Outcome of EGFR-mutated NSCLC patients with MET-driven resistance to EGFR tyrosine kinase inhibitors

Baldacci, S.; Mazières, Julien; Tomasini, Pascale; Girard, Nicolas; Guisier, Florian; Audigier-Valette, Clarisse; Monnet, I.; Wislez, Marie; Pérol, Maurice; Dô, Pascal; Dansin, Éric; Leduc, Charlotte; Leprieur, Étienne Giroux; Moro-Sibilot, Denis; Tulasne, David; Kherrouche, Zoulika; Labreuche, Julien; Cortot, A.

doi:10.18632/oncotarget.21707

Cited by 28 publications

(18 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Four patients harbored cMET amplification and they observed a median PFS of 3.5 months. Baldacci et al [16] reported on 19 patients with cMET amplification after firstor second generation EGFR TKI treatment. Thirteen patients received a cMET TKI, as monotherapy (n = 12) or in combination with an EGFR TKI (n = 1).…”

Section: Discussionmentioning

confidence: 99%

Crizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI therapy results in short-lived and heterogeneous responses

et al. 2018

View full text Add to dashboard Cite

Next to secondary epidermal growth factor receptor (EGFR) mutations, cMET amplification plays an important role in mediating acquired resistance to EGFR tyrosine kinase inhibitors (TKI) treatment. Crizotinib, a dual ALK and cMET inhibitor, can induce responses in patients with EGFR mutation positive non-small cell lung cancer (NSCLC) that acquire cMET amplification after EGFR TKI treatment. However, little is known about the duration of response and post-progression resistance mechanisms. Here, we report on the clinical outcome of a series of patients with cMET-driven resistance to EGFR TKIs, treated with crizotinib. Materials and methods: Eight patients with EGFR mutation positive NSCLC that acquired cMET amplification after EGFR TKI treatment were treated with crizotinib 250 mg twice daily, as monotherapy (n = 2) or in combination with an EGFR TKI (n = 6). Results: Four out of eight patients (50%) showed a partial response (PR) according to RECIST 1.1. Median progression-free survival (PFS) was 1.4 (95% CI 1.2-5.0) months. Responses were short-lasting with a median PFS of 3.5 (95% CI 1.4-5.2) months in patients with a PR. Median overall survival was 5.9 (95% CI 1.3-6.0) months and not statistically different between responders and non-responders (p = 0.37). All but one patient tolerated crizotinib treatment well. Heterogeneous responses were seen in patients with progressive disease as best response with a marked size decrease of the biopsied (cMET amplification positive) lesion and progression of other lesions. cMET amplification was not always mutually exclusive with other EGFR TKI resistance mechanisms. Post-progression biopsies were negative for cMET amplification. Conclusion: Crizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI treatment results in short-lived and often heterogeneous responses, possibly due to subclonality of cMET-driven resistance and co-occurrence of other EGFR TKI resistance mechanisms.

show abstract

Section: Discussionmentioning

confidence: 99%

Crizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI therapy results in short-lived and heterogeneous responses

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In a multicenter retrospective study, the clinical response to MET inhibitors, mostly crizotinib, was investigated in patients with metastatic EGFR-mutated NSCLC with MET amplification or overexpression as evaluated on a post-progression re-biopsy. Among patients receiving a MET inhibitor as a single agent or in combination with anti-EGFR agents, an objective response was reported in only 2 out of 19 evaluable patients [171]. Another phase II trial evaluated whether acquired resistance to erlotinib in patients who harbored MET overexpression could be overcome by emibetuzumab, a monoclonal anti-MET antibody.…”

Section: Iii-b-met Activation Biomarkers As a Guide To Stratify Patiementioning

confidence: 99%

HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers

Moosavi

Giovannetti

Saso³

et al. 2019

Critical Reviews in Clinical Laboratory Sciences

115

View full text Add to dashboard Cite

Cancer is a major cause of death worldwide. MET tyrosine kinase receptor [MET, c-MET, hepatocyte growth factor (HGF) receptor] pathway activation is associated with the appearance of several hallmarks of cancer. The HGF/MET pathway has emerged as an important actionable target across many solid tumors; therefore, biomarker discovery becomes essential in order to guide clinical intervention and patient stratification with the aim of moving towards personalized medicine. The focus of this review is on how the aberrant activation of the HGF/MET pathway in tumor tissue or the circulation can provide diagnostic and prognostic biomarkers and predictive biomarkers of drug response. Many meta-analyses have shown that aberrant activation of the MET pathway in tumor tissue, including MET gene overexpression, gene amplification, exon 14 skipping and other activating mutations, is almost invariably associated with shorter survival and poor prognosis. Most meta-analyses have been performed in non-small cell lung cancer (NSCLC), breast, head and neck cancers as well as colorectal, gastric, pancreatic and other gastrointestinal cancers. Furthermore, several studies have shown the predictive value of MET biomarkers in the identification of patients who gain the most benefit from HGF/MET targeted therapies administered as single or combination therapies. The highest predictive values have been observed for response to foretinib and savolitinib in renal cancer, as well as tivantinib in NSCLC and colorectal cancer. However, some studies, especially those based on MET expression, have failed to show much value in these stratifications. This may be rooted in lack of standardization of methodologies, in particular in scoring systems applied in immunohistochemistry determinations or absence of oncogenic addiction of cancer cells to the MET pathway, despite detection of overexpression. Measurements of amplification and mutation aberrations are less likely to suffer from these pitfalls. Increased levels of MET soluble ectodomain (sMET) in circulation have also been associated with poor prognosis; however, the evidence is not as strong as it is with tissue-based biomarkers. As a diagnostic biomarker, sMET has shown its value in distinguishing cancer patients from healthy individuals in prostate and bladder cancers and in melanoma. On the other hand, increased circulating HGF has also been presented as a valuable prognostic and diagnostic biomarker in many cancers; however, there is controversy on the predictive value of HGF as a biomarker. Other biomarkers such as circulating tumor DNA (ctDNA) and tumor HGF levels have also been briefly covered. In conclusion, HGF/MET aberrations can provide valuable diagnostic, prognostic and predictive biomarkers and represent vital assets for personalized cancer therapy.

show abstract

“…The receptor tyrosine kinase, MET, is one of the most commonly dysregulated oncogenes in non-small cell lung cancer (NSCLC) and met gene amplification has been shown to be a major mechanism in which cancers develop resistance to EGFR inhibitors (Bean et al 2007 ). Phase III studies which solely targeted MET have failed to show clinical benefit in NSCLC (Baldacci et al 2017 ) but dual targeting of MET and EGFR using bispecific antibodies is promising (Tang et al 2008 ; Castoldi et al 2013 ) and is currently being explored in NSCLC [NCT02609776] (No Title. clinicaltrials.gov n.d. ) and other solid tumors [NCT02221882] (No Title.…”

Section: Other Agents Including Those In Developmentmentioning

confidence: 99%

Bi-specific and tri-specific antibodies- the next big thing in solid tumor therapeutics

Runcie

Budman

John

et al. 2018

Mol Med

119

View full text Add to dashboard Cite

Antibody-based therapy has revitalized the world of cancer therapeutics since rituximab was first approved for the treatment of Non-Hodgkin’s Lymphoma. Monoclonal antibodies against cancer antigens have been successful strategies for only a handful of cancer types due to many reasons including lack of antibody specificity and complex nature of tumor milieu which interfere with antibody efficacy. Polyspecific antibodies are promising class of anti-cancer agents which can be directed at multiple tumor antigens to eradicate tumor cells more precisely and effectively. They may overcome some of these limitations and have already changed treatment landscape for some malignancies such as B cell acute lymphoblastic leukemia. Pre-clinical studies and early phase clinical trials have demonstrated that this approach may be an effective strategy even for solid tumors. This review focuses on the development of bispecific and trispecific antibody therapy for the treatment of solid tumor malignancies and highlights the potential they hold for future therapies to come.

show abstract

Outcome of EGFR-mutated NSCLC patients with MET-driven resistance to EGFR tyrosine kinase inhibitors

Cited by 28 publications

References 38 publications

Crizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI therapy results in short-lived and heterogeneous responses

Crizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI therapy results in short-lived and heterogeneous responses

HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers

Bi-specific and tri-specific antibodies- the next big thing in solid tumor therapeutics

Contact Info

Product

Resources

About