Aumolertinib in NSCLC with leptomeningeal involvement, harbouring concurrent EGFR exon 19 deletion and TP53 comutation: a case report

Abstract

Background: Aumolertinib (HS-10296), a 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has been shown to have efficacy in treating tumors harboring EGFR sensitive mutations: EGFR in-frame deletions or insertions within exon 19 deletion (19Del) and the exon 21 L858R mutation and EGFR T790M resistance mutation. Research has shown that tumor protein p53 (TP53) mutations and leptomeningeal metastases (LM) are associated with reduced responsiveness and a poor prognosis in patients with advanced non-small cell lung cancer (NSCLC) who have received targeted therapy with EGFR-TKIs. The TP53 mutation is a common concomitant mutation of EGFR amplification in solid tumors. First-line aumolertinib treatment is effective in EGFR concurrent mutated NSCLC, however, the efficacy and survival outcomes in these patients with leptomeningeal metastasis remain unknown.

Case description: We retrospectively examined the data of a lung adenocarcinoma patient, 51 years old, male, multi-mutations of EGFR and TP53, who received 1st-line treatment with a 1st-generation TKI followed by 2nd-line treatment with aumolertinib. Before the 1st-line treatment, the patient underwent a lung biopsy to examine the 520 genes of all cancers using illumia high-throughput sequencing. The sequencing results showed that the patient had the EGFR 19del (p.Leu747_Thr751del)/TP53 (p.lys120fs)/EGFR amplified multiple mutation with a low tumor mutational burden. The patient was treated with gefitinib and achieved progression-free survival (PFS) for 10 months until secondary malignancy of the lymph nodes. The first-generation TKI combined with chemotherapy was applied and then the patient was diagnosed with leptomeningeal metastases. Subsequently, the patient was treated with aumolertinib for 12 months without disease progression. The efficacy evaluation was partial response (PR) with grade 2 rash. Adenocarcinoma cells were found in the cerebrospinal fluid (CSF). CSF-derived circulating tumor deoxyribonucleic acid was detected using the target area probe capture and 2nd-generation high-throughput sequencing technology. The CSF gene detection showed the EGFR p. L747_T751 del, TP53 p. K120fs and EGFR amplification mutations.

Conclusions: This is the first reported case in which aumolertinib was used to treat a patient with the multi-mutations of EGFR 19Del, TP53, and EGFR amplification and leptomeningeal metastases. The findings suggested that almonertinib may result in long-period clinical improvement and tolerable safety in concurrent mutated LM NSCLC.

Keywords: Aumolertinib; case report; co-mutation; leptomeningeal metastases.

Figure 1

Treatment timeline. 19Del, exon 19 deletion; TP53, tumor protein p53; EGFR, epidermal growth factor receptor; SRT, stereotactic radiotherapy; PR, partial response; SD, stable disease.

Figure 2

The clinical course according to the CT scan findings. (A) July 31, 2020: left frontal metastasis. (B) Whole body PET/CT images showed bilateral hilar and mediastinum metastasis (in the 2R area, 4R area, 5 area, and 7 area), bilateral neck metastasis (in the bilateral I–IV area and right neck V area) and bilateral clavicle area lymph nodes metastasis. (C) August 21, 2020: the original metastatic lesion in the left frontal lobe disappeared. (D) August 21, 2020: the left cerebellum was thickened and enhanced. (E) August 21, 2020: The left frontal membrane was thickened and enhanced. (F) June 4, 2021: the left meningeal had thickened and strengthened, and was similar to that in August 2020. (G) June 4, 2021: the meningeal membrane of the left frontal lobe had thickened and strengthened, and was similar to that in August 2020. Red arrow, locations of tumor lesions.

Figure 3

Tumor cells in the CSF. (A) Adenocarcinoma cells were found in the CSF in June 2021, high power (×400), liquid-based, papanicolaou stain; (B) adenocarcinoma cells were found in the CSF in August 2021, medium power (×200), liquid-based, papanicolaou stain. CSF, cerebrospinal fluid.

Figure 4

The cell absolute counts and SCMM of the T lymphocytes in the peripheral blood as detected by flow cytometry. The absolute number of CD3⁺, CD3⁺CD4⁺, and CD3⁺CD8⁺ T lymphocytes in the peripheral blood increased over time. Conversely, the SCMM showed a decreasing trend during hospitalization. Abs. count, absolutely count; SCMM, single cell mitochondrial mass.

Figure 5

A CSF sample of the human T lymphocyte subset clinic test as detected by flow cytometry. (A) The first clinic test on July 2, 2021 showed a high CD8⁺ cell percentage, indicating an inflammatory response in the brain of the patient; (B) the second clinic flow cytometry test on August 6, 2021 showed a normal ratio of CD4⁺/CD8⁺, indicating the treatment was significantly effective. CSF, cerebrospinal fluid; PE-H, phycoerythrin-high.