Afatinib and osimertinib in lung adenocarcinoma harbored EGFR T751_I759delinsS mutation: A case report.

Tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) are the standard treatment for lung cancer patients with activating EGFR mutation. The traditional direct polymerase chain reaction (PCR) has lower sensitivity in the detection of EGFR mutations in patient tissue samples. Whilst PCR amplification kits increase the sensitivity in detecting some types of EGFR mutations, not many types of rare mutations are found. Here, we report a patient who had lung adenocarcinoma harboring EGFR T751_I759delinsS mutation and had good response to afatinib initially and osimertinib after developing resistance to afatinib. This rare EGFR mutation was not detected by Scorpion and ARMS method but was found using the next-generation sequencing method. There are less prospective trials in the treatment of lung adenocarcinoma with very rare EGFR mutations. Our case report could therefore provide clinical experience to the clinicians in the management of their patients.

INTRODUCTION

Lung adenocarcinoma patients diagnosed with mutant EGFR usually have a good response to EGFR tyrosine kinase inhibitors (TKIs). Complex mutation patterns can be detected by traditional direct polymerase chain reaction (PCR). Direct PCR showed a lower sensitivity in patient samples which had a lower proportion of cancer cells. Some EGFR PCR kits increase the sensitivity but can only detect some specific mutations. The Scorpion and amplification refractory mutation system (ARMS) can detect several types of point mutations (G719X, S768I, T790M, L858R, L861Q), three subtypes of exon 20 insertion and 25 subtypes of exon 19 deletions. Many subtypes of rare EGFR mutations cannot be detected by PCR kits. In these patients, next‐generation sequencing (NGS) is a good method to find the rare EGFR mutations and other oncogenic mutations or amplifications.

There have been fewer prospective trials in the treatment of rare EGFR mutations. , Retrospective studies of real‐world data in lung cancer patients have reported the outcome of EGFR TKIs treatments in lung cancer patients. , Some case reports of vary rare EGFR mutations provide details of clinical experience and suggestions for clinicians for patient treatment. , , Deletion in exon 19 of EGFR has been found in many lung adenocarcinomas, but insertion in exon 19 of EGFR is less commonly reported in lung cancer patients. Here, we report the case of a lung adenocarcinoma patient who was found to have EGFR exon 19 insertion and achieved a good response to EGFR TKIs.

CASE REPORT

In March 2019, a 58‐year‐old male presented to our clinic with a cough and chest X‐ray revealed a mass in the right lung. Following biopsy, the pathology confirmed that the patient had pulmonary adenocarcinoma. Positron emission tomography (PET‐CT) showed a positive uptake in the right lung mass and bilateral mediastinal lymph nodes but there was no distal metastasis. Brain magnetic resonance imaging (MRI) with contrast showed no brain metastasis. The Scorpion and ARMS method showed no detectable EGFR mutation. Immunohistochemistry staining of anaplastic lymphoma kinase (ALK) was negative. Programmed‐death 1 ligand staining was 10%. He received concurrent chemoradiotherapy (CCRT) with docetaxel and cisplatin from April 9 to May 13 for stage III lung cancer. Chest computed tomography (CT) showed a partial response after CCRT. The patient received immunotherapy with durvalumab on June 19 and July 7 and had progressive dyspnea and grade 3 pneumonitis which was diagnosed on July 15. He was treated with steroids and had no further immunotherapy after his recovery from pneumonitis (Figure 1).

FIGURE 1

The patient was diagnosed with adenocarcinoma stage III (a) and received concurrent chemoradiotherapy (CCRT). Regression of the tumor (b) was noted and the patient subsequently received durvalumab after CCRT. The patient had pneumonitis after two cycles of durvalumab (c) but his pneumonitis improved after steroid treatment (d)

However, chest CT and brain MRI showed disease progression in the right lung with lymphangitic carcinomatosis and brain metastases in December 2019. Brain radiotherapy was performed for brain metastases. The NGS panel ACTDrug+ (ACT Genomics) showed EGFR T751_I759delinsS and EGFR amplification (copy number 23.5). The patient subsequently received afatinib on January 21, 2020 and brain MRI and chest CT showed a partial response. However, grade 1 skin rash and paronychia were reported. Chest CT showed progressed lymphangitic carcinomatosis of the right lung after treatment with afatinib for 9 months. The pathology of rebiopsy of the lung tumor confirmed a positive EGFR exon 20 p.T790M mutation by the Scorpion and ARMS method. We subsequently prescribed osimertinib for the patient commencing on October 5, 2020 and his chest CT and brain MRI have revealed a partial response. Our report showed EGFR T751_I759delinsS and EGFR amplification are sensitive to afatinib. Progression‐free survival was 9 months for the patient in our study. Osimertinib was effective for this rare mutation after the patient was found to be resistant to afatinib because of EGFR exon 20 p.T790M mutation (Figure 2).

FIGURE 2

Next‐generation sequencing of the patient's tissue showed EGFR mutation with T751_I759delinsS and amplification (copy number 23.5)

DISCUSSION

Here, we present the report of a patient who was found to harbor EGFR T751_I759delinsS and amplification of EGFR and had a good response to afatinib and osimertinib. Deletion from E746 or L747 of exon 19 are common mutations of EGFR and have shown a good response to EGFR TKIs. A study of 195 patients with exon 19 deletion showed shorter progression‐free survival (PFS) 2.9 months of first‐generation EGFR TKIs in the patients who had deletion from T751 or S752. The lower detection rate (16.7%) of EGFR exon 20 p.T790M may have resulted in shorter PFS in a previously reported study. A case report showed a patient had PFS 7.0 months to icotinib and had resistant mutation T751_I759delinsS after icotinib treatment. The patient had no response to three combinations with chemotherapy, bevacizumab and erlotinib but had a good response to osimertinib for 16 months. The EGFR T751_I759delinsS should be sensitive osimertinib depended on our report (Figure 3).

FIGURE 3

The patient received afatinib for recurrent lung cancer (a) and had a partial response (b). The patient had progressive disease (c) and rebiopsy of the lung tumor showed positive EGFR exon 20 p.T790M mutation. He had a partial response to osimertinib treatment (d)

EGFR amplification has been reported as one resistant mechanism to EGFR TKIs. , Our patient had coexisting EGFR T751_I759delinsS mutation and EGFR amplification and received 9 months PFS following afatinib treatment. The 9‐months PFS was shorter than in those patients who receive first‐line treatment with afatinib for common EGFR exon 19 deletions. In patients with other uncommon EGFR mutations, PFS was less than 9 months and depended on retrospective analysis of clinical trial and real‐world evidence.

The T751_I759delinsS in EGFR exon 19 could not be detected by several commercial PCR kits. NGS should be a better method to detect complex variants of EGFR mutations. Half lung adenocarcinoma patients had common EGFR mutations or expression of ALK in Asia. For economic reasons, NGS is often only performed in patients who have been confirmed to ahve negative EGFR mutations by PCR kits and low expression of ALK in Asia. In a subgroup of patients who had a lower ratio of EGFR mutation, NGS was reported to be the better method of detecting driver genes.

In summary, we report a case of lung adenocarcinoma with T751_I759delinsS in EGFR exon 19 which may be a predictive factor of poor response to first generation TKIs as reported in a previous study. Our case showed acceptable PFS to afatinib after CCRT and checkpoint immunotherapy. This rare mutation may indicate good PFS to osimertinib but more real‐world data is needed to support our findings.

CONFLICT OF INTEREST

The authors do not report any conflicts of interest.