Crizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI therapy results in short-lived and heterogeneous responses. (October 2018)

• Record Type: Journal Article
• Authors: van Veggel, Bianca; de Langen, Adrianus J.; Hashemi, Sayed; Monkhorst, Kim; Rosenberg, Efraim H.; Heideman, Daniëlle A.M.; Radonic, Teodora; Smit, Egbert F.
• Is Part Of: Lung cancer. Volume 124(2018)
• Page Start: 130
• Page End: 134
• Publication Date: 2018-10
• Subjects: EGFR mutation -- cMET amplification -- Resistance -- Crizotinib; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2018.07.030
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Crizotinib treatment results in short-lasting responses. Heterogeneous responses, possibly due to subclonality of cMET driven resistance. Poor prognosis after cMET amplification as acquired resistance mechanism. Abstract: Purpose: 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.