Case Report: Durable partial response to icotinib plus crizotinib in a lung adenocarcinoma patient with double uncommon EGFR G719D/L861Q mutations and an acquired novel CUX1-MET fusion

Abstract

Non-small cell lung cancer (NSCLC) patients harboring MET exon 14 skipping or high MET amplification display a high rate of response to MET inhibitors. However, MET fusions in NSCLC have rarely been revealed. In this report, a 63-year-old woman with lung adenocarcinoma (LADC), harboring EGFR exon 18 G719D and exon 21 L861Q mutations, received first-generation, EGFR-tyrosine kinase inhibitor (TKI) icotinib therapy. Next generation sequencing (NGS) results only displayed an EGFR T790M point mutation following icotinib resistance. Thus, the patient was treated with osimertinib and achieved a stable disease (SD). However, disease progressed after 15 months and a novel MET fusion (CUX1 exon14-MET exon15) in addition to EGFR G719D/L861Q mutations were simultaneously detected in a tissue biopsy sample. After more than nine months, the patient subsequently achieved a PR with the combination of icotinib and crizotinib. To our knowledge, this is the first case of LADC patient displaying the presence of EGFR double uncommon mutations and an acquired novel CUX1-MET fusion that has benefited from icotinib plus crizotinib treatment. Following nine months of PR with icotinib plus crizotinib, the patient, until the time of publication, is exhibiting stable disease. The results suggest that the CUX1-MET fusion may be sensitive to crizotinib, although previous reports indicated that some MET fusion cases did not respond to crizotinib. Given this disparity, distinguishing MET fusion partners when crizotinib is used in LADC treatment is also very important.

Identification of MET fusions as novel therapeutic targets sensitive to MET inhibitors in lung cancer

“…In addition, chemotherapy plus bevacizumab may benefit patients harboring sensitive EGFR mutations and acquired MET amplifications after the failure of EGFR-TKI treatment. In this study, we collected the published cases [14][15][16][17][18][19][20] of patients harboring MET fusions, and the findings cast new light on the role of crizotinib in benefiting these patients. The findings suggested that crizotinib as a single agent can serve as a suitable treatment option for patients harboring primary MET fusions, and combined therapy with crizotinib and EGFR-TKIs could significantly benefit patients with EGFR mutations also harboring acquired MET fusions after the development of resistance to EGFR-TKIs.…”

“…Immunotherapy is another treatment option for NSCLC patients with MET alterations [11][12][13]. Recently, a series of reports revealed novel detectable alterations of MET, MET fusions, which are involved in the development of lung cancer and exhibit a special response to the given treatment [14][15][16][17][18][19][20]. However, MET fusions are rare in lung cancer, and a systematic analysis of patients harboring this kind of genomic alteration is lacking.…”

MET fusions are targetable genomic variants in the treatment of advanced malignancies

“… 8 60 Female Lung ADC IV NGS FFPE Primary ARL1-MET – – 1 L Crizotinib (PR, PFS 5.0 m) Ou L, et al Front Oncol. 2022 [ 13 ]. 9 63 Female Lung ADC IV NGS FFPE Acquired (EGFR) CUX1-MET – – 4 L Crizotinib+Icotinib (PR, PFS 9.0 m) Li Y, et al Clin Lung Cancer.…”

The novel EGFR mutations (p.E746_S752delinsI, p.T751_I759delinsG, p.L747_S752delinsAA) in patients with non-small cell lung cancer and the clinical treatment strategy: three case reports

“…While Ou et al. reported that the patient with G719D/L861Q mutations experienced progressive disease during Icotinib therapy ( 16 ). Even so, there is rare evidence reported on the efficacy of Icotinib in the uncommon EGFR 19 del mutation.…”

“…For example, Zhou et al reported that an advanced LDAC patient with rare G719A/L833V double mutation of EGFR responded well to Icotinib and the progression-free survival was 8 months (15). While Ou et al reported that the patient with G719D/L861Q mutations experienced progressive disease during Icotinib therapy (16). Even so, there is rare evidence reported on the efficacy of Icotinib in the uncommon EGFR 19 del mutation.…”