Precision targeted therapy for EGFR mutation‐positive NSCLC: Dilemmas and coping strategies

Abstract

The most common driver gene mutation in patients with non‐small‐cell lung cancer (NSCLC) is an epidermal growth factor receptor (EGFR) mutation. With the introduction of EGFR‐tyrosine kinase inhibitors, the treatment prospects and prognosis of NSCLC patients with EGFR‐sensitive mutations have significantly improved. Nonetheless, therapies targeting NSCLC are still associated with a risk of primary or secondary nonclassical drug resistance mutations. In recent years, the research and methodology have led to the continuous discovery of new drugs and drug resistance targets. These explorations have also resulted in continuously discovering new drugs. Consequently, rapid advancements have been made to overcome NSCLC drug resistance. This study aimed to review the current dilemma of targeted therapy for EGFR mutation‐positive NSCLC and the coping strategies for these difficulties.

Overview of the dilemma and coping strategies of targeted therapy for epidermal growth factor receptor mutation‐positive non‐small‐cell lung cancer. A variety of therapeutic strategies for the drug resistance mechanism of targeted therapy for lung cancer have been developed, including the research and development of fourth‐generation targeted therapy drugs, the combination with mesenchymal epithelial transition factor (MET) inhibitors, antibody‐drug conjugate (ADC) drugs and immune checkpoint inhibitors. Some driver gene mutation types are blocked in drug research and development due to their special spatial structure, and the development of novel targeted drugs, allosteric inhibitors, and therapies targeting protein degradation may provide new hope for such patients.

INTRODUCTION

Somatic activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are present in approximately 15% of Caucasians and nearly 50% of Asian patients with advanced non‐small‐cell lung cancer (NSCLC). ¹ , ² EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs) are competitive inhibitors of adenosine triphosphate (ATP) at binding sites on EGFR. These binding sites prevent EGFR autophosphorylation and the activation of downstream signal transduction pathways. EGFR‐TKIs inhibit tumor cell proliferation and metastasis, and plays an essential role in targeted therapy for NSCLC. ³ The introduction of EGFR‐TKIs has improved the outlook for patients with primary treated EGFR‐sensitive in NSCLC. According to the data from these patients, the administration of EGFR‐TKI drugs in NSCLC patients resulted in slight improvement, and progression‐free survival (PFS) increased from 6–13 months to more than 20 months. ⁴ , ⁵ , ⁶ An increase in PFS demonstrates the importance of precision‐targeted therapy in NSCLC with EGFR‐sensitive mutations. Nevertheless, most NSCLC patients develop acquired drug resistance after 8–16 months of targeted therapy with EGFR‐TKIs ⁷ Due to the complex and variable types of drug resistance, including primary or rare and nonclassical secondary drug resistance mutations, targeted therapy is a dilemma. In recent years, in‐depth research and methodology exploration has led to the continuous discovery of new drugs and resistance targets. The continuous and rapid development of drug synthesis technologies for these new targets and overcoming drug resistance targets has emphasized the role of precision therapy in EGFR mutation‐positive (EGFR⁺) NSCLC patients. This study aims to review the current dilemmas and progress in the corresponding treatment strategies for patients with EGFR⁺ NSCLC.

DRUG RESISTANCE DILEMMAS OF TARGETED THERAPY AND COPING STRATEGIES

The drug resistance mechanism of targeted therapies in patients with EGFR⁺ lung cancer involves three factors. The first includes pharmacological factors, such as drug compliance or underdose, inadequate absorption, increased metabolism, and inadequate blood–brain barrier penetration. Failure of the drug to deliver its target also may contribute to drug resistance in these patients. ⁸ The second factor for drug resistance in EGFR⁺ lung cancer drug mechanism includes factors in cell biology (secondary mutation and copy number increase, of which EGFR Cys797 to Ser797 [C797S] point mutation is the most common), downstream effector protein‐activated signaling pathways (Janus Kinase 1 [JAK1], mitogen‐activated protein kinase 2 [MAP2K2], Mammalian Target of Rapamycin [MTOR], phophatidylinositol‐4‐phosphate 3‐kinase catalytic subunit type 2 alpha [PIK3C2A]), bypass signaling pathway activation (such as mesenchymal epithelial transition factor [MET] amplification, Anexelekto [AXL] activation, and erb‐b2 receptor tyrosine kinase 2 [ErbB2] amplification), histological transformation (such as small cell lung cancer transformation), and phenotypic changes. ⁸ The FLAURA trial focused on patients who progressed or interrupted treatment after receiving first‐generation EGFR‐TKI and osimertinib (AZD‐9291). The results of the FLAURA trial showed that the most common acquired resistance mechanism was MET amplification, accounting for approximately 15% of the resistance mechanism; EGFR C797S mutation accounted for approximately 7% of the resistance mechanism. ⁴ The third factor for drug resistance in the EGFR⁺ lung cancer drug mechanism involves the spatiotemporal heterogeneity of the tumor. In intratumoral temporal heterogeneity, resistance mutations arise from adaptive evolution under pressure, while in intratumoral spatial heterogeneity, drug resistance arises from pre‐existing mutations. ⁹

In addition to the resistance mechanisms associated with DNA alterations, studies have revealed potential resistance mechanisms for other pathways. Transcriptome analysis revealed that the RNA‐binding protein MUSASHI‐2 (MSI2) is one of the highly upregulated stem cell‐related genes in EGFR‐TKI‐resistant cells, and its increased expression is a novel mechanism of EGFR‐TKI resistance, providing proof of principle that targeting the MSI2‐Nanog axis in combination with EGFR‐TKI can effectively prevent the emergence of acquired resistance. ¹⁰ It also reveals an unprecedented mechanism by which RNA structural switches regulate EGFR‐TKI resistance by controlling the yrdC N6‐threonylcarbamoyltransferase domain containing (YRDC) mRNA translation in an embryonic lethal abnormal vision‐like 1 (ELAVL1) ‐dependent manner. ¹¹ Recent work by Nie et al. ¹² revealed that EGFR‐TKI treatment in NSCLC leads to metabolic remodeling of the neurotransmitter acetylcholine (ACh) in cells with drug‐tolerant persister (DTP) and its regulatory mechanism. Zhang et al.¹³ screened the protein molecule AKR1B1 associated with drug resistance in the in vitro and in vivo drug resistance model in line with the clinical treatment pathway and the clinical drug resistance recurrence database based on the results of previous studies, combined with transcriptomic analysis, and functional studies found that the survival, growth, and drug resistance of a variety of tumor cell models resistant to first‐ and third‐generation EGFR‐TKIs were dependent on AKR1B1. Emerging findings from this study and the implications of antidiabetic drug repositioning for strategies could have implications for overcoming resistance to EGFR‐targeted agents in lung cancer. ¹³ It has also been found that CD70 is rapidly upregulated in people with persistent resistance following TKI therapy, which raises the possibility that CD70 could be targeted early in NSCLC patients with EGFR‐mutated disease. ¹⁴ Another study revealed that several key proteins, including DUSP1, DUSP6, GAB2, and FOS, may play a role in the development and maintenance of EGFR TKI resistance in lung cancer by performing differential gene expression analysis of the dataset, followed by pathway analysis, as well as structural disorder analysis of key proteins in these pathways, and helped design more efficient combination therapy strategies to prevent the development of resistance. ¹⁵ Based on these mechanisms, a variety of therapeutic strategies for the drug resistance mechanism of targeted therapy for lung cancer have been developed, including the research and development of fourth‐generation targeted therapy drugs and the combination of MET inhibitors, antibody‐drug conjugates (ADC) drugs, and immune checkpoint inhibitors (ICIs). Ongoing or completed clinical trials for these strategies have promoted the development of precision therapy for lung cancer.

The types and proportion of different resistance mechanisms against EGFR‐TKIs are shown in Figure 1.

FIGURE 1.

Types and proportion of different resistance mechanisms against EGFR‐TKIs. (a) Types and proportion of resistance to first‐ and second‐generation EGFR‐TKIs. (b) Type of resistance after first‐line treatment with third‐generation EGFR‐TKIs.

THERAPEUTIC STRATEGIES TARGETING SIGNALING PATHWAYS

Targeting driver gene mutation pathways

The fourth‐generation targeted therapy drugs

The EGFR C797S mutation is a commonly reported resistance mechanism to third‐generation EGFR‐TKIs. ⁴ This mutation is located at codon 797 of EGFR in the kinase binding site. This EGFR C797S mutation results in the substitution of cysteine at codon 797 of the ATP binding site for serine. The drug osimertinib (AZD9291) was specifically designed to bind covalently to C797 in the EGFR kinase binding site. ¹⁶ Thus, this mutation results in the loss of the covalent binding activity of osimertinib to EGFR. C797S mutation leads to resistance of all third‐generation irreversible EGFR inhibitors. EAI045 was the first allosteric TKI to overcome T790M and C797S mutations ¹⁷ successfully. However, when used alone, these allosteric inhibitors are ineffective due to receptor dimerization. In a genetically engineered mouse model of EGFR‐mutant lung cancer, EAI045 in combination with cetuximab resulted in the complete activity of EAI045 against T790M and C797S, induced tumor response, and the response rates improved by nearly 80%. ¹⁸ To improve the activity and monotherapy efficacy of EAI045, Eck et al. optimized the drug again with a mother nucleus to obtain a novel allosteric inhibitor, JBJ‐04‐125‐02. JBJ‐04‐125‐02 has high efficacy, low toxicity, and is effective against EGFR mutations. JBJ‐04‐125‐02 effectiveness was confirmed in vitro and in vivo models containing the EGFR C797S mutation. ¹⁹ , ²⁰ JBJ‐04‐125‐02 combined with osimertinib can form a dual drug that co‐binds and significantly improves the inhibitory effect on tumor cells and delays tumor cell resistance development. ¹⁹ BLU‐945 selectively inhibited the autophosphorylation of EGFR⁺/T790M/C797S and EGFR⁺/T790M. BLU‐945 also inhibited cancer cell lines harboring EGFR‐sensitive mutations (Del19 or L858R), T790M mutation, and the triple mutations of the C797S mutation. BLU‐945 has a lethality that is 1000–2000 times higher than that of marketed first‐ and third‐generation targeted drugs. ²¹ A study investigating BLU‐945 is ongoing (phase 1/2, NCT04862780). BLU‐701 can inhibit EGFR‐sensitive mutations (Del19 or L858R) or double mutations with C797S. However, BLU‐945 is unable to inhibit T790M and triple mutations. TQB3804 had inhibitory activity against EGFRd746‐750/T790M/C797S, L858R/T790M/C797S, d746‐750/T790M, and L858R/T790M, with IC50 values of 0.46, 0.13, 0.26, and 0.19 nM, respectively, especially for resistant tumors with C797S mutation. TQB3804 inhibits double and triple mutations after second‐ and third‐generation EGFR‐TKI resistance. ²² A phase I trial of TQB3804 is currently ongoing (NCT04128085). BBT‐176 inhibits triple mutations, including C797S (Del19/T790M/C797S and L858R/T790M/C797S), and it is in phase 1/2 (NCT04820023). CH7233163 has better pharmacological effects than EAI045 and osimertinib, and it acts on EGFR Del19, L858R, and T790M in a noncovalent bonding mode. CH7233163 interferes with the C797S mutation and weakly inhibits wild EGFR. ²³ In the EGFR Del19/T790M/C797S biochemical assay, CH7233163 had an IC50¼ = 0.28 nmol/L, while osimertinib had an IC50 > 100 nmol/L and the first fourth‐generation inhibitor EAI045 > 1000 nmol/L, which had no inhibitory activity; in the cell biological activity assay, CH7233163 effectively inhibited the proliferation of Del19/T790M/C797S_NIH3T3 cells and blocked EGFR phosphorylation in the cells. ²³ Ahmad et al. ²⁴ linked the binding site of p38a MAPK to the L858R/T790M/C797S triple mutant EGFR. They observed that the p38a MAP kinase was similar to the mutant T790M/C797S EGFR's ATP competitive binding site's hinge region, HR‐I and HR‐II. Ahmad et al. also reviewed the clinical trials of the p38a MAPK kinase inhibitors SD‐06, Amgen 16, RWJ67657, and SCIO‐323 as fourth‐generation EGFR TKIs to overcome both the triple mutation of L858R/T790M/C797S and the problem of drug resistance in NSCLC. The EGFR L718Q mutation commonly occurs, representing another mechanism of osimertinib (AZD9291) resistance. ²⁵ It is therefore possible to develop TKIs that target this specific mutant.

TKI combination therapy

Exploration of the driver gene mutation pathways has revealed that combined therapy with different generations of EGFR‐TKIs may result in delaying drug resistance. Preclinical models have shown that osimertinib and gefitinib prevent acquired second‐line EGFR resistance. The results of the first‐line treatment of patients with EGFR⁺ NSCLC with osimertinib combined with gefitinib showed an objective response rate (ORR) of 85.2% (95% confidence interval [CI] 67.5−94.1%) and a disease control rate (DCR) of 100%. Plasma droplet digital PCR (ddPCR) (n = 25) detected driver EGFR mutations at baseline in 68% of patients; 82.4% of these patients had undetectable plasma EGFR 2 weeks after starting treatment. Median PFS was not achieved at a follow‐up of 14.8 months. ²⁶ The combination of osimertinib and gefitinib for the first‐line treatment of EGFR‐mutated NSCLC is therefore tolerable and leads to rapid plasma clearance of EGFR mutations. The observed ORR was consistent with previously reported first‐line response rates of osimertinib. Analysis of the survival outcomes and mechanisms of acquired resistance awaits data maturation and will contribute to understanding the role of first‐line dual EGFR TKIs therapy in patients with EGFR⁺ NSCLC. In the single‐arm phase II WJOG10818L/Alt trial ²⁷ of the first‐line rotation therapy with osimertinib‐afatinib conducted in Japan, 1‐year PFS was 70.18% (95% CI 54.22−81.48%) and the primary endpoint was not met. This study's ORR and 1‐year overall survival (OS) rates were 69.6% (95% CI 54.2−82.3%) and 93.48% (95% CI 81.13 − 97.85%), respectively. The most common treatment‐related adverse events were diarrhea (73.9%, grade 3 4.3%), rash acne (63.0%, grade 3 2.2%), and paronychia (52.2%, grade 3 0%). A single‐arm phase II OSCILLATE study ²⁸ , ²⁹ was conducted in Australia and explored the efficacy of second‐line rotation therapy with osimertinib‐gefitinib. This study showed an ORR of 40% (19/47, 95% CI 28–55%), 1‐year PFS of 38% (27–55%), PFS of 9.2 months (7.2–13), and time to treatment failure (TTTF) of 9.4 months (7.6–13). Two‐drug treatment rotations were well‐tolerated; the most common grade 3–4 reported adverse events (AEs) included headaches and nausea. Headaches and nausea were not considered treatment related. A patient died during the study due to a lung infection. In addition, TKIs can be combined with monoclonal antibody therapy against EGFR to delay drug resistance. In a phase I study, 55 patients with EGFR mutations were treated with osimertinib plus necitumumab. Clinical activity was observed in EGFR‐dependent resistance (T790M positive and C797S positive) and EGFR exo20ins after progression with a third‐generation TKI. This regimen proved feasible and was well‐tolerated by the patients. ³⁰

Targeting driver gene downstream signaling pathways

In addition to therapeutic strategies targeting driver gene mutation pathways, inhibiting downstream signaling pathways is also important to overcome drug resistance in patients with EGFR⁺ NSCLC. Signal transduction pathways downstream of EGFR mainly include the RAS/RAF/MEK/ERK–MAPK pathway and the PI3K/AKT/PTEN/mTOR pathway. EGFR can trigger downstream PI3K/AKT and MAPK signaling axes, which stimulate transcription factors to drive gene expression associated with proliferation, angiogenesis, invasion, and metastasis. ³¹ , ³² Thus, overactivation of this pathway inhibits apoptosis and stimulates tumor growth, therefore PI3K/AKT/PTEN/mTOR is an important mechanism of acquired resistance to EGFR‐TKIs in NSCLC. This study retrospectively included patients with both EGFR and PI3K pathway mutations and assessed the effect of EGFR TKIs plus everolimus, an mTOR inhibitor. ³³ The results showed that 49 patients (14.9%) with resistance to EGFR‐TKIs had at least one genetic variant in the PI3K pathway. PIK3CA, PTEN, and AKT1 variants were found in 31 (9.5%), 18 (5.5%), and three (0.9%) patients, respectively. For patients treated with everolimus and EGFR‐TKIs, five patients (5/6, 83.3%) achieved stable disease (SD), while disease control was not achieved in one patient (1/6, 16.7%). The PFS was 2.1 months, and the most common AEs were oral ulcers (6/6) and rash (1/6). ³³ Therefore, EGFR‐TKIs combined with everolimus have limited antitumor activities in patients with EGFR‐mutated NSCLC with aberrant activation of the PI3K pathway. An experimental study of in vitro tumor cell lines and in vivo models at the 2018 American Association of Cancer Research meeting showed that the combination of brigatinib and selumetinib (MEK inhibitors) may overcome the resistance to osimertinib caused by the C797S mutation. ³⁴ Currently, a clinical study of osimertinib plus selumetinib is being conducted in the treatment of naïve advanced EGFR⁺ NSCLC (NCT03392246). The downstream signaling pathways mediating resistance to EGFR T790M driver mutations include activation of JAK1/STAT3. A phase I study (NCT02145637) of afatinib combined with oral JAK1 and JAK2 tyrosine kinase inhibitor ruxolitinib in EGFR‐targeted resistance included 30 patients. In this study, 66.7% of the patients were T790M positive, and 50% had received ≥2 prior regimens. This study population's ORR, DCR, PFS, and OS were 23.3% and 93.3%. The PFS of this study population was 4.9 months, while the OS was 9.6 months. For T790M‐positive patients, the ORR was 25%, while the DCR was 100%. ³⁵ The knockdown of STAT3 or inhibition of JAKs therefore enhances the anticancer activity of afatinib in T790M tumor cells.

Targeting bypass activation pathways

Targeting MET gene amplification

When EGFR‐TKIs inhibit the cell signaling pathways mediated by EGFR, excessive activation of bypass pathways will continue to maintain the malignant biological behavior of tumor cells, resulting in resistance to EGFR‐TKIs. The combination of EGFR‐TKIs with other drugs targeting bypass activation pathways should be the focus of future studies to eliminate the effect of drug‐resistant tumor clones. MET amplification is the most common cause of bypass activation and can consistently activate EGFR downstream pathways, resulting in resistance to third‐generation osimertinib (AZD9291). ³⁶ Typically, MET amplifications occur in 5% of NSCLC patients with EGFR‐sensitive mutations who have failed first‐ or second‐generation TKI therapy. The number of MET amplifications is 25% in patients who have progressed to the third‐generation EGFR‐TKI osimertinib. ³⁷ , ³⁸ , ³⁹ MET belongs to the RTK family, and it is associated with TKI resistance (particularly in lung cancer) and is amplified in EGFR‐dependent cancers. The dual drug targeting of EGFR and MET may provide an effective way to prevent the development of EGFR‐TKI‐resistant tumors with MET amplification. Synergy has therefore been identified between EGFR and MET inhibitors. Several advanced clinical trials are currently underway to assess the availability of MET‐targeted agents (MET‐TKIs or EGFR‐MET bispecific antibodies) in combination with EGFR‐TKIs for treating MET‐amplified EGFR‐mutated tumors. The CHRYSALIS study (NCT02609776) is a phase I clinical trial that evaluates the anti‐EGFR‐MET bispecific antibody amivantamab and the effectiveness of its combination with lazertinib in patients with NSCLC with EGFR 19Del or L858R mutations. ⁴⁰ , ⁴¹ In the treatment of NSCLC with insertion mutations in EGFR exon 20 (EGFR ex20ins) after prior chemotherapy, the 2020 World Conference on Lung Cancer showed that the BICR‐assessed ORR of amivantamab was 40%, the investigator‐assessed ORR was 36%, PFS was 8.3 months, the median duration of response (mDOR) was 11.1 months, and DCR was 74%. Amivantamab also showed some efficacy in patients resistant to osimertinib, with an overall response rate of 28% in 58 patients resistant to EGFR third‐generation drugs and 16 tumors achieving partial response (eight C797S mutations, three MET amplification, and five other resistance mechanisms: non‐EGFR resistance mutation or MET amplification). The overall response rate to combination therapy was 36% in 45 patients with osimertinib resistance, including one case of complete response and 15 cases of PR. ⁴² In these patients, the detection of resistance biomarkers based on EGFR and MET identified patients more likely to respond to combination therapy. The PFS for biomarker‐positive and ‐negative patients was 6.7 months (95% CI 3.4–NR) and 4.1 months (95% CI 1.4–9.5), respectively. Twenty patients had sufficient tissue for immunohistochemistry (IHC) staining; 90% (9/10) of these patients had a high IHC score (EGFR⁺ MET H score > 400) and responded to treatment, while only two patients had a low IHC score. ⁴² The efficacy and safety of amivantamab in combination with lazertinib versus osimertinib as a first‐line therapy for locally advanced or metastatic NSCLC with EGFR mutations is currently being investigated in an ongoing phase III MARIPOSA trial. ⁴³

Relevant studies on MET‐TKI‐targeted drugs (capmatinib [INC280] and savolitinib) combined with the EGFR‐TKI drugs osimertinib or gefitinib are ongoing. The phase II INSIGHT study (NCT03940703) of tepotinib in combination with gefitinib in MET‐amplified (GCN>5), EGFR⁺/T790M negative, and previously first/second‐generation TKI‐resistant patients showed an ORR of 66.7% and a PFS of 16.6 months in MET‐amplified patients; the results of this study group were significantly better than that of the chemotherapy control group. ⁴⁴ Capmatinib (INC80) in combination with gefitinib in patients with MET amplification (GCN>5), EGFR⁺/T790M negative status, and previous phase II clinical trials of first/second‐generation TKI‐resistant patients showed that patients with MET amplification had an ORR of 47% and a PFS of 5.49 months, significantly better than those with low MET levels. ⁴⁵ The multi‐arm, multicenter, open‐label phase 1b TATTON Ib/II extension study ⁴⁶ explored the combination of savolitinib with osimertinib. It showed that among patients who have received third‐generation treatment, ORR was 33.3% (95% CI 22.4–45.7) and PFS was 5.5 months (95% CI 4.1–7.7), ORR was 64.7–66.7% and PFS was 9.0–11.1 months in patients without third‐generation treatment; these patients tolerated the drugs well and had acceptable safety profile. ⁴⁷ Based on TATTON study data, the SAVANNAH study ⁴⁷ , ⁴⁸ (NCT03778229) is ongoing to assess the efficacy of osimertinib in combination with savolitinib for the treatment of advanced NSCLC patients with EGFR‐sensitive mutations with MET amplification after resistance to osimertinib. In addition, the multiagent phase II platform ORCHARD study ⁴⁹ (NCT03944772) is ongoing and involves treatment arm assignment with multiple resistance mechanisms after first‐line osimertinib treatment; the first‐line osimertinib treatment includes osimertinib combined with savolitinib. The phase III SACHI study (savolitinib in combination with osimertinib in patients who have progressed after EGFR‐TKI therapy due to MET amplification, NCT05015608) and the phase III SANOVO study (savolitinib in combination with osimertinib in treatment‐naive EGFR⁺ NSCLC patients with MET overexpression, NCT05009836) are also being conducted. These ongoing clinical studies will further evaluate the best method to detect MET‐driven resistance. They are also expected to evaluate better the therapeutic potential of the combination treatment of osimertinib and savolitinib for patients with EGFR⁺ and acquired MET amplification.

Targeting other bypass activation pathways

In addition to MET mutations, the activation of BCL‐2 signaling can also mediate resistance to EGFR mutations. A phase 1b study of pelcitoclax (APG‐1252) combined with osimertinib in the treatment of EGFR‐TKI‐resistant NSCLC showed ⁵⁰ that ORR was 5% and DCR was 80% in dose expansion cohort 1 (third‐generation EGFR‐TKI‐resistant patients); the ORR was 36.4% and 95.5%, respectively, in dose expansion cohort 2 (patients not treated with osimertinib), with a good safety profile noted. The recommended phase II dose (RP2D) was pelcitoclax 160 mg/week combined with osimertinib 80 mg once daily, therefore the combination of pelcitoclax with osimertinib is safe and feasible, and a preliminary synergy of this combination regimen has been observed in patients with osimertinib‐resistant NSCLC. Cabozantinib, called XL184, is a small‐molecule tyrosine kinase inhibitor with multiple targets (including MET, VEGFR1, VEGFR 2, VEGFR 3, ROS1, RET, AXL, NTRK, and KIT). XL184 is used in combination with osimertinib to provide significant inhibition of drug‐resistant cells. XL184 was also found to have antitumor efficacy in vivo. ⁵¹ The ACTIVE study/CTONG1706 ⁵² was the first phase III study to evaluate the oral anti‐angiogenic agent VEGFR‐2‐TKI apatinib in combination with EGFR‐TKI gefitinib as first‐line treatment for advanced NSCLC patients with EGFR mutations. Although it showed no significant difference in ORR and DCR, independent radiology review committee‐assessed PFS was significantly prolonged (13.7 months vs.10.2 months, p = 0.02) with a 12‐month PFS rate of 53.4% at 13.7 months and 35.6% at 10.2 months. ⁵² In the combined TP53 mutation population, the dual TKI group had a higher efficacy without a new safety signal. ⁵² Similarly, in the RELAY study ⁵³ (NCT02411448) of ramucirumab + erlotinib versus erlotinib in patients with advanced treatment‐naïve EGFR mutations, the combined TP53 mutation population benefited more significantly from the A (anti‐angiogenic) + T (TKIs) combination. In addition, activated AXL, together with EGFR and HER3, plays an important role in maintaining cell survival and inducing the formation of osimertinib‐resistant cells. ⁵⁴ Bemcentinib is a first‐in‐class, potent, highly selective AXL inhibitor that targets and binds to the intracellular catalytic kinase domain of AXL receptor tyrosine kinase and inhibits its activity. ⁵⁵ A phase 1/2 trial of the AXL kinase inhibitor BGB324 (bemcentinib) in combination with erlotinib in patients with T790M negative advanced NSCLC after resistance to the first‐generation EGFR‐TKI erlotinib is currently evaluating its overall efficacy. ⁵⁶

In advanced EGFR‐mutated NSCLC patients, co‐alterations in cell cycle genes such as CCND1/2, CCNE1, and CDK4/6 are significantly associated with intrinsic resistance to osimertinib. ⁵⁷ Alterations in genes encoding cell cycle regulators have also been reported in almost 10% of patients who progressed to osimertinib treatment on second‐ or first‐line therapy. ⁵⁸ , ⁵⁹ According to FLAURA, AURA3, and real‐world studies, approximately 10–12% of patients have overexpression of CDK4, CDK6, and/or CCND1, CCND2, and low expression of CDKN2a or loss of CDKN2a. ⁵⁷ , ⁶⁰ , ⁶¹ Therefore, osimertinib combined with CDK4/6 inhibitors may overcome the resistance dilemma of targeted therapy for EGFR‐mutated NSCLC. A recent study demonstrated that abemaciclib, a CDK4/6 inhibitor, alone or in combination with Osimertinib, may be an effective strategy for osimertinib‐resistant patients with NSCLC who have progressed after first‐ or second‐line therapy. ⁶² Interestingly, this combination is being clinically evaluated in phase II trials (NCT04545710): abemaciclib in combination with osimertinib was evaluated in patients with drug‐resistant EGFR‐mutated lung cancer after progression on osimertinib therapy starting in September 2020. The combination of osimertinib with abemaciclib strongly reduced the emergence of resistance and may represent a potential strategy for future first‐line therapy. Another study found that CDK4 expression and Rb phosphorylation were increased in osimertinib‐resistant lung cancer cells, and RB phosphorylation was downregulated when CDK4/6 was inhibited using palbociclib and blocked acquired resistant cells in the G1 phase, which significantly enhanced the sensitivity of resistant cells to osimertinib, providing a basis for targeting CDK4/6 as a potential therapy to overcome third‐generation EGFR‐TKIs in lung cancer therapy. ⁶³

THERAPEUTIC STRATEGIES TARGETING MECHANISMS OTHER THAN SIGNALING PATHWAYS

Antibody drug conjugates

ADCs include monoclonal antibodies targeting specific antigens, linkers, and highly potent cytotoxic small molecules with dual activities of chemotherapeutic drugs (narrow therapeutic window, easy resistance, and low selective tumor cell lethality) and targeted antibody drugs (high specific antitumor activity). ⁶⁴ , ⁶⁵ Resistance mediated by the HER2 pathway accounted for approximately 15% of EGFR TKIs resistance cases; the ORR of trastuzumab plus paclitaxel against this resistance was 41%. Trastuzumab‐DM1 (T‐DM1) is an ADC drug composed of trastuzumab and the small molecule microtubule inhibitor DM1. T‐DM1 is indicated for HER2‐positive metastatic breast cancer. ⁶⁶ , ⁶⁷ An interim analysis of the phase II TRAEMOS study focused on the effectiveness of T‐DM1 combined with osimertinib in HER2‐bypass‐resistant EGFR⁺ NSCLC ⁶⁸ showed an ORR of 11% (n = 3/27) and a DCR of 48% (n = 13/27). In the analysis, the ORR was 17% versus 7% and the 12‐week DCR was 42% versus 53% in HER‐2 IHC 2+ and IHC 3+ patients, respectively. The median progression‐free surviva of this study was 2.7 months (95% CI 2.1–3.5 months). Thus, the clinical efficacy of T‐DM1 in combination with osimertinib in treating HER2‐bypass‐resistant EGFR⁺ NSCLC is limited; however, the combination of ADC drugs with osimertinib is a new exploration direction in patients with HER2‐bypass‐resistant EGFR⁺ NSCLC. The novel ADC drug DS‐8201 (T‐DXd) consists of a recombinant humanized IgG1 anti‐HER2 monoclonal antibody, trastuzumab, a tetrapeptide‐based cleavable linker, and topoisomerase I inhibitor (DXd) (camptothecin derivative), which can penetrate cell membranes, kill nearby cancer cells, and produce a “bystander effect.” ⁶⁵ , ⁶⁹ , ⁷⁰ The US FDA approved DS‐8201 in December 2019 to treat adult patients with unresectable or metastatic HER2‐positive breast cancer who have received at least two prior anti‐HER2 therapies. In the DESTINY‐Lung 01 trial, DS‐8201 showed significant efficacy in advanced NSCLC with HER2 mutation. DS‐8201 had an ORR of 61.9%, PFS of 14.0 months, and the mDOR has yet to be reached. ⁷¹ However, the safety profile of T‐DXd limits its clinical application. Data from the DESTINY‐Breast01 study ⁷² showed that 25 T‐DXd patients experienced AEs such as interstitial lung disease (ILDs), with a median investigator‐reported time to onset for ILD being 193 days, and 20 days for grade 2 or higher; four patients died 9–60 days after being diagnosed with ILD, therefore ILD is an important risk factor in T‐DXd therapy and requires careful recognition and intervention. T‐DXd received a Breakthrough Therapy Designation in May 2020 for patients with metastatic HER2‐mutated NSCLC who have progressed or after platinum‐based chemotherapy, and it is now included in the National Comprehensive Cancer Network guidelines. ⁷³ Another ADC representative drug is U3‐1402, mainly composed of patritumab, an antibody that acts on HER3, and DX‐8951. U3‐1402 is a cytotoxic drug (exatecan, a topoisomerase inhibitor) conjugated by cystine residues. ⁷⁴ U3‐1402 is resistant to multiple EGFR resistance mechanisms and is effective in patients with different resistance mechanisms to EGFR‐TKIs, such as C797S, T790M, HER2, and CDK4 amplifications that can be controlled. ⁷⁴ , ⁷⁵ , ⁷⁶ U3‐1402 alone or in combination with EGFR‐TKIs can be a novel therapy for NSCLC with EGFR‐TKI‐resistant EGFR mutations. ⁷⁷ The efficacy of U3‐1402 in NSCLC patients with resistance to EGFR‐TKI therapy is currently being explored (phase 1/2, NCT03260491, NCT02980341).

Monotherapy and combination treatment strategies involving ICIs

ICIs have been used to treat a variety of advanced cancers, ⁷⁸ , ⁷⁹ , ⁸⁰ but some retrospective analyses have shown that EGFR⁺/ALK⁺ NSCLC tumors respond poorly to these treatments compared to EGFR⁻/ALK⁻ tumors. ⁸¹ , ⁸² Recently, the ATLANTIC study ⁸³ assessed the effect of durvalumab therapy in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumor expression of PD‐L1. Among patients with at least 25% tumor cells expressing PD‐L1 who were evaluable for an objective response by an independent central review, nine of 74 (12.2%) patients achieved ORR in cohort 1 (patients with EGFR⁺/ALK⁺ NSCLC), 24 of 146 (16.4%) patients achieved ORR in cohort 2 (patients with EGFR⁻/ALK⁻NSCLC), and 21 of 68 (30.9%) patients achieved ORR in cohort 3 (patients with EGFR⁻/ALK⁻NSCLC). Grade 3 or 4 treatment‐related adverse events (TRAEs) occurred in 40 (9%) of the total 444 patients. These TRAEs commonly included pneumonia (1%), fatigue (1%), and infusion‐related events (1%). ⁸³ , ⁸⁴ The clinical efficacy of durvalumab in EGFR⁺ NSCLC patients with ≥25% tumor cells expressing PD‐L1 is encouraging. In addition, the level of PD‐L1 expression in tumor cells may also contribute to the objective response of EGFR⁺/ALK⁺ NSCLC patients. ⁸³ , ⁸⁵ Further studies on durvalumab in EGFR⁺/ALK⁺ NSCLC patients are required. Su et al. ⁸⁶ reported a favorable response to anti‐PD‐1 therapy in a patient with de novo resistance to EGFR‐TKIs in addition to double positivity for PD‐L1 and CD8, therefore checkpoint therapy should not be completely excluded from candidate treatment strategies for patients with NSCLC who develop resistance to EGFR‐TKIs. It is thus necessary to reveal the regulatory mechanism of PD‐L1 in EGFR‐TKI‐resistant NSCLC. Acquired EGFR‐TKI resistance has been shown to promote immune escape in lung cancer by upregulating PD‐L1 expression and the PI3K‐Akt, MAPK, NF‐kappa B signaling pathway, and AP‐1. PI3K‐Akt, MAPK, the NF‐kappa B signaling pathway, and AP‐1 are involved in the upregulation of PD‐L1 expression induced by different EGFR‐TKI resistance mechanisms. ⁸⁷ These results partially explain the different PD‐L1 statuses in EGFR‐TKI‐sensitive and EGFR‐TKI‐resistant tumors and reveal the regulatory mechanism of PD‐L1 in EGFR‐TKI‐resistant NSCLC. The regulatory mechanism of PD‐L1⁺ may have specific implications for the use of ICIs in EGFR‐TKI‐resistant NSCLC. Anti‐angiogenic drugs can normalize tumor blood vessels, activate immune status, promote immune cell differentiation, and improve immune cell function, therefore ICIs combined with anti‐angiogenic therapy may improve the tumor immune microenvironment and enhance immune effects. ⁸⁸ Several phase III clinical studies on immunotherapy combined with anti‐angiogenic therapy after EGFR‐TKI resistance are ongoing. A small post hoc analysis of the IMpower150 study showed that the atezolizumab plus bevacizumab and platinum‐based chemotherapy (ABCP) four‐drug regimen showed increased prognosis after resistance to TKI. Even so, the number of NSCLC patients with EGFR mutations was limited, accounting for only 9.9% (79/800) of the total enrollment of the IMpower150 study. ⁸⁹ A large prospective phase III clinical trial is therefore required to verify the efficacy of the four‐drug combination therapy in this population. The phase III ORIENT 31 study shows significant survival benefits in treating patients with EGFR‐TKI‐resistant nonsquamous NSCLC. The results of this trial show that compared to chemotherapy, the combination of sintilimab, bevacizumab, and chemotherapy significantly prolongs PFS and increases ORR to 44%, with a tolerable safety profile. ⁹⁰ Ongoing phase III clinical studies of immune combination therapy after EGFR TKI resistance include the Checkmate 722 trial (NCT02864251), Keynote 789 trial (NCT03515837), and Atlas trial (NCT03991403); the results of subsequent clinical trials are also worth looking forward to.

The investigators manually screened and collected 4515 published papers related to cancer immunotherapy and obtained 3267 associated data points. The 3267 associated data points included 218 cancer subtypes and 484 immunotherapies, which also involved 642 cancer immunotherapy‐related biomarkers, 108 targets, and 121 control therapies. The authors subsequently developed the first comprehensive knowledge database to freely provide the latest experimentally validated findings on cancer immunotherapy and its biomarkers, targets, and control therapies, CanImmunother (http://www.biomedical-web.com/cancerit/). In addition, this database can be used to compare and understand the clinical efficacy and AEs of cancer immunotherapies and conventional therapies. The database is intended to help clinicians and researchers to quickly identify and discover advanced immunotherapies and their respective biomarkers and targets for patients with specific cancer subtypes.

Figure 2 shows a schematic diagram of the resistance mechanisms and treatment strategies for EGFR mutation‐positive NSCLC. Table 1 summarizes the coping strategies for the resistance dilemma of targeted therapies.

FIGURE 2.

Resistance mechanisms and corresponding treatment strategies in EGFR mutation‐positive NSCLC. Resistance mechanisms of EGFR mutation‐positive NSCLC include EGFR driver gene mutations (T790M and C79S), fourth‐generation TKIs targeting mutations, and EGFR monoclonal antibodies; Mutations in downstream signaling pathways of driver genes can also cause resistance. Drugs targeting mTOR, BCL2, and other targets have been developed. Corresponding treatment strategies have also been developed for resistance caused by the activation of bypass pathways (such as MET, ALK, and AXL). Immunotherapy, ADC drugs, and anti‐angiogenic therapy are novel strategies to overcome resistance to EGFR mutant drugs. EGFR, epidermal growth factor receptor; NSCLC, non‐small‐cell lung cancer; TKIs, tyrosine kinase inhibitors; TAM, tumor‐associated macrophage; MDSCs, myeloid‐derived suppressor cells

TABLE 1.

Overview of coping strategies for the drug resistance dilemma of targeted therapy

1 Therapeutic strategies targeting signaling pathways
Targeting driver gene mutation pathways	Fourth‐generation targeted therapy drugs EAI045: T790M/C797S; EAI045 + cetuximab JBJ‐04‐125‐02: EGFR+/C797S BLU‐945: EGFR+/T790M/C797S, EGFR+/T790M BLU‐701: EGFR Del19/L858R/C797S TQB3804:EGFRd746‐750/T790M/C797S, L858R/T790M/C797S, d746‐750/T790M and L858R/T790M BBT‐176: Del19/T790M/C797S, and L858R/T790M/C797S CH7233163: EGFR+/T790M/C797S P38a MAPK kinase inhibitors: L858R/T790M/C797S
	TKIs combination therapy Osimertinib + gefitinib Osimertinib + afatinib Osimertinib + necitumumab
	Targeting driver gene downstream signaling pathways Targeting PI3K/AKT/PTEN/mTOR: everolimus, an mTOR inhibitor Targeting JAK1/STAT3 activation: ruxolitinib
Targeting bypass activation pathways	Targeting MET gene amplification Amivantamab (EGFR‐MET bispecific antibodies) ± lazertinib MET‐TKIs: selumetinib, capmatinib (INC280), savolitinib, tepotinib
	Targeting other bypass activation pathways Targeting BCL‐2 signaling: pelcitoclax (APG‐1252) Cabozantinib(XL184), a small molecule tyrosine kinase inhibitor with multiple targets Antiangiogenic agent: apatinib, ramucirumab AXL inhibitor: bemcentinib

2 Therapeutic strategies targeting other mechanisms than signaling pathways
Antibody drug conjugates	T‐DM1: trastuzumab + DM1(a small molecule microtubule inhibitor) DS‐8201: trastuzumab + a tetrapeptide‐based cleavable linker + a topoisomerase I inhibitor (DXd) (camptothecin derivative) U3‐1402: patritumab + DX‐8951 (exatecan, a topoisomerase inhibitor)
Monotherapy and combination treatment strategies involving ICIs	ATLANTIC: durvalumab IMpower150: ABCP (atezolizumab plus bevacizumab and platinum‐based chemotherapy) ORIENT 31: sintilimab + bevacizumab + chemotherapy Ongoing trails: Checkmate 722 (NCT02864251), Keynote 789 (NCT03515837), Atlas trial (NCT03991403)

Abbreviations: EGFR, epidermal growth factor receptor; NSCLC, non‐small‐cell lung cancer; TKIs, tyrosine kinase inhibitors; ICIs, immune checkpoint inhibitors; PROTACs, proteolysis‐targeting chimeras.

How to implement more accurate targeted therapy strategies

Gene mutation structures may be effective in predicting the efficacy of targeted therapies. This study describes a structure‐based approach to define the functional group of EGFR mutations. These EGFR mutations can be classified according to sensitivity and structural changes into four distinct subgroups of EGFR mutations: classic‐like mutations distant from the ATP‐binding pocket, T790M‐like hydrophobic core mutations, C‐terminal insertion loops in the αC‐helix of exon 20, and mutations on the inner surface of the ATP‐binding pocket or the C‐terminus of the αC‐helix, which were predicted to be P‐loop and αC‐helix compressing (PACC). ⁹¹ This method can effectively guide the treatment and clinical trial selection of NSCLC patients with EGFR mutations. The method also indicates that structure–function‐based methods can improve the prediction of mutations sensitive to drugs targeted by different oncogenes. In addition, the MINERVA score model constructed based on the five genes can effectively guide patient targeting or chemotherapy. ⁹² The final OS of the ADJUVANT study showed no significant difference, but stratification using the MINERVA molecular efficacy model significantly stratified DFS and OS. The 5‐year OS rate of patients in the adjuvant‐targeted therapy highly beneficial group was 67.3%. The mOS was not reached, and this OS did not show a significant benefit compared to chemotherapy. ⁹² Personalized precision strategies targeting EGFR TKI resistance also included the phase 2, open‐label, multicenter, multiagent, biomarker‐directed ORCHARD study (NCT03944772) in patients with locally advanced or metastatic EGFRm NSCLC who progressed after first‐line treatment with osimertinib. Cui et al. ⁹³ proposed that a multiparameter framework, the CTONG score, based on the Chinese population, can effectively assess the value of lung cancer treatment options. The CTONG score may therefore provide a reference for developing guidelines on treatment options and developing new therapeutic drugs. In addition to constructing models or scoring systems to stratify patients for targeted therapy, it is necessary to use a liquid biopsy to dynamically monitor the drug resistance of targeted therapy. Multigene heterogeneity analysis should also be done after drug resistance of targeted therapy to clarify the drug resistance mechanism and develop a subsequent precision lung cancer treatment plan.

DEVELOPMENT DILEMMAS FOR DRUGS TARGETING SPECIFIC TARGETS AND COPING STRATEGIES

Difficulties in drug development for rare EGFR mutations and coping strategies

EGFR ex20ins mutation is a representative mutation that can be used to demonstrate the dilemma in drug development. Most targeted therapeutics are developed for the ATP‐binding site of kinases. Steric hindrance is caused by the kinase mutation site mutated in EGFR ex20ins and is associated with difficulties in the research and development of drugs targeting this site. ⁹⁴ , ⁹⁵ , ⁹⁶ , ⁹⁷ , ⁹⁸ , ⁹⁹ EGFR ex20ins mutants also make normal tissue toxicities a major challenge in developing such drugs because they are similar to wild‐type EGFR in enzymatic kinetics and structure. Many new drugs have been developed in response to the drug dilemma of EGFR ex20ins mutations. For example, smaller, more compact, flexible drugs can be developed ¹⁰⁰ to enable them to bind tightly to the mutated drug‐binding pocket. Representative agents, such as poziotinib, have modest drug activity, but refined doses of poziotinib need further evaluation ⁹⁹ , ¹⁰¹ to improve toxicity management and enhance treatment compliance. The drug is being further investigated in patients enrolled in the ZENITH20 trial. ¹⁰² There was also a lesson in developing EGFR TKIs based on improvements in the backbone core of third‐generation TKIs, represented by TAK‐788, which is highly selective for EGFR ex20ins with enhanced inhibitory activity. ¹⁰¹ Data from subsequent studies on TAK‐788 are expected. CLN‐081 (TAS6417) is a potent novel small‐molecule TKI inhibitor against common EGFR mutations and less common and refractory EGFR ex20 ins. ¹⁰³ Compared with other agents, TAS6417 has a more favorable selectivity index for EGFR mutations, indicating a safer treatment profile. ¹⁰⁴ TAS6417 is currently being investigated in an open‐label, multicenter phase I/IIa trial (NCT04036682). In addition to efforts to change the structure of drugs, other drugs with different mechanisms of action have been developed, such as hypoxia‐activated prodrug (HAP) tarloxotinib, highly potent Hsp90 inhibitor luminespib (AUY922), and onalespib lactate (AT13387).

Development of SHP2 allosteric inhibitors to overcome drug development dilemmas

SHP2, a protein tyrosine phosphatase containing two SH2 domains, is a key downstream regulator of various growth factors and cytokine signaling. SHP2 plays a key role in cell proliferation and survival, mainly activating the RAS–ERK signaling pathway. ¹⁰⁵ , ¹⁰⁶ , ¹⁰⁷ However, mutations in the upstream protein tyrosine kinases (PTKs) caused by excessive activation of SHP2 can lead to the development of various tumors, ¹⁰⁶ therefore the inhibition of SHP2 activity is an essential strategy for cancer therapy. Due to the polar and hydrophilic nature of the residues in the orthosteric site of SHP2, orthosteric drug design faces great challenges. Allosteric inhibitors of SHP2, which can act as “molecular glues,” stabilize the autoinhibited “closed” conformation of SHP2, reduce the abundance of SHP2 at the plasma membrane, and inhibit the enzymatic function of SHP2, were serendipitously discovered after high‐throughput screening. ¹⁰⁵ These features allow allosteric inhibition of SHP2 proteins to effectively inhibit RAS activation and reduce their ability to promote RAS activation. Currently, optimized SHP099 has been identified as an effective and highly selective allosteric inhibitor of SHP2 that binds to a tunnel‐like allosteric site composed of three domains (two Src homology‐2 domains [N‐SH2, C‐SH2] and a protein tyrosine phosphatase [PTP] domain). SHP099 thereby stabilizes SHP2 in an autoinhibited conformation. ¹⁰⁷ Allosteric resistance has also emerged with SHP099. It has been suggested that gain‐of‐function mutations may occur at the N‐SH2/PTP interface, greatly reducing the sensitivity of SHP2 to SHP099. ¹⁰⁷ , ¹⁰⁸ Further examination of the COSMIC database indicated that D61, E76, and A72 are the most commonly mutated allosteric residues in clinical practice, with typical mutations including D61Y, A72V, and E76K. ¹⁰⁹ The main mechanism of allosteric resistance is that these allosteric mutations lead to a decrease in the stability of the autoinhibited conformation and an increase in the number of open‐state conformations. For example, the E76K mutation disrupts the hydrogen bond (E76‐S502) and salt bridge (E76‐R265), which are essential for the N‐SH2/PTP interaction. ¹⁰⁹ The focus of current research should therefore be on the discovery of novel allosteric inhibitors that can overcome the problem of common drug resistance. Compound‐23, a recently developed allosteric inhibitor, effectively targeted the SHP2E76A mutant. ¹⁰⁷ Combining allosteric and orthosteric drugs can stabilize the protein conformation in the desired state, thereby delaying resistance mutations at these allosteric and orthosteric sites.

Targeted protein degradation therapy to overcome drug development dilemmas

Targeted protein degradation (TPD), the process of eliminating proteins of interest (POI), is an emerging small‐molecule pharmaceutical technology that aims to overcome diseases by targeted degradation of pathogenic proteins. TPD has a promising role in the development of cancer therapy. ¹¹⁰ TPD is focused on developing heterobifunctional small‐molecule degradants, including proteolytic‐targeting chimeras (PROTACs), which consist of three parts: target proteins, conjugates, and E3 ubiquitin ligases. PROTACs are an emerging drug type, different from antibodies and traditional small‐molecule inhibitors, with good tissue distribution and targeting ability; they do not need high‐affinity binding pockets. ¹¹⁰ PROTAC molecules targeting AR, ER, BTK, IKZF1/3, BRD9, Bcl‐xl, IRAK4, and other targets have entered phase I/II of clinical development. TPD therapy can continuously induce the rapid and efficient degradation of pathogenic proteins, greatly increasing the barrier to the emergence of drug resistance in target proteins. There are difficulties in optimizing drug design, such as large molecular weight, oral administration, and PK of TPD drugs. ¹¹⁰ While challenges in targeting E3 ligases remain, PROTAC technology has now made it possible to develop a large knowledge base for E3 ligases and complex ubiquitin‐proteasome systems to target oncoproteins. Overall, exciting advances have been made in the TPD field. Despite these challenges, the pace of discovery of heterobifunctional degradants is expected to continue to accelerate and enter clinical development in recent years.

Table 2 summarizes the dilemmas in drug development and coping strategies for specific targets.

TABLE 2.

Drug development dilemmas and coping strategies for specific targets

1 Difficulties in drug development for rare EGFR mutations and coping strategies
Challenges in the development of EGFR TKIs targeting EGFR ex20ins mutations The spatial hindrance in structure EGFR ex20ins mutants are similar to wild‐type EGFR in enzymatic kinetics and structure
TKIs Poziotinib: a less rigid quinazoline derivative with a smaller terminal and substituent linker, which makes it smaller, more compact, and flexible; ZENITH20 trail TAK‐788: an improved EGFR TKI based on the backbone core of osimertinib, which exerts antitumor activity by irreversible, covalent binding of EGFR‐Cys797/HER2‐Cys805 to mutated EGFR/HER2, respectively CLN‐081 (TAS6417): a novel small molecule potent TKIs against common EGFR mutations (Del19, L858R, T790M), less common mutations (EGFR G719X, L861Q and S768I mutations), and refractory EGFR ex20ins mutations Other drugs with different mechanisms of action Hypoxia‐activated drug (HAP) tarloxotinib: phase II RAIN trail (NCT03805841) HSP90 inhibitors luminespib (AUY922), Onalespib lactate (AT13387)

2 Development of SHP2 allosteric inhibitors to overcome drug development dilemmas
Allosteric inhibitors of SHP2: act as “molecular glues”, stabilize the autoinhibited ‘closed’ conformation of SHP2 SHP099: a highly selective allosteric inhibitor of SHP2 Compound‐23: targeting SHP2E76A mutant

3 Targeted protein degradation therapy to overcome drug development dilemmas
PROTACs: target proteins + conjugates + E3 ubiquitin ligases PROTAC molecules targeting AR, ER, BTK, IKZF1/3, BRD9, Bcl‐xl, IRAK4 and other targets

Abbreviations: EGFR, epidermal growth factor receptor; TKIs, tyrosine kinase inhibitors; PROTACs, proteolysis‐targeting chimeras.

SUMMARY AND PROSPECTS

EGFR mutation is the most common driver of gene mutation in NSCLC patients, and the introduction of EGFR‐TKIs has significantly improved the survival outcomes and treatment prospects of such patients. Nevertheless, targeted therapy for EGFR⁺ NSCLC still faces important problems, including the emergence of primary or rare, nonclassical acquired drug resistance, problems in drug design, and research and development of new targets. Recently, explorations of tumor progression and drug resistance mechanisms have become increasingly in‐depth, and many new signaling pathways and drivers have been discovered. Currently, a variety of new drugs for EGFR⁺ NSCLC and therapeutic strategies for drug resistance mechanisms in such patients have been developed, including fourth‐generation targeted therapy drugs, MET inhibitors, and ADC drugs; combinations with chemotherapy, immunotherapy, and anti‐angiogenic therapy have also been developed. Clinical trials for these strategies are ongoing or being completed, promoting the development of precision treatments for lung cancer. Moreover, some driver gene mutation types are blocked in drug research and development owing to their special spatial structure, therefore developing novel targeted drugs, allosteric inhibitors, and therapies targeting protein degradation may provide new hope for such patients and should be further explored. In addition, novel drug delivery methods, including in vivo nanoparticle transport, in vitro modification using nanoparticles, controlled release systems, and biomaterial implantation scaffolds may provide solutions for precisely targeted drug delivery. It has been found that siRNA targeting MDR1 mRNA (siMDR1) and siRNA targeting survivin mRNA (siSurvivin) can be efficiently co‐delivered by a complex nanoparticle while interfering with both genes, and this delivery method targeting mRNA will be a promising method to overcome NSCLC drug resistance. ¹¹¹ Another study developed a single low‐dose INC280‐loaded nanoparticle, and the results showed that NPs had high anti‐MET/antimetastatic activity, real‐time MRI visualization, and high biocompatibility after a single low dose, achieving multiple delivery of MET‐targeted primary and liver‐metastatic NSCLC, and this new strategy has the potential for widespread applicability in the treatment of advanced NSCLC. ¹¹² Multiple mRNA‐based cancer vaccines are currently undergoing clinical trials (NCT02283320, NCT01792479, NCT01380769, and NCT04381910) based on lipid nanoparticle–mRNA formulations, and RNA vaccines using these lipid nanoparticles further reveal therapeutic options that can be combined with chemotherapy/immunotherapy to improve current lung cancer treatment. In the future, it will be necessary to conduct an in‐depth exploration of basic research and methodology, such as multi‐omics technology, and discover new targets and develop new drugs in combination with basic research and clinical practice to provide more options for lung cancer driver mutation‐positive patients.

AUTHOR CONTRIBUTIONS

YM and RLB performed manuscript writing and JWC reviewed and revised the manuscript. All authors read and approved the final manuscript.

CONFLICT OF INTEREST STATEMENT

No potential conflicts of interest are disclosed.

Meng Y, Bai R, Cui J. Precision targeted therapy for EGFR mutation‐positive NSCLC: Dilemmas and coping strategies. Thorac Cancer. 2023;14(13):1121–1134. 10.1111/1759-7714.14858