Durable clinical benefit from afatinib in a lung adenocarcinoma patient with acquired EGFR L718V mutation-mediated resistance towards osimertinib: a case report and literature review

Introduction

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) could be very effective for EGFR mutation positive patients. The third-generation EGFR-TKI osimertinib, targeting the EGFR T790M mutation which is related to about half of the acquired resistance cases, has further improved the efficacy (1). However, the majority of patients treated with osimertinib inevitably develop drug resistance. The heterogeneity of tumors leads to genetically distinctive mechanisms of acquired resistance to osimertinib, including the tertiary EGFR mutations, EGFR amplification and EGFR-independent bypass pathway activation (2,3). Nevertheless, the understanding of osimertinib resistance and subsequent treatment strategies are far from complete. The advent of next-generation sequencing (NGS) has significantly accelerated this process and been shown to bring benefit when NGS was done on rebiopsy samples at osimertinib resistance. Herein, we present the case of a metastatic lung adenocarcinoma (LUAD) patient who developed EGFR L718V at osimertinib resistance and derived a durable response to afatinib with a progression-free survival (PFS) of 18 months and counting.

We present the following article in accordance with the CARE reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-21-3731/rc).

Case presentation

A 55-year-old Chinese female without smoking history was diagnosed with stage IV LUAD in August 2017. The computed tomography (CT) scan indicated a nodular lesion (4.1 cm × 3.3 cm, Figure 1A,1B) in the right upper lung, and pleural metastases. The patient had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 1. A percutaneous needle lung biopsy was performed and the NGS analysis (168 solid cancer-related genes panel, Burning Rock Biotech, Guangzhou, China) revealed an EGFR L858R mutation. After 3 rounds of circular intrapleural hyperthermic perfusion, the patient was started on icotinib, 125 mg 3 times per day on 26 September 2017, together with bevacizumab (500 mg every 3 weeks). A CT scan after 5 weeks of this treatment showed obvious shrinkage of the nodular lesion (2.4 cm × 2.1 cm), which was assessed as a partial response (PR) on 7 November 2017 (Figure 1B). The lesion size remained stable until the follow-up examination on 13 August 2018. Enlargement of the lesion was observed between 13 August 2018 and 3 September 2018 (from 2.2 cm × 1.5 cm to 2.3 cm × 1.6 cm). The patient continued on the treatment of icotinib. The NGS test with biopsy sample confirmed the emergence of EGFR T790M mutation on 19 November 2018 (Figure 1A). The patient received osimertinib (80 mg/day) as second-line treatment on 10 December 2018, following which, stable disease (SD) was achieved for 10 months. A CT scan on 12 October 2019 indicated progressive disease (PD) (Figure 1B). The patient commenced on apatinib (250 mg/day) and osimertinib (80 mg/day) as the third-line treatment. The CT scan after 1 month of combination treatment showed obvious lesion size decrease, contributing to PR (Figure 1B). The treatment lasted for 6 months until PD in April 2020 (Figure 1B).

Figure 1 Summary of disease course, therapies, and molecular findings. (A) The entire treatment procedure; (B) CT scan of the primary lung tumor at treatment milestones. CT, computed tomography; NGS, next-generation sequencing; EGFR, epidermal growth factor receptor; PR, partial response; SD, stable disease; PD, progressive disease.

The repeated NGS with CT-guided biopsy sample indicated the presence of EGFR L718V (Figure 2) in conjunction with EGFR L858R, as well as the disappearance of EGFR T790M. Based on the findings of previous studies, the patient was shifted to afatinib (40 mg/day) and apatinib (250 mg/day) as fourth-line treatment on 14 June 2020. The CT scan after 3 months’ treatment showed obvious lesion size reduction (from 2.5 cm × 2.2 cm to 2.0 cm × 1.9 cm, Figure 1B). The clinical response assessment was SD with a ECOG PS of 0. The patient continued on the treatment with no evidence of progression and a PFS of more than 18 months (the data cut-off date: 17 December 2021). Besides loss of appetite and grade I nausea that did not require medical treatment, the patient reported no other complaints. She had good adherence to the treatment of afatinib plus apatinib.

Figure 2 The integrative genomics viewer (IGV) screenshots revealed the harboring of EGFR exon 18 L718V. * indicates a stop codon. EGFR, epidermal growth factor receptor; NGS, next-generation sequencing.

We also reviewed 9 previously reported cases harboring EGFR L718X. Among 4 cases who received afatinib treatment, 3 showed a response to it. The clinical characteristics and outcomes of non-small cell lung cancer (NSCLC) patients with acquired EGFR L718X to osimertinib in our and previous studies are summarized in Table 1.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

It has been well documented that acquired resistance to osimertinib is mainly mediated by EGFR C797S mutation or loss of EGFR T790M in patients with EGFR-T790M-positive NSCLC. Herein, we have presented that EGFR L718V also contributed to resistance to osimertinib and retention of sensitivity to afatinib in a LUAD patient with a PFS of 18 months and counting. To the best of our knowledge, this is the longest PFS among all reported studies.

EGFR-mutated NSCLC is a genetically heterogeneous disease that includes more than 200 distinct mutations. The most common EGFR mutations—exon 19 deletions or L858R mutations, which account for approximately 50% of all NSCLC in Asians and 10-15% in Western patients (4,5), predict sensitivity to EGFR-TKI. Gefitinib, icotinib, and osimertinib as EGFR-TKIs have been used as first-line treatment for NSCLC patients bearing EGFR sensitizing mutations based on the results from clinical trials as previously reported indicating that EGFR-TKI has significantly improved clinical outcomes compared with chemotherapy (1,6,7). However, NSCLC patients with EGFR mutations inevitably develop acquired resistance to EGFR-TKI. The common cause of the failure of EGFR-TKI is the emergence of new actionable alterations, while in up to 30% of cases, the mechanisms underlying acquired resistance remain unknown (8,9). Recent studies have revealed that epigenetic factors are involved in the acquired mechanisms to EGFR-TKI, such as epigenetic regulation of EGFR, epigenetic silencing of microRNA-483-3p, and epigenetic repression of DUSP1 (10-12). Further studies are needed to investigate whether epigenetic factors are implicated in the resistance mechanisms to osimertinib.

Osimertinib, a third-generation EGFR-TKI, could be used as the preferred first-line treatment for EGFR mutation-positive NSCLC patients, and also as a salvage therapy with the presence of EGFR T790M mutation (1,13). Despite the efficacy of osimertinib exerted in vitro and in the clinical setting, the inevitable drug resistance poses a challenge due to the paucity of post-osimertinib pharmacological strategies available to date. Besides the most common EGFR exon 20 C797S mutation (1), the acquired mutations in L718 have been reported to be related with osimertinib resistance (14,15). The residue L718 is located at the adenosine triphosphate (ATP) binding site in EGFR, and it would induce the spatial confliction for osimertinib binding (16). Previous in vitro studies have demonstrated that those with mutation in L718X (L718Q and L718V) might remain sensitive to afatinib, especially with the concurrent loss of EGFR T790M (15,16).

National Comprehensive Cancer Network guidelines (NCCN) and Chinse Society of Clinical Oncology (CSCO) recommend immunotherapy, radiotherapy, continuing osimertinib, anti-angiogenesis therapy, and chemotherapy as palliative treatment options for NSCLC patients who progress on osimertinib (17,18). In the present work, the patient who acquired EGFR L718V resistant to osimertinib was challenged with afatinib based on the previous studies indicating that NSCLC patients who acquired EGFR L718V might derive durable response to afatinib. Afatinib has been indicated for the first-line treatment of patients with metastatic NSCLC whose tumors have non-resistant EGFR mutations based on the results from clinical trial LUX-Lung 3 (NCT00949650) that patients with EGFR mutation-positive, metastatic NSCLC who receive afatinib as the first-line treatment have a significantly longer PFS than those receiving pemetrexed/cisplatin (19). Afatinib is also indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy according to its promising efficacy in clinical trial LUX-Lung 8 [NCT01523587] that previously treated, metastatic squamous NSCLC who receive afatinib have a significantly longer overall survival than those receiving erlotinib (20).

The current literature on the treatment option for NSCLC patients with EGFR L718X conferring resistance to osimertinib is limited. To our knowledge, there are 5 case reports in the literature. Due to the lack of the standard-of-care, patients who developed EGFR L718X at progression on osimertinib were treated with EGFR-TKI erlotinib or dacomitinib in 3 previous case reports; however, they failed to respond to those 2 EGFR-TKIs (21-23). In another 2 case reports in the literature, LUAD patients who developed EGFR L718V/Q at progression on osimertinib could respond to afatinib treatment (24,25).

Raez et al. demonstrated that 2 of 3 NSCLC patients with EGFR L718V respond to afatinib with disease stabilization (25) and Fang et al. revealed that the use of afatinib in an EGFR-mutated LUAD patient with acquired L718V mutation yielded a PFS of at least 6 months (24). Consistent with these 2 previous case reports, our case with EGFR L718V and loss of T790M responded to afatinib. Furthermore, this patient showed a durable response to afatinib with a PFS of 18 months and counting, which is obviously longer than that of 6 months as previously reported (24). Among the 5 cases who developed EGFR L718V at the progression to osimertinib as reported in the previous and our study, 4 cases responded to afatinib, achieving an objective response rate (ORR) of 80.0%. The most common adverse reactions of afatinib as first-line treatment reported in clinical trial LUX-Lung 3 are diarrhea, rash, stomatitis, paronychia, and dry skin (19). In addition, the most common adverse reactions of afatinib for the treatment of metastatic squamous NSCLC patients progressing after platinum-based chemotherapy reported in clinical trial LUX-Lung 8 are diarrhea, rash, stomatitis, and decreased appetite (20). In the present work, the patient reported decreased appetite and nausea that did not require medical treatment during the treatment of afatinib. These findings suggest that afatinib serves a crucial role in overcoming the acquired resistance caused by EGFR L718V. Our work highlights that dynamically monitoring the mutation status could improve progression survivals of NSCLC patients.

Immune checkpoint inhibitors (ICIs) have emerged as a pillar in the management of advanced malignancies, which could be used as palliative treatments for NSCLC patients who acquire osimertinib resistance. Positive expression of programmed cell death ligand-1 (PD-L1) predicts favorable prognosis in NSCLC patients who received ICIs. However, of the patients who initially respond, some develop resistance at a later time and experience tumor relapse, leading to a poor survival (26). The emergence of new actionable alterations or mechanisms contributing to the acquired resistance to EGFR-TKIs and ICIs could promote the development of efficacious strategies for NSCLC patients. Collectively, drug resistance is the key clinical barrier to further improve outcomes of patients with metastatic NSCLC and developing treatment strategy to overcome drug resistance for NSCLC patients is an unmet need.

A few limitations are associated with our study. Due to the nature of our work, only 1 patient was involved in the study. More evidences or clinical trials are needed to evaluate the efficacy and safety of afatinib in NSCLC patients harboring EGFR L718V.

Our case not only supports that the EGFR L718V mutation is responsible for osimertinib resistance, but also provides clinical evidence that patients harboring EGFR L718V mutation and the loss of T790M might derive a durable response to afatinib. Our study suggests that afatinib might be an effective treatment option for NSCLC patients harboring the uncommon EGFR L718V.

Acknowledgments

We would like to express our sincere gratitude to the patient and her family. We also thank all investigators, coordinators, and operating staff for their contribution and efforts in this project.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-21-3731/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-21-3731/coif). HD and YS were employed by the company Burning Rock Biotech Ltd. at the time of writing this report. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Jones)