Icotinib plus osimertinib overcome epidermal growth factor receptor 19del/T790 M/C797S/V834L quadruplet resistance mutation in a patient with non-small cell lung cancer.

To the Editor: A 66-year-old woman presented with a severe cough and was admitted into hospital in April 2014. Positron emission tomography/computed tomography (PET/CT) scan showed a 2.0 cm × 2.0 cm node located on the lower lobe of left lung, multi-mediastinal lymph nodes enlargement and pleural effusion [Figure 1A]. She was also found multi-brain lesions on PET scan. Pleural core needle biopsy was performed, and lung adenocarcinoma was confirmed by pathologists. Direct genetic sequencing was performed with tumor tissue and epidermal growth factor receptor (EGFR) exon 19 deletion was found. Icotinib (Betta, China), a first-generation EGFR tyrosine kinase inhibitor (EGFR TKI), at a dose of 125 mg orally, three times a day was administered. She also received intensity-modulated radiation therapy (IMRT) on brain metastatic tumors with a dose of 56GY/28f. The patient got a partial response (PR) according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). After 30 months remission, disease progressed and the left lung tumor was enlarged [Figure 1B]. Re-biopsy was performed from left lung lesion, the EGFR gene panel was examined, by Amplification Refractory Mutation System polymerase chain reaction (ARMS PCR), EGFR 19 del and EGFR T790 M mutations were detected. Osimertinib was initiated and the patient achieved a PR after 3 months of treatment [Figure 1C]. Nine months later, lung tumor progressed slowly [Figure 1D]. Next-generation sequencing (NGS) was done with new biopsied lung tissue, EGFR 19 del, T790 M, C797G, and V834L mutations were found; and the mutant allele fractions (MAFs) were 85.5%, 61.5%, 36.6%, and 91.1%, respectively. EGFR T790 M and C797G were located in cis. Third-line treatment with icotinib and osimertinib in combination was administered. There was no diarrhea, rash, pneumonitis, or transaminitis happened. A stable disease was achieved on CT scan after 2 months of the treatment [Figure 1E]. However, the patient suffered severe back pain after 4 months of the combined treatment. Magnetic resonance imaging showed multiple vertebral metastases. NGS was done with patient's blood; the results indicated EGFR19 del/T790 M/C797G/V834L mutation and MAF were 0.4%, 0.3%, 0.6%, and 0.8%, respectively. Systemic chemotherapy with carboplatin, pemetrexed plus bevacizumab and currently palliative vertebroplasty then vertebral irradiation were performed. The patient had a stable disease at the last follow-up on April 10, 2018.

Figure 1

Primary tumor changes on CT scan. (A) Primary tumor located on the lower lobe of left lung and pleural effusion. (B) Progressed disease after 30 months of icotinib treatment. (C) The largest dimension of the primary tumor had decreased by 45% after 3 months of osimertinib treatment. (D) Tumor increased by 38% after 9 months of osimertinib treatment. (E) CT scan after 2 months of icotinib and osimertinib treatment.

EGFR-C797S/G mutation is the most common secondary mutation leading to the resistance of the third-generation EGFR-TKIs.[ The mutation disrupts the covalent binding between the cysteine at position C797 and third-generation EGFR TKIs.[In vitro study, cancer cells would be sensitive to a combination of first- and third-generation EGFR TKIs if the EGFR T790 M mutation and C797S mutation happened in trans, but would be resistant to it if they happened in cis.[ Wang et al[ first reported the clinical evidence of efficacy generated by combination therapy of first- and third-generation of EGFR TKIs targeting concomitant EGFR T790 M and C797S in trans.

In this case, the patient developed resistance after 30 months of treatment with icotinib, which was longer than the median PFS of 10 months reported by the prior study.[ Subsequent gene panels showed EGFR T790 M mutation and V834L mutations. EGFR V834L mutation was barely reported in literature. One study found that this mutation did not affect the efficacy and resistance of EGFR TKIs therapy, it might associate with a longer PFS, but further data is still needed.[

The treatment method for patients with secondary C797S/G mutation after the third generation of EGFR TKIs is still in the exploratory stage. For patients harboring EGFR exon 19 del/V834L/T790 M/C797G, the combination of the first- and third-generation of EGFR TKIs may achieve certain results. It is very important for timely detection of resistance related genes in patients with non-small cell lung cancer after acquired TKIs resistance. The strategies to overcome drug resistance should be individualized based on the mechanisms of drug resistance as well as the ways of progression.

In conclusion, EGFR 19 del/T790 M/C797G/V834L quadruplet mutation is very rare in non-small cell lung cancer after resistance to osimertinib treatment; it may benefit from first- and third-generation EGFR TKIs, but more patients are needed into the study in the future.

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The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.

Conflicts of interest

None.