ALK fusion gene is one of the driver gene mutations in lung cancer. The formation mechanism of resistance to ALK inhibitors is as follows: (1) ALK kinase region mutation; (2) ALK gene amplification; (3) the emergence of alternative pathways such as KRAS and EGFR activation; (4) ) Pharmacokinetic resistance is associated with poor ability of the drug to be transported across the blood-brain barrier to the central nervous system.
The third-generation ALK inhibitor lorlatinib was developed for the treatment of ALK inhibitor-resistant lung cancer. The G1202R and G1202del mutations are representative of resistance gene mutations to first- and second-generation ALK inhibitors, and lorlatinib has been shown to be effective in tumors with these mutations. In addition, lorlatinib has good drug transport to the central nervous system and shows good efficacy on brain metastases.
On April 4, 2022, Thoracic Cancer reported a case of an ALK-positive lung cancer patient with refractory brain metastases who responded good to lorlatinib< /strong>.
Case study
A 44-year-old woman was diagnosed with ALK-positive lung adenocarcinoma cT2aN3M1b stage IV (brain metastases). After Gamma Knife (gamma knife) treatment of brain metastases, the patient started oral crizotinib (500 mg/day).
Although lung lesions shrank after treatment with crizotinib, new brain metastases appeared one year later, so brain metastases were again subjected to Gamma Knife treat.
Cranial MRI two years after diagnosis showed brain metastases and spinal cord tumor progression. Brain metastases and spinal cord tumors shrank after changing the anticancer drug to alectinib.
In the following year, brain metastases and spinal cord tumors deteriorated, and whole brain radiotherapy and cervical spinal cord radiotherapy were performed. Alectinib was discontinued and the patient was switched to carboplatin+pemetrexed+bevacizumab.
However, the patient developed new brain metastases and severe fatigue from chemotherapy. Therefore, alectinib was used again. However, despite repeated Gamma Knife treatments, the brain metastases worsened.
As a result, the patient was switched to lorlatinib. ALK gene PCR was performed using plasma samples prior to lorlatinib administration. No resistance gene mutations were detected in plasma samples.
Legend: (a) The first chest X-ray showed bilateral small grain shadows. (b) Chest CT at the first visit showed a left lower lobe mass and bilateral small granular shadows. (c, d) Contrast-enhanced (CE) magnetic resonance imaging (MRI) of the brain showed a mass in the frontal and temporal lobes.
Legend: (ac) Contrast-enhanced (CE) brain magnetic resonance imaging (MRI) showing progressive brain metastases and intramedullary tumors. (d-f) Brain MRI showing reduction of brain metastases and intramedullary tumors. (g) Chest CT showed improved lung shadow. (h) CE brain MRI showing improvement in brain metastases and intramedullary tumors.
No new brain metastases were observed following lorlatinib treatment. In addition, the lung lesions disappeared after crizotinib treatment, and no new lesions were seen.
Discussion
A 44-year-old female patient with ALK-positive advanced lung adenocarcinoma was treated with crizotinib and her lung lesions disappeared. The patient received alectinib and chemotherapy, but the brain metastases worsened; therefore, ALK resistance gene mutation testing was performed using plasma samples, and no ALK resistance gene mutation was detected. But after switching to lorlatinib treatment, the brain metastases shrank significantly. This suggests that in ALK-positive advanced lung cancer, plasma-based drug resistance gene detection may be helpful for treatment decisions.
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