PMC8674488_01
Case summary. (A) Summary of disease course, treatment timeline, and key molecular findings. (B) Hematoxylin-eosin staining, TTF1 and NapsinA positive immunohistochemical (IHC) staining before treatment; MET positive immunohistochemical staining during progression after platinum-based chemotherapy. Scale bars: 100 microm. (C) Detailed molecular alterations of tissue and liquid biopsy. FC, fold change; TPS, tumor proportion score.
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The treatment timeline and molecular alterations are shown in  Figure 1 . A biopsy revealed MET overexpression (IHC 3+), and ctDNA next-generation sequencing confirmed the EGFR E746_A750del mutation ( Figures 1A, B ). Figure 1 ). The patient chose to continue gefitinib plus cabozantinib, and died of multiple organ dysfunction two months later. From the diagnosis of metastatic EGFR-mutant NSCLC in 2013, this patient achieved an overall survival of 54 months.
Gefitinib plus crizotinib treatment and rechallenge for EGFR-mutated NSCLC with MET overexpression/amplification. Based on the result of MET overexpression, the patient began gefitinib plus crizotinib. A partial response was observed 16 days after the initiation of this combination therapy (upper left panel). After disease progression, therapy was changed to chemotherapy plus cetuximab for two cycles. Due to chemotherapy-related toxicity, the patient was rechallenged with gefitinib plus crizotinib (reduced dose, 250 mg QD) with stable disease. Upon the development of new liver metastases, molecular testing of a biopsy confirmed concurrent EGFR mutation and MET amplification. Crizotinib dose was then increased to 250 mg BID (lower panel). Another partial response was observed 16 days after the crizotinib dose increase (upper right).
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After 16 days, computed tomography imaging showed an almost complete reduction of the target lesions ( Figure 2 ). On day 16, imaging showed a dramatic improvement of the target lesions ( Figure 2 ).
The combination of gefitinib, cabozantinib, and pembrolizumab for PD-L1-positive, EGFR-mutated, MET-amplified, MET Y1230H NSCLC. A partial response was observed one month after the initiation of this triplet regime (upper panel). Bevacizumab was added when the patient developed new metastases in April 2017. Both bevacizumab and pembrolizumab were stopped in October 2017 due to acute patient deterioration (lower panel).
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Imaging demonstrated a dramatic radiographic response which lasted for 13 months ( Figure 3 ).