LBA52 Tepotinib + osimertinib for EGFRm NSCLC with MET amplification (METamp) after progression on first-line (1L) osimertinib: Initial results from the INSIGHT 2 study

Kim, T.M.; Lim, Boon-Khaw; Wislez, Marie; Dooms, Christophe; Finocchiaro, Giovanna; Hayashi, Hiroko; Ck, Liam; Raskin, Jo; Tho, L.M.; Marinis, Filippo de; Nadal, Ernest; Smit, Ewoud J.; Le, Xiao-Feng; Brutlach, S.; Grupp, A.M. O'Brate; Adrian, Svenja; Karachaliou, Niki; Wu, Yi‐Long

doi:10.1016/j.annonc.2022.08.054

Cited by 30 publications

(30 citation statements)

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“…The INSIGHT2 trial tested the combination of tepotinib (MET TKI) plus osimertinib for patients with EGFR-mutant NSCLC whose tumors acquired METamp after progression on first-line osimertinib. This study showed an ORR of 45-56% based on METamp detection from tissue or liquid biopsy (48).…”

Section: Activation Of Parallel Pathwaysmentioning

confidence: 65%

Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review

Desai¹,

Lovly²

2023

Transl Lung Cancer Res

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Background and Objective: Anaplastic lymphoma kinase (ALK) rearrangements are detected in 3-7% of advanced non-small cell lung cancer (NSCLC). There are currently 5 U.S Food and Drug Administration (FDA)-approved ALK tyrosine kinase inhibitors (TKIs) for the treatment of patients with ALK-positive lung cancer in the advanced/metastatic disease setting. Despite these advances, most patients with ALK-positive lung cancer who are treated with ALK TKI therapy ultimately experience disease progression due to various mechanisms of drug resistance. In this review, we discuss strategies to address acquired therapeutic resistance to ALK inhibition, novel agents and combinatorial strategies in development for both on and off-target resistance, and some emerging approaches to prolong response to ALK inhibitors.Methods: We performed a search of peer-reviewed literature in the English language, conference abstracts, and trial registrations from the MEDLINE (Ovid), Embase (Elsevier), and CENTRAL (Cochrane Library) databases and major international oncology meetings up to August 2022. We then screened for studies describing interventions to overcome ALK resistance based on review of each title and abstract. Key Content and Findings: For patients with oligo-progression, treatment may include maintaining the same systemic treatment beyond progression while adding local therapies to progressing lesions. Strategies to combat ALK TKI resistance mediated by on-target resistance mechanisms include 4 th generation TKIs (TPX-0131, NVL-655) and Proteolysis-targeting chimeras (PROTACs) currently in development. While for those patients who develop tumor progression due to off-target (ALK independent) resistance, options may include combination therapies targeting ALK and other downstream or parallel pathways, novel antibody drug conjugates, or combinations of ALK inhibitors with chemotherapy and immunotherapy. Lastly, other potential strategies being explored in the clinic include circulating tumor DNA (ctDNA) surveillance to monitor for molecular mediators of drug resistance prior to frank progression on imaging studies and utilization of ALK TKIs in the adjuvant and neoadjuvant settings.Conclusions: Strategies to overcome resistance to currently available ALK inhibitors are urgently needed.Given the variety of resistance mechanisms, tailormade approaches are required for disease control.

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Section: Activation Of Parallel Pathwaysmentioning

confidence: 65%

Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review

Desai¹,

Lovly²

2023

Transl Lung Cancer Res

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“…However, as acquired resistance mechanisms to osimertinib are heterogenous, perhaps the application of NGS panels to analyze ctDNA is the best approach as it allows the detection of actionable genomic alterations [9]. For instance, in 10-30% of patients with EGFR-mutant NSCLC treated with first-line osimertinib, the acquired resistance mechanism is the development of MET amplification [10]. In the INSIGHT 2 study, this amplification could be detected by fluorescence in-situ hybridization (FISH) in tissue biopsy and/or NGS in liquid biopsy [10]; another important resistance mechanism is small-cell lung cancer transformation (3-10% of all EGFR TKI cases) [9].…”

Section: Discussionmentioning

confidence: 99%

“…For instance, in 10-30% of patients with EGFR-mutant NSCLC treated with first-line osimertinib, the acquired resistance mechanism is the development of MET amplification [10]. In the INSIGHT 2 study, this amplification could be detected by fluorescence in-situ hybridization (FISH) in tissue biopsy and/or NGS in liquid biopsy [10]; another important resistance mechanism is small-cell lung cancer transformation (3-10% of all EGFR TKI cases) [9]. Due to the frequent use of liquid biopsy and the absence of re-biopsy at the time of progression, this incidence may be underestimated [9].…”

Section: Discussionmentioning

confidence: 99%

A Case of Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer: Multi-Line Treatment and Resistance Mechanisms

Teixeira¹,

Fernandes²,

Rodrigues³

2023

Cureus

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In the non-small-cell lung cancer (NSCLC) subtype, adenocarcinoma is the most common histology. The choice of first-line treatment depends on the mutational status.We present a case of a 54-year-old non-smoker woman with lung adenocarcinoma and extensive metastatic disease at diagnosis. The genetic analysis demonstrated a sensitizing epidermal growth factor receptor (EGFR) exon 19 mutation and she began treatment with a first-generation EGFR tyrosine kinase inhibitor (TKI), erlotinib. Due to successively acquired resistances and disease progression, six treatment lines were pursued, including third-generation EGFR TKI and chemotherapy. The patient accomplished an overall survival of 47 months. This case emphasized the importance of monitoring tumor mutational alterations, allowing us to implement a multi-line treatment. Targeted therapy in advanced NSCLC largely improved the overall survival of these patients.

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“…The two-arm Phase II INSIGHT 2 study addressed the response to the combination of tepotinib plus osimertinib for patients with advanced EGFR-mutated NSCLC with MET amplification that recurred after first-line osimertinib. 9 About 425 subjects with advanced EGFR-mutated NSCLC were screened for MET amplification following progression on the TKI osimertinib. Of these, 25% resulted positive for MET amplification via fluorescent in situ hybridisation in tissue biopsy samples, 3% were positive by NGS liquid biopsy, and 8% had MET amplification with both methods.…”

Section: Investigating Resistance Using Liquid Biopsy Has a Clear Pot...mentioning

confidence: 99%

Precision Medicine and Next-Generation Sequencing Diagnostic at European Society for Medical Oncology Congress 2022: The Unbreakable Bond

Rolando¹,

Quagliata²

2022

EMJ Oncol

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LBA52 Tepotinib + osimertinib for EGFRm NSCLC with MET amplification (METamp) after progression on first-line (1L) osimertinib: Initial results from the INSIGHT 2 study

Cited by 30 publications

References 0 publications

Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review

Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review

A Case of Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer: Multi-Line Treatment and Resistance Mechanisms

Precision Medicine and Next-Generation Sequencing Diagnostic at European Society for Medical Oncology Congress 2022: The Unbreakable Bond

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