Earlier extracranial progression and shorter survival in ALK- rearranged lung cancer with positive liquid rebiopsies

Christopoulos, Petros; Dietz, Stefanie; Angeles, Arlou Kristina; Rheinheimer, Stephan; Kazdal, Daniel; Volckmar, Anna‐Lena; Janke, Florian; Endris, Volker; Meister, Michael; Kriegsmann, Mark; Zemojtel, Thomasz; Reck, Martin; Thomas, Michael; Sültmann, Holger

doi:10.21037/tlcr-21-32

Cited by 16 publications

(19 citation statements)

References 60 publications

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“…In our study population, VAF mean > 0 at therapy baseline predicted shorter therapy duration compared to cases without detected variants (VAF mean = 0). This parallels findings demonstrating that ctDNA at baseline indicates poor prognosis in various cancers 18 , 27 , 45 – 47 . Pretreatment VAF levels have also been shown to be prognostic of treatment response with immune checkpoint inhibitors in patients with advanced solid tumors 31 , 48 .…”

Section: Discussionsupporting

confidence: 86%

Early identification of disease progression in ALK-rearranged lung cancer using circulating tumor DNA analysis

et al. 2021

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Targeted kinase inhibitors improve the prognosis of lung cancer patients with ALK alterations (ALK+). However, due to the emergence of acquired resistance and varied clinical trajectories, early detection of disease progression is warranted to guide patient management and therapy decisions. We utilized 343 longitudinal plasma DNA samples from 43 ALK+ NSCLC patients receiving ALK-directed therapies to determine molecular progression based on matched panel-based targeted next-generation sequencing (tNGS), and shallow whole-genome sequencing (sWGS). ALK-related alterations were detected in 22 out of 43 (51%) patients. Among 343 longitudinal plasma samples analyzed, 174 (51%) were ctDNA-positive. ALK variant and fusion kinetics generally reflected the disease course. Evidence for early molecular progression was observed in 19 patients (44%). Detection of ctDNA at therapy baseline indicated shorter times to progression compared to cases without mutations at baseline. In patients who succumbed to the disease, ctDNA levels were highly elevated towards the end of life. Our results demonstrate the potential utility of these NGS assays in the clinical management of ALK+ NSCLC.

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Section: Discussionsupporting

confidence: 86%

Early identification of disease progression in ALK-rearranged lung cancer using circulating tumor DNA analysis

et al. 2021

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“…Several studies reported a compound mutations rate of ∼30%-35% on treatment with multiple lines of ALK TKI. 28 , 29 Here, we identified three compound mutations, ALK D1203N/L1196M, ALK G1202R/L1196M, and ALK G1202R/F1174C, after patients progressed on later-line lorlatinib. G1202R-based compound mutations including ALK G1202R/L1196M, ALK G1202R/F1174C, ALK G1202R/l1198F, ALK G1202R/G1269A have been shown to be potentially lorlatinib resistant through steric hindrances in the ALK kinase domain.…”

Section: Discussionmentioning

confidence: 91%

Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients

Hua

Zhang

et al. 2022

ESMO Open

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Background: Sequential treatment with different generations of anaplastic lymphoma kinase (ALK) inhibitors have been widely applied to ALK-positive lung cancer; however, resistance mutations inevitably developed. Further characterization of ALK resistance mutations may provide key guidance to subsequent therapies. Here we explored the emergence of secondary ALK mutations during sequential ALK tyrosine kinase inhibitor (TKI) treatment in a realworld study of Chinese lung adenocarcinoma (ADC) patients. Methods: A clinical-genomic database was queried for lung ADC patients with at least one ALK inhibitor treatment and at least one plasma sample collected following ALK inhibitor treatment. Targeted genome profiling was performed with a 139-gene panel in baseline tumor tissue and serial plasma samples of patients. Results: A total of 116 patients met inclusion criteria. ALK G1202R was more common in patients with echinoderm microtubule-associated protein-like 4 (EML4)-ALK v3 fusion, whereas ALK L1196M was more common in v1. TP53 mutant patients were significantly associated with harboring multiple ALK resistance mutations (P ¼ 0.03) and v3þ/ TP53 mutant patients had the highest rate of multiple ALK resistance mutations. The sequential use of ALK TKI led to an increased incidence of concurrent ALK mutations along the lines of therapies. Alectinib had a lower rate (9%) harboring ALK resistance mutation as first-line ALK TKI compared with crizotinib (36%). ALK compound mutations identified included ALK D1203N/L1196M, ALK G1202R/L1196M, and ALK G1202R/F1174C, which may be lorlatinib resistant. Using paired pretreatment and post-treatment samples, we identified several ALK-independent resistancerelated genetic alterations, including PTPRD and CNKN2A/B loss, MYC, MYCN and KRAS amplification, and EGFR 19del . Conclusions: Sequential postprogression plasma profiling revealed that increased lines of ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance, which may provide guidance for clinical decision making.

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“…In this context and considering that in lung cancer the tumor is often difficult to reach and may need an invasive and potentially harmful procedure, the continuing development of the analyses of liquid biopsies can noninvasively detect any targetable genomic alteration and guide corresponding targeted therapy. Moreover, liquid biopsy might help in monitoring the response to treatment and exploring the genetic changes at resistance, overcoming spatial and temporal heterogeneity [43,44].…”

Section: Discussionmentioning

confidence: 99%

Systemic Therapy for Oligoprogression in Patients with Metastatic NSCLC Harboring Activating EGFR Mutations

Rossi¹,

Galetta

2022

Cancers

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After a variable period of activity of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment, patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations develop resistance to these TKIs. In some cases, an oligoprogression is diagnosed, and its management is still controversial. The oligoprogression represents an intermediate stage of metastatic NSCLC between localized and widely disseminated disease, and is characterized by a limited number and/or sites of metastases in which a disease progression appears, together with a more indolent tumor biology. Currently, the management of oligoprogressed NSCLC involves local treatment, including radiotherapy and/or surgery, to control the progressive lesions. Systemic therapy should also be a potential approach to boost the activity of EGFR-TKIs. However, considering the lack of large trials addressing this topic, the optimal therapeutic strategies remain undefined and should be evaluated on an individualized basis. In this paper, we review the most relevant scientific evidence of continuing the systemic therapy with the same EGFR-TKI for the management of patients with NSCLC harboring EGFR mutations and oligoprogressed to first-line EGFR-TKIs, also discussing the controversies and potential future directions.

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Earlier extracranial progression and shorter survival in ALK- rearranged lung cancer with positive liquid rebiopsies

Cited by 16 publications

References 60 publications

Early identification of disease progression in ALK-rearranged lung cancer using circulating tumor DNA analysis

Early identification of disease progression in ALK-rearranged lung cancer using circulating tumor DNA analysis

Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients

Systemic Therapy for Oligoprogression in Patients with Metastatic NSCLC Harboring Activating EGFR Mutations

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