EGFR is one of the four HER family receptor members, and the EGFR gene is an important oncogene in NSCLC. Blocking EGFR by specific TKIs through competitive binding with the EGFR binding region can inhibit EGFR activation and its downstream signaling pathways, with significant antitumor effects in NSCLC. EGFR TKIs such as gefitinib, erlotinib, afatinib, icotinib and third-generation TKIs such as osimertinib have been approved as standard care for NSCLC patients with mutations in the EGFR tyrosine kinase domain (TKD). However, acquired resistance almost inevitably develops after 9–15 months of treatment. Several mechanisms of acquired resistance have been demonstrated, including secondary EGFR mutations and mutations in bypass signaling pathways (Liu et al., 2017; Wu and Shih, 2018). The T790M mutation, involving substitution of threonine to methionine at amino acid 790, is the most common mechanism of resistance to first- and second-line EGFR TKI treatment. Osimertinib, currently approved as standard first-line treatment for NSCLC patients carrying EGFR mutations, also shows good activity for NSCLC patients with EGFR T790M mutants (Remon et al., 2018). Unfortunately, these patients, even those with EGFR T790M mutations, also eventually develop acquired resistance to osimertinib. The mechanisms reported include activating mutations in the bypass signaling pathway, loss of the T790M mutation, histological transformation, and acquisition of the EGFR C797S or EGFR L718Q mutation (Ma et al., 2019; Taniguchi et al., 2019; Mu et al., 2020). Overcoming drug resistance is a clinical problem that needs to be solved urgently, but there is no clear and solid strategy to date. Some alternatives for overcoming resistance to osimertinib have recently been reported, such as osimertinib, bevacizumab, and brigatinib combination therapy and brigatinib (Uchibori et al., 2017; Zhao et al., 2018; Shaikh et al., 2021). Based on a phase 2 expansion study of a phase 1/2 trial, the third-generation EGFR inhibitor almonertinib was approved in China in March 2020 for the treatment of advanced EGFR T790M-positive NSCLC (Yang et al., 2020; Nagasaka et al., 2021). Recent studies report that almonertinib has a good safety profile, with the parent drug as its main circulating component, and pharmacokinetic studies in a mouse model demonstrate a good ability of almonertinib to cross the blood–brain barrier (Zhang et al., 2021; Zhou et al., 2021). Herein, we present a case of resistance to osimertinib due to acquired EGFR L718Q mutation and subsequent response to almonertinib.

Despite the robust efficacy of osimertinib, resistance to this drug is inevitable due to the lack of postosimertinib options (Leonetti et al., 2019). Mutation at EGFR L718 are responsible for osimertinib resistance in vitro and in vivo, and the amino acid is most frequently substituted with glutamine. This has recently been shown to be a mechanism of resistance to osimertinib, but few therapies can effectively overcome it (Yang et al., 2018; Leonetti et al., 2019). In the crystal structure of osimertinib in complex with EGFR, L718 is in direct contact with the aniline ring. Thus, the L718Q mutation may mediate drug resistance through steric hindrance and influence drug binding; that is, the glutamine side chain at position 718 is expected to sterically interfere with the position of osimertinib, reducing the efficiency of covalent bond formation (Yosaatmadja et al., 2015; Bersanelli et al., 2016). We used MODELLER, a computational protein structure modeling (Webb and Sali, 2016) technique, to predict the three-dimensional structure of the EGFR protein with the L718Q mutation, and the predicted structure is supported by the above theory that mutation of EGFR L718Q may affect binding between osimertinib and EGFR-TKD (Figure 1F). Amino acid 718 is found inside the p-loop of the EGFR TKD, which interacts with the aniline ring of osimertinib. According to the predicted model, mutation of this residue may cause spatial restriction and prevent osimertinib from binding to EGFR, that is, cause resistance to the drug. Despite some case reports that patients carrying the EGFR L718Q mutation might respond to afatinib (Starrett et al., 2020), there are no feasible and solid strategies available for overcoming acquired resistance to osimertinib caused by EGFR L718Q, especially with EGFR T790M and L718Q comutation (Shaikh et al., 2021). In fact, previous case reports and in vitro studies have revealed that afatinib only exhibits an inhibitory effect on phosphorylation in the presence of EGFR L858R + L718V/Q comutation (Starrett et al., 2020). Although our case involved EGFR L718Q in addition to the T790M mutation, resistance to osimertinib had already emerged.

The safety and efficacy of almonertinib (HS-10296), a novel, third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), was evaluated in a phase I trial including patients with locally advanced or metastatic EGFR-mutated nonsmall-cell lung cancer (NSCLC) whose disease had progressed after prior EGFR TKI therapy (Yang et al., 2020). As previously reported, the main adverse events of all grades with almonertinib treatment of NSCLC patients were rash, pruritis, leukopenia, and increases in creatinine phosphokinase, alanine aminotransferase and aspartate aminotransferase, with increases in creatinine phosphokinase and alanine aminotransferase being the most common grade 3–4 adverse events (Yang et al., 2020; Nagasaka et al., 2021). In our case, unfortunately, almonertinib treatment ultimately discontinued due to serious electrolyte disorders and heart failure. However, according to previous evidence, electrolyte disorders and heart failure may be associated with accumulation of toxicity due to previous multiline treatment, whereby the physical constitution becomes very poor, rather than being due to almonertinib treatment.

We report an NSCLC patient with metastasis and osimertinib resistance who benefitted from almonertinib. First, this case confirms resistance to osimertinib caused by the L718Q mutation. In addition, this case suggests that almonertinib has the potential to overcome resistance to osimertinib associated with the L718Q mutation and that NGS can be used as an effective method for EGFR mutation analysis. It may be very meaningful that NGS detection accompanies systemic treatment of advanced NSCLC patients or is used for monitoring NSCLC patients postoperatively. As more evidence accumulates, NGS accompanying monitoring may become a powerful clinical diagnosis and treatment tool.