Crizotinib Plus Erlotinib Overcomes Osimertinib Resistance in a Seriously-Ill Non-Small Cell Lung Cancer Patient with Acquired MET Amplification
Non-small cell lung cancer (NSCLC) remains a significant global health challenge, particularly when patients develop resistance to targeted therapies. This case report highlights the successful use of a combination therapy involving crizotinib and erlotinib to overcome osimertinib resistance in a critically ill NSCLC patient with acquired MET amplification. The patient, a 59-year-old Chinese man, initially presented with severe symptoms, including a persistent cough and shortness of breath, leading to his hospitalization in October 2018.
Initial diagnostic imaging revealed a 4.0 cm by 2.0 cm tumor in the lower lobe of the right lung, accompanied by multiple bone lesions. A core needle biopsy confirmed the diagnosis of metastatic lung adenocarcinoma, staged as T4N3M1c, indicating a stage IVB disease. Next-generation sequencing (NGS) of the biopsied tumor tissue identified an epidermal growth factor receptor (EGFR) exon 21 L858R mutation, with a mutant allele fraction (MAF) of 24.8%. Based on these findings, the patient was started on icotinib, a first-generation EGFR tyrosine kinase inhibitor (TKI), at a dose of 125 mg orally three times daily.
After five months of icotinib treatment, the patient achieved a partial response (PR) as per the Response Evaluation Criteria in Solid Tumors 1.1. However, subsequent imaging at nine months revealed disease progression, including multiple brain metastases and an enlargement of the primary lung tumor. Repeat NGS of the progressed lung tissue showed a decrease in the MAF of EGFR exon 21 L858R to 1.83% and confirmed the absence of the T790M mutation. Given the patient’s refusal of chemotherapy, osimertinib, a third-generation EGFR-TKI, was initiated at a dose of 80 mg once daily. Unfortunately, the lung tumor progressed after just one month of osimertinib treatment.
Following the progression on osimertinib, the patient underwent systemic chemotherapy with carboplatin and pemetrexed, which resulted in stable disease for two months. However, the disease progressed again after four months, and the patient’s Eastern Cooperative Oncology Group (ECOG) performance status (PS) deteriorated to grade 4. At this critical juncture, NGS of the patient’s serum revealed an increase in the MAF of EGFR exon 21 L858R to 5.5% and identified MET amplification with a copy number of 3.1. Due to the patient’s critical condition, re-biopsy was not feasible, and MET amplification could not be confirmed by immunohistochemistry or fluorescence in situ hybridization.
In light of these findings, a combinatorial treatment approach was adopted, involving crizotinib, a MET inhibitor, at a dose of 250 mg twice daily, and erlotinib, a first-generation EGFR-TKI, at a dose of 150 mg once daily. This combination therapy led to significant clinical improvement. The patient’s ECOG PS improved to grade 2, and the primary lung tumor decreased by 51% in size. Additionally, the patient experienced relief from symptoms such as cough, dyspnea, and loss of appetite. The disease remained under control for two months at the last follow-up visit, with only mild side effects of acne and anorexia reported. No severe adverse events, such as diarrhea, pneumonitis, or transaminitis, were observed.
Osimertinib is widely used to treat EGFR-mutant NSCLC, particularly in cases of TKI resistance mediated by the EGFR T790M mutation. However, acquired resistance to osimertinib poses a significant clinical challenge, with MET amplification emerging as a key resistance mechanism. Patients with MET amplification combined with T790M mutations often exhibit earlier resistance to third-generation EGFR-TKIs. Previous studies have shown that patients with MET amplification after osimertinib resistance have inferior median progression-free survival (3.5 months) compared to those without MET amplification (9.9 months). Similarly, the median overall survival is significantly shorter in the MET amplification group (15.6 months) compared to the MET amplification-negative group (30.7 months).
MET, a tyrosine kinase receptor located at 7q21-q31, plays a crucial role in cancer cell proliferation and survival. Amplified c-MET can bypass EGFR-TKI-induced cell death by activating downstream signaling pathways, thereby promoting cancer cell proliferation and contributing to drug resistance. Consequently, simultaneous inhibition of EGFR and MET is essential to overcome resistance mechanisms driven by MET amplification.
This case underscores the clinical efficacy of combining a first-generation EGFR-TKI with a MET inhibitor in managing osimertinib resistance associated with MET amplification. Despite the patient’s poor PS before initiating MET inhibitor therapy, the combination of crizotinib and erlotinib led to a PR and significant symptom improvement. This suggests that poor PS should not be a contraindication for combined targeted therapy in critically ill patients. Repeated NGS-based detection following drug resistance acquisition is crucial for guiding individualized treatment strategies tailored to the specific mechanisms of resistance and disease progression patterns.
In conclusion, the combination of crizotinib and erlotinib offers a promising therapeutic approach for NSCLC patients with MET amplification following osimertinib resistance. This case highlights the importance of personalized treatment strategies based on comprehensive molecular profiling and the potential benefits of combined targeted therapy, even in critically ill patients. Further studies with larger sample sizes are warranted to validate these findings and optimize treatment protocols for this challenging patient population.
doi.org/10.1097/CM9.0000000000001184
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