cryoballoon catheter for pulmonary vein isolation remains limited.

    OBJECTIVE: To report and describe the adverse events related to the use of Artic Front cryoballoon catheters (Arctic Front, Arctic Front Advance, and Arctic Front Advance Pro) reported in the Food and Drug Administration's (FDA) Manufacturers and User Defined Experience (MAUDE) database.

    METHODS: We reviewed all the adverse events reported to the FDA MAUDE database over a 10.7-year study period from January 01, 2011 to September 31, 2021. All events were independently reviewed by two physicians.

    RESULTS: During the study period, a total of 320 procedural-related adverse events reported in the MAUDE database were identified. The most common adverse event was transient or persistent phrenic nerve palsy (PNP), accounting for 48% of all events. This was followed by cardiac perforation (15%), pulmonary vein stenosis (8%), transient ischemic attack or stroke (6%), vascular injury (4%), transient or persistent ST-elevation myocardial infarction (3%), hemoptysis (2%), pericarditis (2%), and esophageal ulcer or fistula (1%). There were six reported intra-procedural death events as a result of cardiac perforation.

    CONCLUSION: The two most common procedural adverse events associated with cryoballoon ablation were PNP and cardiac perforation. All cases of procedural mortality were due to cardiac perforation.

  12. Tan MC, Yeo YH, Mirza N, San BJ, Tan JL, Lee JZ, et al.
    J Am Heart Assoc, 2024 Apr 02;13(7):e031484.
    PMID: 38533928 DOI: 10.1161/JAHA.123.031484
    BACKGROUND: Despite significant cardiac involvement in sarcoidosis, real-world data on death due to cardiovascular disease among patients with sarcoidosis is not well established.

    METHODS AND RESULTS: We queried the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research database for data on patients with sarcoidosis aged ≥25 years from 1999 to 2020. Diseases of the circulatory system except ischemic heart disease were listed as the underlying cause of death, and sarcoidosis was stated as a contributing cause of death. We calculated age-adjusted mortality rate (AAMR) per 1 million individuals and determined the trends over time by estimating the annual percentage change using the Joinpoint Regression Program. Subgroup analyses were performed on the basis of demographic and geographic factors. In the 22-year study period, 3301 cardiovascular deaths with comorbid sarcoidosis were identified. The AAMR from cardiovascular deaths with comorbid sarcoidosis increased from 0.53 (95% CI, 0.43-0.65) per 1 million individuals in 1999 to 0.87 (95% CI, 0.75-0.98) per 1 million individuals in 2020. Overall, women recorded a higher AAMR compared with men (0.77 [95% CI, 0.74-0.81] versus 0.58 [95% CI, 0.55-0.62]). People with Black ancestry had higher AAMR than people with White ancestry (3.23 [95% CI, 3.07-3.39] versus 0.39 [95% CI, 0.37-0.41]). A higher percentage of death was seen in the age groups of 55 to 64 years in men (23.11%) and women (21.81%), respectively. In terms of US census regions, the South region has the highest AAMR from cardiovascular deaths with comorbid sarcoidosis compared with other regions (0.78 [95% CI, 0.74-0.82]).

    CONCLUSIONS: The increase of AAMR from cardiovascular deaths with comorbid sarcoidosis and higher cardiovascular mortality rates among adults aged 55 to 64 years highlight the importance of early screening for cardiovascular diseases among patients with sarcoidosis.

  13. Ng XJK, Mohd Khairuddin AS, Liu HC, Loh TC, Tan JL, Khor SM, et al.
    Clin Chim Acta, 2025 Feb 11;570:120191.
    PMID: 39947574 DOI: 10.1016/j.cca.2025.120191
    Lung cancer is the leading cause of cancer-related deaths worldwide, primarily due to late-stage detection, which limits treatment options. Early detection and screening can increase survival rates, but traditional medical imaging methods are costly and inconvenient. Point-of-care biosensors present a promising alternative, being user-friendly, less labor-intensive, and minimally invasive. With high sensitivity and selectivity, these biosensors detect lung cancer-associated biomarkers, including protein and nucleic acid, in biological fluids such as serum, urine, and saliva. Integrating artificial intelligence (AI) with biosensors has further improved their performance. AI algorithms can analyze complex data, differentiate lung cancer patients from healthy individuals, and even predict the risk of cancer metastasis. Despite these advancements, a comprehensive review of AI-coupled biosensors for lung cancer screening and detection has not yet been conducted. The clinical translation of these biosensors is challenged by a lack of standardization in biomarker selection, the number of biomarkers tested, and the determination of clinical cut-off values. This review focuses on recent advances in biosensors for lung cancer screening and detection, the challenges in their clinical application, and the role of AI in improving biosensor performance. Additionally, it explores future perspectives on the evolution of AI-assisted biosensors into comprehensive health monitoring systems, aiming to bridge the gap between technological innovation and practical clinical use.
  14. Soo CI, Ong DB, Chin KK, Sia LC, Munusamy V, Ibrahim NH, et al.
    Respirol Case Rep, 2023 Jul;11(7):e01181.
    PMID: 37350988 DOI: 10.1002/rcr2.1181
    Neoadjuvant chemotherapy is a therapeutic option for potentially resectable non-small cell lung cancer (NSCLC). The role of neoadjuvant targeted therapy (NTT) remains less explored. This case highlights the use of neoadjuvant osimertinib in a case of advanced NSCLC. A 67-year-old woman had a left lower lobe lung mass measuring 5.0 × 5.1 × 7.0 cm with an enlarged subcarinal lymph node (LN) on her positron emission tomography scan. Following biopsy, a diagnosis of stage IIIB N2 (cT3N2M0) EGFR exon 19 deletion mutation-positive lung adenocarcinoma was established. NTT using osimertinib 80 mg once daily was commenced. Subsequent re-imaging at 3 months (ycT2bN2M0), 6 months (ycT1cN2M0) and 9 months showed tumour downstaging and resolution of the subcarinal LN (ycT1cN0M0). She underwent left lower lobectomy with systematic nodal dissection. All surgical specimens demonstrated no evidence of malignant cells (ypT0N0). Osimertinib could be the preferred NTT for potentially resectable NSCLC.
  15. Liam CK, Yew CY, Pang YK, Wong CK, Poh ME, Tan JL, et al.
    BMC Cancer, 2023 Jul 14;23(1):659.
    PMID: 37452277 DOI: 10.1186/s12885-023-11156-y
    BACKGROUND: In non-small cell lung cancer (NSCLC), there may be a relationship between programmed death-ligand 1 (PD-L1) expression, driver mutations and cigarette smoking.

    METHODS: In this single-center retrospective study, the relationship between common driver mutations (EGFR mutation and ALK rearrangement) and PD-L1 expression in advanced NSCLC according to the patients' smoking history was examined. Light, moderate and heavy smokers had smoked 

  16. Lee BKB, Gan CP, Chang JK, Tan JL, Fadlullah MZ, Abdul Rahman ZA, et al.
    J Dent Res, 2018 07;97(8):909-916.
    PMID: 29512401 DOI: 10.1177/0022034518759038
    Head and neck cancer (HNC)-derived cell lines represent fundamental models for studying the biological mechanisms underlying cancer development and precision therapies. However, mining the genomic information of HNC cells from available databases requires knowledge on bioinformatics and computational skill sets. Here, we developed a user-friendly web resource for exploring, visualizing, and analyzing genomics information of commonly used HNC cell lines. We populated the current version of GENIPAC with 44 HNC cell lines from 3 studies: ORL Series, OPC-22, and H Series. Specifically, the mRNA expressions for all the 3 studies were derived with RNA-seq. The copy number alterations analysis of ORL Series was performed on the Genome Wide Human Cytoscan HD array, while copy number alterations for OPC-22 were derived from whole exome sequencing. Mutations from ORL Series and H Series were derived from RNA-seq information, while OPC-22 was based on whole exome sequencing. All genomic information was preprocessed with customized scripts and underwent data validation and correction through data set validator tools provided by cBioPortal. The clinical and genomic information of 44 HNC cell lines are easily assessable in GENIPAC. The functional utility of GENIPAC was demonstrated with some of the genomic alterations that are commonly reported in HNC, such as TP53, EGFR, CCND1, and PIK3CA. We showed that these genomic alterations as reported in The Cancer Genome Atlas database were recapitulated in the HNC cell lines in GENIPAC. Importantly, genomic alterations within pathways could be simultaneously visualized. We developed GENIPAC to create access to genomic information on HNC cell lines. This cancer omics initiative will help the research community to accelerate better understanding of HNC and the development of new precision therapeutic options for HNC treatment. GENIPAC is freely available at http://genipac.cancerresearch.my/ .
  17. Sapriel G, Konjek J, Orgeur M, Bouri L, Frézal L, Roux AL, et al.
    BMC Genomics, 2016 Feb 17;17:118.
    PMID: 26884275 DOI: 10.1186/s12864-016-2448-1
    In mycobacteria, conjugation differs from the canonical Hfr model, but is still poorly understood. Here, we quantified this evolutionary processe in a natural mycobacterial population, taking advantage of a large clinical strain collection of the emerging pathogen Mycobacterium abscessus (MAB).
  18. Pang YK, Ismail AI, Chan YF, Cheong A, Chong YM, Doshi P, et al.
    BMC Infect Dis, 2021 Jul 05;21(1):644.
    PMID: 34225647 DOI: 10.1186/s12879-021-06360-9
    BACKGROUND: Available data on influenza burden across Southeast Asia are largely limited to pediatric populations, with inconsistent findings.

    METHODS: We conducted a multicenter, hospital-based active surveillance study of adults in Malaysia with community-acquired pneumonia (CAP), acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and acute exacerbation of asthma (AEBA), who had influenza-like illness ≤10 days before hospitalization. We estimated the rate of laboratory-confirmed influenza and associated complications over 13 months (July 2018-August 2019) and described the distribution of causative influenza strains. We evaluated predictors of laboratory-confirmed influenza and severe clinical outcomes using multivariate analysis.

    RESULTS: Of 1106 included patients, 114 (10.3%) were influenza-positive; most were influenza A (85.1%), with A/H1N1pdm09 being the predominant circulating strain during the study following a shift from A/H3N2 from January-February 2019 onwards. In multivariate analyses, an absence of comorbidities (none versus any comorbidity [OR (95%CI), 0.565 (0.329-0.970)], p = 0.038) and of dyspnea (0.544 (0.341-0.868)], p = 0.011) were associated with increased risk of influenza positivity. Overall, 184/1106 (16.6%) patients were admitted to intensive care or high-dependency units (ICU/HDU) (13.2% were influenza positive) and 26/1106 (2.4%) died (2.6% were influenza positive). Males were more likely to have a severe outcome (ICU/HDU admission or death).

    CONCLUSIONS: Influenza was a significant contributor to hospitalizations associated with CAP, AECOPD and AEBA. However, it was not associated with ICU/HDU admission in this population. Study registration, NMRR ID: NMRR-17-889-35,174.

  19. Tiew PY, Dicker AJ, Keir HR, Poh ME, Pang SL, Mac Aogáin M, et al.
    Eur Respir J, 2021 Mar;57(3).
    PMID: 32972986 DOI: 10.1183/13993003.02050-2020
    INTRODUCTION: The chronic obstructive pulmonary disease (COPD) bacteriome associates with disease severity, exacerbations and mortality. While COPD patients are susceptible to fungal sensitisation, the role of the fungal mycobiome remains uncertain.

    METHODS: We report the largest multicentre evaluation of the COPD airway mycobiome to date, including participants from Asia (Singapore and Malaysia) and the UK (Scotland) when stable (n=337) and during exacerbations (n=66) as well as nondiseased (healthy) controls (n=47). Longitudinal mycobiome analysis was performed during and following COPD exacerbations (n=34), and examined in terms of exacerbation frequency, 2-year mortality and occurrence of serum specific IgE (sIgE) against selected fungi.

    RESULTS: A distinct mycobiome profile is observed in COPD compared with controls as evidenced by increased α-diversity (Shannon index; p<0.001). Significant airway mycobiome differences, including greater interfungal interaction (by co-occurrence), characterise very frequent COPD exacerbators (three or more exacerbations per year) (permutational multivariate ANOVA; adjusted p<0.001). Longitudinal analyses during exacerbations and following treatment with antibiotics and corticosteroids did not reveal any significant change in airway mycobiome profile. Unsupervised clustering resulted in two clinically distinct COPD groups: one with increased symptoms (COPD Assessment Test score) and Saccharomyces dominance, and another with very frequent exacerbations and higher mortality characterised by Aspergillus, Curvularia and Penicillium with a concomitant increase in serum sIgE levels against the same fungi. During acute exacerbations of COPD, lower fungal diversity associates with higher 2-year mortality.

    CONCLUSION: The airway mycobiome in COPD is characterised by specific fungal genera associated with exacerbations and increased mortality.

  20. Passaro A, Wang J, Wang Y, Lee SH, Melosky B, Shih JY, et al.
    Ann Oncol, 2024 Jan;35(1):77-90.
    PMID: 37879444 DOI: 10.1016/j.annonc.2023.10.117
    BACKGROUND: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial.

    PATIENTS AND METHODS: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion.

    RESULTS: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy.

    CONCLUSIONS: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.

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