Current treatment strategies for EGFR-mutated non-small cell lung cancer: from first line to beyond osimertinib resistance

Abstract

Osimertinib, a third-generation EGFR TKI, is the standard therapy for previously untreated EGFR-mutated non-small cell lung cancer patients following the landmark FLAURA study. However, resistance inevitably hinders patient prognosis, increasing the need for new therapeutic strategies beyond osimertinib. Frontline osimertinib-based combination strategies (platinum-based chemotherapy and angiogenesis inhibitors) are currently being tested primarily to prevent initial resistance. In the later-line setting after osimertinib, many next-line therapeutic candidates have been actively examined in clinical trials. Notably, several drugs with novel mechanisms of action, such as antibody–drug conjugates and EGFR -MET bispecific antibodies, have shown promising efficacy despite the resistance mechanisms and are close to clinical application. In addition, genotype-based target strategies have been investigated for a better understanding of osimertinib resistance mechanisms based on molecular profiling tests at relapse. The C797S mutation and MET gene alterations are commonly identified following osimertinib resistance, for which targeting strategies are actively tested. This review describes current pharmacotherapeutic strategies for EGFR-mutated non-small cell lung cancer based on the results of clinical trials and the latest published data, broadly grouped into two sections: 1) EGFR TKIs-based combination therapy in the front-line setting and 2) novel therapeutic strategies after osimertinib resistance.

The pharmacotherapeutic management of epidermal growth factor receptor-mutated advanced non-small cell lung cancer has been rapidly updated to a new phase with the advent of genomic medicine.

Introduction

Epidermal growth factor receptor (EGFR) mutation was the first driver oncogene identified in lung cancer (1). The development of EGFR tyrosine kinase inhibitors (TKIs) targeting activating EGFR mutations has led to a paradigm shift in pharmacotherapy for patients with advanced non-small cell lung cancer (NSCLC). Several other driver oncogenes have been discovered in NSCLC, and the corresponding molecular targeting agents are preferentially used in clinical practice (2).

EGFR TKIs are the major first-line (1L) therapy for patients with advanced NSCLC with activating EGFR mutations. Substantial evidence for EGFR TKI has historically been established in randomized controlled trials, demonstrating superior efficacy to conventional platinum-based chemotherapy. Gefitinib (3,4), erlotinib (5–7) and afatinib (8,9) have shown survival benefits over standard-of-care platinum-based chemotherapy in the 1L setting, with better response and significantly improved progression-free survival (PFS). Subsequently, studies were conducted for a head-to-head comparison of EGFR TKIs. Second-generation (2G) TKIs, afatinib and dacomitinib, were compared with the first-generation (1G) TKI, gefitinib, in randomized controlled trials, demonstrating prolonged PFS (10,11); however, both were more toxic than gefitinib (10–13).

Osimertinib is an irreversible third-generation (3G) EGFR TKI that selectively inhibits sensitizing EGFR and T790M resistance mutations (14). In the phase III AURA3 trial, osimertinib showed better efficacy over platinum-based chemotherapy for T790M-positive NSCLC patients previously treated with prior-generation EGFR TKIs approved as salvage therapy in this setting (15). Later, the phase III FLAURA trial demonstrated significantly prolonged PFS in the osimertinib arm compared with the gefitinib or erlotinib arm [18.9 vs. 10.2 months; hazard ratio (HR), 0.46; 95% confidence interval (CI), 0.37–0.57] in the 1L setting (16); therefore, osimertinib was also approved as a 1L regimen for EGFR-mutated advanced NSCLC. Furthermore, constant superiority in overall survival (OS) was observed in the osimertinib arm until the final OS analysis (38.6 vs. 31.8 months; HR, 0.80; 95% CI, 0.64–1.00) despite crossover to osimertinib being permitted in the comparator TKI arm upon T790M emergence at disease progression (17). In addition, osimertinib had a higher response rate to central nervous system (CNS) lesions and showed a reduced risk of CNS progression (18,19). Regarding toxicity, osimertinib was relatively well tolerated, with a comparable rate of grade ≥3 adverse events to the comparator EGFR TKIs, and no serious safety concerns were observed (16,17). This evidence supports the validity of choosing 1L treatment for EGFR-mutated advanced NSCLC patients, boosting osimertinib to a forefront agent in this setting.

Despite the robust evidence established by the AURA3 and FLAURA trials, most patients eventually develop osimertinib resistance. However, the next-line therapy for osimertinib resistance is yet to be confirmed. Therefore, it is necessary to establish effective and novel therapeutic strategies for this population. To date, various treatment strategies have been investigated in the clinic to address osimertinib resistance and improve patient prognosis. This review focuses on current therapeutic strategies for EGFR-mutated NSCLC, EGFR TKI-based combination strategies to outperform osimertinib monotherapy and the next-line novel drug candidates following 1L osimertinib, based on data from ongoing clinical trials and published literature.

EGFR TKI-based combination strategy

Osimertinib monotherapy prolonged PFS and OS in a 1L setting (16,17); however, there is room for improvement in survival outcomes. A strategy to either prevent or postpone resistance acquisition to 1L EGFR TKI is desired, offering a combination strategy of EGFR TKI with other anticancer agents. Furthermore, the organ-specific efficacy properties might also allow for a combination strategy after 1L EGFR TKI resistance. This section describes the current status of frontline combination strategies for EGFR-mutated advance NSCLC patients.

Combining EGFR TKI with platinum-based chemotherapy

Intratumoral and intrapatient molecular heterogeneity within EGFR-mutated NSCLC may be associated with intrinsic resistance to EGFR TKI. It has been assumed that EGFR TKI monotherapy cannot treat innate TKI-resistant cancer cells (20). In theory, a combination of cytotoxic chemotherapeutic agents with different mechanisms of action could regulate intratumor heterogeneity and delay resistance to EGFR TKIs (21,22). Therefore, combination strategies of EGFR TKI and platinum-based chemotherapy have been investigated.

This combination strategy for EGFR-mutated advanced NSCLC patients was examined before the launch of osimertinib. Therapeutic schemes, including the timing of platinum-based chemotherapy, vary across trials. The phase III IMPRESS trial assessed continuing gefitinib combined with cisplatin plus pemetrexed compared with chemotherapy alone when the disease progressed with 1L gefitinib. It failed to demonstrate the PFS benefit of continuing gefitinib [median PFS, 5.4 vs. 5.4 months; HR (95% CI), 0.86 (0.65–1.13)] (23), and OS was inferior in the continuing group [median OS, 13.4 vs. 19.5 months; HR (95% CI), 1.44 (1.07–1.94)] (24), showing the disadvantage of continuing gefitinib with cisplatin plus pemetrexed at disease progression on 1L gefitinib.

In contrast, a concurrent combination of gefitinib with platinum-based chemotherapy as a 1L regimen is an effective approach. In the phase III NEJ009 trial, gefitinib in combination with carboplatin plus pemetrexed (CGP) was compared with gefitinib alone in a 1L setting (25). PFS was significantly prolonged in the CGP group (median, 20.9 vs. 11.9 months; HR, 0.49; 95% CI, 0.39–0.62) (25), and OS was also extended in the CGP group (median, 49.0 vs. 38.5 months, HR, 0.82; 95% CI, 0.64–1.06) (26). Another phase III trial conducted in India to compare CGP and gefitinib alone in a 1L setting showed significantly improved PFS (median, 16 vs. 8 months; HR, 0.51; 95% CI, 0.39–0.66) and OS (median, not reached vs. 20.5 months; HR, 0.45; 95% CI, 0.31–0.65) (27). These results supported that the CGP regimen would be an effective 1L approach for EGFR-mutated advanced NSCLC patients.

Following the approval of 1L osimertinib, these combination strategies were investigated by replacing gefitinib with osimertinib. A combination strategy following osimertinib resistance in a scheme analogous to that in the IMPRESS trial is being investigated based on the higher CNS activity of osimertinib. In the phase III COMPEL trial (NCT04765059), patients with non-CNS progression after initial response to 1L osimertinib were randomized to platinum-pemetrexed plus osimertinib or placebo groups. The primary endpoint will be PFS, stratified by the presence or absence of stable CNS metastases (28). The randomized phase II TORG1938/EPONA trial (jRCTs071200029) being conducted in Japan is evaluating the efficacy of platinum-pemetrexed with or without continuation of osimertinib. In this trial, the feasibility of platinum-pemetrexed plus osimertinib for non-CNS progression after initial response to osimertinib in patients with brain metastatic EGFR-mutated NSCLC is being investigated with PFS as the primary endpoint (29). These trials will elucidate the plausibility of the beyond progressive disease (PD) combination strategy during the progression of extracranial lesions after 1L osimertinib.

The concurrent strategy of osimertinib plus platinum-based chemotherapy is also being tested. The phase II OPAL trial evaluated the safety and efficacy of osimertinib plus platinum-pemetrexed in the 1L setting, reporting an objective response rate (ORR) of 90.9% (95% CI, 84.0–97.8), median PFS of 31.0 months (95% CI, 26.8 months-not reached) and an acceptable safety profile (30). Moreover, the phase III FLAURA2 trial (NCT04035486) is investigating the efficacy of 1L osimertinib with or without platinum-pemetrexed chemotherapy for EGFR-mutated locally advanced or metastatic NSCLC with 587 patients (31). In the 30 patients who participated in the safety run-in component of the trial, no specific pattern of toxicities was reported in the combination therapy group (32). The initial data cutoff for the primary endpoint of PFS was April 3, 2023. Another treatment scheme involving the insertion of platinum pemetrexed during EGFR TKI therapy is also under investigation. The JCOG1404/WJOG8214L (UMIN000020242) is a randomized phase III trial that compares 1L osimertinib (or gefitinib) and inserted cisplatin plus pemetrexed with osimertinib (or gefitinib) alone for patients with advanced EGFR-mutated NSCLC (33). In the experimental group, gefitinib or osimertinib was administered on days 1–56. After a drug-free period of 2 weeks, three cycles of cisplatin and pemetrexed were administered on days 71, 92 and 113. Gefitinib or osimertinib was reinitiated on day 134 and continued until the disease progressed. The investigators hypothesized that initiating platinum doublet chemotherapy after the initial response to EGFR TKIs might prevent the emergence of acquired resistance to EGFR TKIs and increase patient survival. Unlike the FLAURA2 trial, OS is the primary endpoint of the JCOG1404/WJOG8214L trial. Patient enrollment was completed, and the results are expected to be published shortly. These trials provide instructive information regarding the optimal timing for combining 1L of osimertinib with platinum-based chemotherapy.

Overall, the combination strategy of EGFR TKI and platinum-based chemotherapy is feasible because the CGP regimen has shown survival benefits as a 1L regimen in randomized phase III trials. However, increased toxicities associated with the addition of chemotherapy should be considered (23–27).

To date, the superiority of combination regimens over osimertinib monotherapy is questionable; therefore, progress in ongoing randomized trials comparing osimertinib plus chemotherapy with osimertinib will draw further clinical interest.

Combining EGFR TKI with VEGF inhibitor

Combination therapies using EGFR TKI and angiogenesis inhibitors have also been extensively investigated. EGFR activation and VEGF expression are reportedly closely interrelated (34). These have common downstream pathways, and signaling from both can stimulate their shared pathway and act in a protumorigenic manner (35–38). Therefore, EGFR-VEGF dual inhibition is considered a rational strategy in EGFR-mutated NSCLC.

Several clinical studies have reported that adding the anti-VEGF antibody, bevacizumab, to the 1G EGFR TKI, erlotinib, prolonged PFS but not OS. A randomized phase II JO25567 trial first reported improved PFS of erlotinib plus bevacizumab over erlotinib alone in previously untreated EGFR-mutated NSCLC patients (median PFS, 16.0 vs. 9.7 months; HR, 0.54; 95% CI, 0.36–0.79) (39). The efficacy of this combination therapy was validated in subsequent phase III trials. The NEJ026 and ARTemis/CTONG1509 trials successfully demonstrated the prolonged PFS with erlotinib plus bevacizumab over erlotinib (NEJ026: median PFS, 16.9 vs. 13.3 months; HR, 0.605; 95% CI, 0.417–0.877 (40)) (ARTemis/CTONG1509: median PFS, 17.9 vs. 11.2 months, HR: 0.55; 95% CI, 0.41–0.73 (41)). In addition, subgroup analysis in both trials for types of EGFR mutations showed a PFS benefit in patients with exon19 deletion and patients with the L858R mutation, a population known to have a reduced response to EGFR TKIs.

The RELAY trial is a global, placebo-controlled, double-blinded phase III trial conducted to assess the efficacy of erlotinib plus the anti-VEGFR 2 antibody, ramucirumab, compared with erlotinib plus placebo in previously untreated advanced NSCLC patients with activating EGFR mutations (42). A total of 449 patients, of whom 336 East Asian, were enrolled. PFS, as the primary endpoint, was significantly improved with erlotinib plus ramucirumab compared with erlotinib plus placebo (median, 19.4 vs. 12.4 months; HR, 0.59; 95% CI, 0.46–0.76). A PFS benefit was consistently observed, irrespective of the EGFR mutation (exon19 deletion or L858R). Moreover, the frequency of acquiring the T790M mutation upon disease progression was similar in the two groups, suggesting that adding ramucirumab did not affect T790M emergence.

In summary, the EGFR-VEGF dual-inhibition strategy confers a PFS benefit for patients with advanced EGFR-mutated NSCLC in a 1L setting. It was also expected to be effective in patients with the L858R mutation based on the results of the subgroup analysis. However, these combinations have yet to improve OS (43,44). Patients receiving a combination regimen have a higher incidence of grade ≥3 treatment-related adverse events (40–42,45), and adverse events specific to angiogenesis inhibitors should be considered.

Currently, combination therapy with osimertinib, bevacizumab or ramucirumab in a 1L setting is being investigated. A phase I/II trial by Yu et al. evaluated osimertinib plus bevacizumab in the 1L setting with 49 patients. The study met the primary endpoint with a 12-month PFS rate of 76% (95% CI, 65–90%), an overall response rate of 80% (95% CI, 67–91%) and a CNS response rate of 100% (6 of 6; 95% CI, 50–100% (46)). However, the randomized phase II WJOG9717L trial, which investigated osimertinib with or without bevacizumab in previously untreated EGFR-mutated NSCLC, failed to show improved PFS with the combination regimen (combination vs. osimertinib alone: median PFS, 22.1 vs. 20.1 months; HR, 0.862; 95% CI, 0.531–1.397 (47)).

Regarding the feasibility of this combination, it will be necessary to await the results of ongoing randomized trials. Clinical trials of osimertinib-based combination regimens are summarized in Table 1.

Table 1.

Summary of clinical trials on osimertinib-based combination strategy

Agent	Trial number (Trial name)	Phase	Number of patients	Arm	Year	Status
EGFR TKI + platinum-based chemotherapy
	NCT04410796	II	571	Osimertinib Osimertinib + CBDCA + PEM	2020	Recruiting
	NCT04695925 (TOP)	III	291	Osimertinib Osimertinib + CBDCA + PEM *concurrent TP53 mutation	2021	Not yet recruiting
	NCT04769388 (FLAME)	II	150	Osimertinib Osimertinib + CBDCA + PEM *3 weeks after 1 L osimertinib without PD	2021	Recruiting
	NCT04765059 (COMPEL)	III	204	Osimertinib + CBDCA/CDDP + PEM Placebo + CBDCA/CDDP + PEM *PD after 1 L osimertinib	2021	Recruiting
	jRCTs071200029 (TORG1938/EPONA)	II	92	Osimertinib + CBDCA/CDDP + PEM CBDCA/CDDP + PEM *PD after osimertinib	2020	Recruiting
	NCT05281406 (PACE-LUNG)	II	50	Osimertinib + CBDCA/CDDP + PEM *ctDNA EGFRm after 3w 1 L osimertinib	2022	Recruiting
	NCT05507606	II	50	Osimertinib + bevacizumab + CBDCA + PEM *concurrent TP53 mutation	2022	Recruiting
	NCT04035486 (FLAURA2)	III	587	Osimertinib Osimertinib + CBDCA/CDDP + PEM	2019	Active, not recruiting
	NCT04335292 (OCELOT)	II	200	Osimertinib → CBDCA/CDDP+PEM → osimertinib	2020	Recruiting
	NCT05493501	III	420	Aumolertinib Aumolertinib + CBDCA/CDDP + PEM Osimertinib	2022	Recruiting
	UMIN000020242 (JCOG1404/WJOG8214L, AGAIN)	III	500	Osimertinib (gefitinib) Osimertinib (gefitinib) → CDDP + PEM → osimertinib (gefitinib)	2015	Active, not recruiting
EGFR TKI + VEGF inhibitor
Bevacizumab	NCT02971501	II	112	Osimertinib Osimertinib + bevacizumab	2016	Active, not recruiting
	NCT04181060	III	300	Osimertinib Osimertinib + bevacizumab	2019	Recruiting
	NCT04988607 (FLAIR)	II	90	Osimertinib Osimertinib + bevacizumab *patients with EGFR L858R only	2021	Not yet recruiting
Ramucirumab	NCT03909334	II	150	Osimertinib Osimertinib + ramucirumab	2019	Recruiting
	JapicCTI-184 146 (TORG1833)	II	120	Osimertinib Osimertinib + ramucirumab	2018	Progressing Recruitment completed
EGFR-MET bispecific antibody
Amivantamab	NCT04487080 (MARIPOSA)	III	1074	Amivantamab + lazertinib Osimertinib + placebo Lazertinib + placebo	2020	Active, not recruiting

Abbreviations: EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; CBDCA, carboplatin: CDDP, cisplatin; PEM, pemetrexed; PD, progressive disease.

Novel therapeutic strategy beyond osimertinib

Several mechanisms underlying acquired resistance to osimertinib have been identified. They can be broadly classified into EGFR-dependent (on-target) and EGFR-independent (off-target) resistance mechanisms. In on-target resistance, cell proliferation and tumor growth are driven by sustained activation of EGFR signaling, including secondary EGFR mutations, amplification, mutation loss and ligand overexpression. Conversely, in off-target resistance, tumor growth depends on pathways other than EGFR signaling, such as alternative pathway kinase activation, downstream signaling pathway activation, histological transformation and cell cycle gene alterations (Fig. 1) (48–52).

Figure 1.

Overview of osimertinib resistance mechanisms and corresponding treatment options. Diverse targeting strategies might be available depending on the resistance mechanism. Abbreviations: 4G, fourth generation; 1G, first generation; 2G, second generation; TKI, tyrosine kinase inhibitor; MoA, mechanism of action; ADC, antibody–drug conjugate; amp., amplification; Pt. chemo, platinum-based chemotherapy; ICI, immune checkpoint inhibitor.

Available data regarding the resistance mechanisms to osimertinib, based on plasma and/or tissue biomarker analyses, have been compiled from several clinical and observational studies, including the AURA3 and FLAURA trials. Based on these studies, the frequency and description of osimertinib resistance mechanisms are summarized in Fig. 2 (53–61). EGFR C797S and MET amplifications are relatively common after the 1L and later-line osimertinib therapies and are considered important therapeutic targets. Other resistance mechanisms have been identified, including alterations in the RAS/MAPK and PIK3/AKT pathways, cell cycle gene alterations, oncogenic fusions and histological transformations (53–61).

Figure 2.

Breakdown of frequency and types of major resistance mechanisms to first-line (A) and later-line (B) osimertinib treatment based on previous reports (53–61). Note: different molecular aberrations might have been identified in the same patient. Abbreviations: amp., amplification; mut., mutation.

Along with the growing understanding of osimertinib resistance mechanisms, next-line novel therapeutic agents are being developed and intensively examined in clinical trials. Progress in ongoing clinical trials has shown promising efficacy of several novel agents such as a HER3-directed antibody–drug conjugate (ADC) and an EGFR-MET bispecific antibody in osimertinib-resistant patients (62). Importantly, these agents reportedly exhibit antitumor activity regardless of resistance mechanisms and are nearing clinical application. Other genotype-based strategies, focusing on EGFR C797S and MET gene alterations, are also being examined, highlighting the importance of molecular testing at relapse. This section provides an overview of the current status of novel therapeutic strategies following osimertinib resistance.

Antibody–drug conjugate

ADC is a novel drug class belonging to the immunotherapeutic agent category, which is rapidly emerging in oncology and especially lung cancer (63). ADCs are designed to bind a cytotoxic payload through a linker to a specific monoclonal antibody directed against a tumor antigen. Internalization occurs once the monoclonal antibody binds to the targeted antigen, resulting in linker degeneration and release of the cytotoxic payload, thereby exerting an antitumor effect (64,65). ADCs targeting HER2, HER3, TROP-2 and MET have potential applicability in NSCLC patients (66). These agents are being investigated in clinical trials, which include patients after they develop osimertinib resistance (MET-directed ADCs will be described in a later section).

A HER3-directed ADC, patritumab deruxtecan (U3–1402) (HER3-DXd), has the closest clinical application in osimertinib-resistant patients. HER3 is not implicated in oncogenicity, although it is involved in EGFR/HER2-mediated resistance through conjugation with MET and has recently been regarded as an important therapeutic target (67). A phase I dose escalation/expansion HER3-DXd study for EGFR-mutated NSCLC patients previously treated with EGFR TKIs, including osimertinib, was conducted (U31402-A-U102, NCT03260491). The participants were heavily pre-treated [median number of prior treatment lines: 4 (1–9)], with 89% of them receiving osimertinib. In the pooled population of patients treated with 5.6 mg/kg HER3-DXd using the recommended dose for expansion, the confirmed ORR was 39%. Median PFS was 8.2 months for osimertinib pretreated patients (68). Importantly, responses to HER3-DXd were observed notwithstanding different EGFR TKI resistance mechanisms not directly associated with HER3, such as EGFR C797S, MET, HER2 amplification and BRAF fusion (68). The phase II HERTHENA-Lung01 trial (NCT04619004) for HER3-DXd in patients with EGFR-mutated NSCLC previously treated with at least one EGFR TKI and a platinum-based chemotherapy regimen is ongoing. Similarly, the phase III HERTHENA-Lung02 trial (NCT05338970) is comparing HER3-DXd and platinum-based chemotherapy in EGFR-mutated NSCLC after progression using a 3G EGFR TKI. Furthermore, the efficacy of combining HER3-DXd and osimertinib for EGFR-mutated NSCLC with osimertinib progression is currently being evaluated in a phase I trial (NCT04676477).

HER2-directed ADCs, trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are being investigated in NSCLC patients with HER2 gene alternations. The phase II TRAEMOS trial (NCT03784599) evaluated the efficacy of T-DM1 in combination with osimertinib for EGFR-mutated NSCLC patients previously treated with EGFR TKIs, including osimertinib who acquired HER2 overexpression and/or amplification with re-biopsy at relapse. However, the reported ORR and median PFS were 13% and 2.8 months, respectively, indicating the limited efficacy of this approach. Therefore, the trial was terminated early (69). On the other hand, T-DXd has demonstrated attractive antitumor efficacy for previously treated HER2 positive (overexpression or mutations) NSCLC (not including EGFR-mutated patients) with an ORR of 55% and a median PFS and OS of 8.2 and 17.8 months, respectively (DESTINY-Lung01, NCT03505710 (70)). An ongoing phase Ib trial (NCT04042701) is investigating T-DXd in combination with pembrolizumab in HER2-expressing or HER2-mutated patients, including those with EGFR-mutated NSCLC who were previously treated with EGFR TKIs.

TROP-2 is an intracellular calcium signaling transducer and an attractive target for ADC. Datopotamab deruxtecan (Dato-DXd), a TROP-2 targeting ADC, has demonstrated satisfactory therapeutic efficacy in patients with NSCLC in a phase I trial (TROPION-PanTumor01, NCT03401385 (71)) and is further being investigated for EGFR-mutated patients who were previously treated with osimertinib in the TROPION-Lung05 (NCT04484142) and TROPION-Lung01 (NCT04656652) trials.

Preliminary data on the efficacy of ADCs in the clinical trials described above underscore the viability of this approach in osimertinib-resistant populations. Despite their impressive efficacy, the reported negligible occurrence of interstitial lung disease (ILD) should be considered. In the DESTINY-Lung01 trial, 24 of 91 patients (26%) developed T-Dxd-related ILD, including four (6.6%) grade 3 and two (2.2%) grade 5 patients (70). A systematic review of advanced HER2-positive solid tumor patients reported an incidence of T-Dxd-related ILD of 11.40%, which was exceptionally high at 24.77% in NSCLC patients (72). Insufficient data are available; however, the frequency of ILD related to HER3-Dxd (68) and Dato-Dxd (71) was reported to be 5–10.6% and 8% in phase I trials, respectively. The definite mechanism is unknown, as it is assumed that these pulmonary toxicities may be associated with the cytotoxic payload carried by ADCs. Safety data for more patients are required in ongoing clinical trials.

In summary, positive preliminary data on ADCs in EGFR-mutated NSCLC after osimertinib resistance were provided. HER3-DXd has been evaluated extensively in clinical trials. If the promising efficacy of ADCs is demonstrated in the above clinical trials, it could change the treatment paradigm for EGFR-mutated NSCLC in TKI-resistant populations.

MET-targeting strategy

The MET oncogene encodes the receptor tyrosine kinase, c-Met, whose dysregulation is an oncogenic driver. MET signaling mediates osimertinib resistance by bypassing EGFR downstream signaling pathways such as PI3K/AKT, JAK/STAT3 and RAS/MAPK/ERK (73). Among the various genomic statuses of the MET oncogene, MET amplification is a common resistance mechanism to osimertinib, detectable in 6–24% of cases (53–61). MET gene alterations are considered an important therapeutic target after osimertinib resistance, and several potential therapeutic candidates have been developed and examined in clinical trials.

MET tyrosine kinase inhibitor

Clinical trials of MET TKIs for osimertinib-resistant patients are ongoing; the efficacy of savolitinib, tepotinib and capmatinib as single agents or combined with osimertinib in patients who acquired resistance to osimertinib has been evaluated.

The phase Ib TATTON trial (NCT02143466) investigated the efficacy of savolitinib and osimertinib for EGFR-mutated NSCLC patients previously treated with EGFR TKIs. The recently published data of the interim analysis revealed the acceptable safety profile and encouraging antitumor activity of this approach; an ORR of 30% and a median PFS of 5.4 months were obtained in patients previously treated with 3G EGFR TKI, reaching 64–67% and 9–11 months, respectively, in 3G EGFR TKI-naïve patients based on the study’s different cohorts (74). In the phase II SAVANNAH trial (NCT03778229), savolitinib in combination with osimertinib in EGFR-mutated NSCLC patients with MET-driven (amplification and/or overexpression) resistance mechanisms acquired after osimertinib is being evaluated. Preliminary data showed an ORR of 32% and a median PFS of 5.3 months in the overall population (75). Notably, the population with higher MET levels with amplification and/or overexpression had an ORR of 49% and a median PFS of 7.1 months, compared with an ORR of 9% and a median PFS of 2.8 months in the population without higher MET levels (75). In the phase II ORCHARD trial, MET-amplified patients are assigned to the osimertinib plus savolitinib arm (76), and the recent interim analysis results showed an ORR of 41% (77). The phase III SACHI trial (NCT05015608) compared osimertinib plus savolitinib with platinum-based chemotherapy in patients with MET amplification acquired after 1L EGFR TKI therapy. In addition, the phase III SAFFRON trial (NCT05261399) compared osimertinib plus savolitinib with platinum-based chemotherapy in MET-amplified and/or MET-overexpressed patients previously treated with osimertinib.

Tepotinib is also being investigated in several clinical trials. The phase Ib/II INSIGHT trial evaluated the efficacy and safety of tepotinib combined with gefitinib. In the phase II part with randomization against platinum-based chemotherapy, tepotinib plus gefitinib was assessed in EGFR-mutated NSCLC patients with MET amplification and/or overexpression previously treated with 1G- or 2G-EGFR TKIs. The survival outcomes were comparable in both arms; however, the median PFS and OS were longer in the tepotinib plus gefitinib arm than in the chemotherapy arm in a prespecified subgroup analysis of the high MET-expressing group (78). The phase II INSIGHT2 trial (NCT03940703) compared the combination of tepotinib plus osimertinib with tepotinib alone in patients previously treated with 1L of osimertinib. The initial results were recently reported; the ORR was high at 55% for tepotinib plus osimertinib compared with 8.3% for tepotinib alone (79). The combination of capmatinib and osimertinib is also being investigated in clinical trials [phase II A Lung-MAP trial (NCT05642572), phase III GEOMETRY-E trial (NCT04816214)].

EGFR-MET bispecific antibody

Amivantamab is a fully humanized bispecific antibody targeting EGFR mutations and MET mutations/amplifications. Amivantamab inhibits ligand binding of EGFR and MET, further inhibits downstream signaling pathways and has been reported to have antibody-dependent cellular cytotoxicity; therefore, it is expected to have a wider range of effects (80). Specifically, it has antitumor activity against various activating and resistant EGFR mutations (del19, L858R, T790M, C797S and exon20 insertion) (81,82) and might have potential clinical use for osimertinib-resistant patients.

The multiarm phase I CHRYSALIS trial (NCT02609776) investigated the combination of amivantamab and lazertinib (a potent brain-penetrant 3G EGFR TKI) immediately after osimertinib resistance in 45 patients with NSCLC with activating EGFR mutations. The ORR was 36%, and overall patients’ median PFS was 4.9 months (83). Notably, this combination approach had an ORR of 47% in patients with EGFR/MET-driven resistances and an ORR of 29% in patients without these resistances (83). In the recently reported CHRYSALIS-2 trial (NCT04077463) results, combining amivantamab with lazertinib showed antitumor activity for EGFR-mutated NSCLC patients who had disease progression with 1 or 2L osimertinib followed by platinum-based chemotherapy (including heavily pretreated patients) with an ORR of 33% and median PFS of 5.1 months (84). A combination of amivantamab and lazertinib is being investigated in phase III trials for EGFR-mutated patients. The MARIPOSA study (NCT04487080), a randomized phase III trial, compares the combination of amivantamab and lazertinib with osimertinib monotherapy in the 1L setting. In addition, the MARIPOSA-2 study (NCT04988295), a randomized, open-label, phase III trial, compared lazertinib, amivantamab, carboplatin and pemetrexed with carboplatin, amivantamab and pemetrexed in EGFR-mutated NSCLC patients following disease progression during or after osimertinib treatment. Regarding the toxicity of amivantamab, skin and mucous membrane disorders and edema associated with EGFR and MET inhibition have been frequently reported (85). Besides, it should be noted that infusion site reactions frequently occur at initial administration (85,86).

MET-directed ADC

Telisotuzumab vedotin (Teliso-V) is a MET-directed ADC composed of ABT-700, an anti-c-Met monoclonal antibody, and monomethyl auristatin E, a potent microtubule inhibitor as a cytotoxic payload (87). Teliso-V has shown antitumor activity in solid tumors with MET gene alterations (88,89) and has been investigated in clinical trials in patients after they acquire osimertinib resistance.

In a phase II trial (NCT03539536), the ORR of Teliso-V monotherapy was reported to be 13.3% in EGFR- and c-Met-positive nonsquamous NSCLC patients (90). The combination of Teliso-V and EGFR TKIs is also being tested in an ongoing phase I/Ib trial (NCT02099058), which involves patients who acquired c-Met overexpression following 1L osimertinib. The safety and efficacy of Teliso-V monotherapy or in combination with osimertinib, erlotinib, or nivolumab are currently being evaluated. In the reported interim analysis results, the combination of Teliso-V and osimertinib showed an ORR of 58% in patients previously treated with 1L osimertinib (91). Moreover, an ongoing randomized phase III trial (NCT04928846) compares Teliso-V and docetaxel in previously treated c-Met-overexpressing NSCLC patients, including EGFR-mutated patients.

In summary, in patients after osimertinib resistance, the MET-targeting strategy would be feasible. MET TKIs have shown a certain efficacy in early-phase clinical trials and are further being evaluated in phase III trials. Drugs with novel mechanisms of action are also promising for acquired MET gene alterations. Specifically, amivantamab in combination with lazertinib has broader antitumor activity and has demonstrated impressive efficacy in patients without EGFR/MET-driven resistances and in heavily pretreated patients. It should be noted, however, that the evaluation criteria for MET gene alterations is yet to be standardized and differs among trials. Amplification might be underestimated in liquid biopsy analysis with plasma specimens.

C797S-targeting strategy

Among on-target resistance mechanisms to osimertinib, the C797S mutation is common and emerging in 7–15 and 14–30% of cases resistant to 1L- and later-line osimertinib therapy, respectively (53–61). The C797S mutation occurs in exon 20 and is responsible for drug resistance by breaking the covalent bond between osimertinib and the mutant EGFR site (92). C797S imparts cross-resistance to other irreversible 3G EGFR TKIs by inhibiting binding to the active EGFR site (92–95).

C797S may have different drug susceptibilities depending on the acquired allelic status. When C797S occurs on a chromosome other than T790M (trans), it retains sensitivity to 1G- and 3G-TKI combination therapy (95). Preclinical data and some case reports have shown the efficacy of osimertinib in combination with gefitinib or erlotinib for EGFR-mutated NSCLC harboring T790M in trans with C797S mutation (96–98). In contrast, if C797S and T790M occur on the same chromosome (cis), they lose activity against any conventional EGFR TKIs (95–97). As a potential approach to C797S in cis, the efficacy of combining brigatinib, an EGFR-ALK dual inhibitor, with anti-EGFR antibodies has been reported. Preclinical data have demonstrated that combining brigatinib with cetuximab or panitumumab has antitumor activity against triple mutant cells with C797S in cis and T790M and activates EGFR mutation (98–100). A phase I/II trial conducted to ascertain the safety and efficacy of brigatinib combined with panitumumab in patients who acquired C797S after osimertinib treatment is ongoing (jRCT2031200231).

As another promising therapeutic agent against C797S mutation, a next-generation EGFR allosteric inhibitor is being developed (101). EGFR allosteric inhibitors that belong to fourth-generation (4G) EGFR inhibitors bind to EGFR far from the ATP-binding site, thereby selectively altering EGFR conformation and bypassing the C797S-mediated resistance mechanism (92,102). These agents have shown antitumor activity alone or combined with osimertinib in vivo/in vitro studies (ongoing clinical trials on 4G EGFR inhibitors are summarized in Table 2). EAI-045 is the first EGFR allosteric inhibitor targeting T790M and C797S mutations (103). EAI-045 exhibited limited activity in vivo as a single agent; however, the marked tumor regression for the triple mutant (L858R/T790M/C797S) Ba/F3 cell line was observed when combined with cetuximab (102). Several novel 4G EGFR inhibitors have shown antitumor activity in in vivo/in vitro research. JBJ-04-125-02 is a more potent EGFR allosteric inhibitor that selectively targets L858R and inhibits triple mutant (L858R/T790M/C797S) EGFR signaling. JBJ-04-125-02, combined with osimertinib, offered increased cell death, more effective inhibition of cell proliferation and increased efficacy compared with either single agent alone (104). Comparing the EAI-045 and JBJ-04-125-02, CH7233163, a potent and selective 4G EGFR inhibitor, showed activity against triple EGFR mutants with del19/T790M/C797S (105). Furthermore, some agents are being evaluated as candidates in clinical trials. BLU-701 is a new, highly selective and potent oral EGFR inhibitor that has demonstrated in vivo antitumor activity against sensitizing EGFR mutations (del19 or L858R) and double mutations with C797S (del19/C797S or L858R/C797S) (106). The phase I/II HARMONY trial (NCT05153408) evaluates the safety and efficacy of BLU-701 in EGFR-mutated NSCLC patients previously treated with EGFR TKIs, including osimertinib. The effectiveness of BLU-701 in patients with C797X mutations will be evaluated in a phase II expansion cohort study. BLU-945 is a selective and potent 4G EGFR inhibitor with activity against triple-resistant mutations (del19 or L858R/T790M/C797S) (107,108). A combination of BLU-945 with either gefitinib or osimertinib exhibited increased antitumor activity compared with BLU-945 alone for del19/T790M/C797S in a patient-derived xenograft model (109). The phase I/II SYMPHONY trial (NCT04862780) also evaluates the safety and efficacy of BLU-945, either a single agent or combined with osimertinib in NSCLC patients with activating EGFR mutations previously treated with EGFR TKIs including osimertinib. The efficacy of BLU-945 in patients with the C797S mutation will be evaluated in a phase II expansion cohort. Other 4G EGFR inhibitors, such as JIN-A02 (NCT05394831) and BBT-176 (NCT04820023), will also be assessed in phase I/II trials.

Table 2.

Summary of clinical trial after osimertinib resistance

Agent	Trial number (Trial name)	Phase	Number of patients	Arm	Year	Status
Fourth-generation EGFR allosteric inhibitor
BLU-701	NCT05153408 (HARMONY)	I/II	160	BLU-701 BLU-701 + osimertinib BLU-701 + CBDCA + PEM	2021	Recruiting
BLU-945	NCT04862780 (SYMPHONY)	I/II	190	BLU-945 BLU-945 + osimertinib	2021	Recruiting
BBT-176	NCT04820023	I/II	168	BBT-176	2021	Recruiting
JIN-A02	NCT05394831	I/II	95	JIN-A02	2022	Not yet recruiting
MET inhibitor
Savolitinib	NCT02143466 (TATTON)	Ib	344	Savolitinib + osimertinib	2014	Active, not recruiting
	NCT03778229 (SAVANNAH)	II	360	Savolitinib + osimertinib Sabolitinib + placebo	2018	Recruiting
	NCT05015608 (SACHI)	III	250	Savolitinib + osimertinib CDDP/CBDCA + PEM	2021	Recruiting
	NCT05261399 (SAFFRON)	III	324	Savolitinib + osimertinib CDDP/CBDCA + PEM	2022	Recruiting
Tepotinib	NCT03940703 (INSIGHT2)	II	120	Tepotinib + osimertinib Tepotinib	2019	Active, not recruiting
Capmatinib	NCT05642572 (A Lung-MAP)	II	66	Capmatinib + osimertinib + ramucirumab Capmatinib + osimertinib	2022	Not yet recruiting
	NCT04816214 (GEOMETRY-E)	III	245	Capmatinib + osimertinib CDDP/CBDCA + PEM	2021	Active, not recruiting
Other specific inhibitor
Selumetinib (MEK1/2 inhibitor)	NCT02143466 (TATTON)	Ib	344	Selumetinib + osimertinib	2014	Active, not recruiting
DS-1205c (AXL inhibitor)	NCT03255083	I	13	DS-1205c + osimertinib	2017	Terminated
ERAS-007 (ERK1/2 inhibitor)	NCT04959981 (HERKULES-2)	I/II	200	ERAS-601 + osimertinib	2021	Active, not recruiting
Sapanisertib (mTOR inhibitor)	NCT02503722	I	36	Sapanisertib + osimertinib	2015	Active, not recruiting
TQ-B3525 (PIKα/δ inhibitor)	NCT05284994	I/II	160	TQ-B3525 + osimetinib	2022	Recruiting
Itacitinib (JAK1 inhibitor)	NCT02917993	I/II	59	Itacitinib + osimertinib	2016	Active, not recruiting
Abemaciclib (CDK4/6 inhibitor)	NCT04545710	II	18	Abemaciclib + osimetinib	2020	Recruiting
Alisertib (AURKA inhibitor)	NCT04479306	I	48	Alisertib + osimetinib	2020	Active, not recruiting
Antibody–drug conjugate
Trastuzumab deruxtecan (T-Dxd) (HER2-ADC)	NCT04042701	Ib	115	T-DXd + pembrolizumab (part 2 dose expansion cohort)	2019	Recruiting
Patritumab deruxtecan (HER3-ADC)	NCT03260491	I	264	HER3-DXd	2017	Recruiting
	NCT04676477	I	252	HER3-DXd + osimertinib	2020	Recruiting
	NCT04619004 (HERTHENA-Lung01)	II	420	HER3-DXd (fixed dose or up-titration)	2020	Recruiting
	NCT05338970 (HERTHENA-Lung02)	III	560	HER3-DXd CDDP/CBDCA + PEM	2022	Recruiting

(Continued)

Table 2.

Continued

Agent	Trial number (Trial name)	Phase	Number of patients	Arm	Year	Status
Datopotamab deruxtecan (Dato-Dxd) (TROP2-ADC)	NCT04484142 (TROPION-Lung05)	II	137	Dato-DXd	2020	Active, not recruiting
	NCT04656652 (TROPION-Lung01)	III	590	Dato-DXd Docetaxel	2020	Recruiting
Telisotuzumab vedotin (Teliso-V) (MET-ADC)	NCT02099058	I	260	Teliso-V Teliso-V + erlotinib Teliso-V + nivolumab Teliso-V + osimertinib	2014	Recruiting
	NCT04928846	III	698	Teliso-V Docetaxel	2021	Recruiting
EGFR-MET bispecific antibody
Amivantamab	NCT02609776 (CHRYSALIS)	I	780	Amivantamab + lazertinib	2015	Recruiting
	NCT04077463 (CHRYSALIS-2)	I/Ib	460	Lazertinib Amivantamab + lazertinib Amivantamab + Lazertinib + CBDCA + PEM	2019	Recruiting
	NCT04988295 (MARIPOSA-2)	III	600	Amivantamab + Lazertinib + CBDCA + PEM CBDCA + PEM Amivantamab + CBDCA + PEM	2021	Recruiting
Immune checkpoint inhibitor
ICI + chemotherapy	NCT02864251 (Checkmate 722)	III	367	Nivolumab + CDDP/CBDCA + PEM CDDP/CBDCA + PEM	2016	Completed
	NCT03515837 (KEYNOTE-789)	III	492	Pembrolizumab + CDDP/CBDCA + PEM CDDP/CBDCA + PEM	2018	Active, not recruiting
	NCT03802240 (ORIENT-31)	III	600	Sintilimab + IBI305 + CDDP + PEM Sintilimab + placebo + CDDP + PEM Placebo + placebo + CDDP + PEM	2019	Recruiting
Multiple study treatment (platform study)
	NCT03944772 (ORCHARD)	II	250	Osimertinib + savolitinib Osimertinib + gefitinib Osimertinib + necitumumab CBDCA + PEM + durvalumab Osimertinib + alectinib Osimertinib + selpercatinib CDDP/CBDCA + etoposide + durvalumab Osimertinib + CDDP/CBDCA + PEM Osimertinib + selumetinib Osimertinib + Dato-Dxd	2019	Recruiting

Abbreviations: CBDCA, carboplatin; PEM, pemetrexed; CDDP, cisplatin: ADC, antibody–drug conjugate; ICI, immune checkpoint inhibitor.

In summary, C797S mutation is a crucial on-target resistance mechanism that can be potentially targeted after osimertinib resistance. Treatment with brigatinib and EGFR antibodies is being evaluated based on the cis/trans strategy for the C797S mutation. Moreover, there are sufficient preclinical data for the efficacy of 4G EGFR inhibitors for C797S, and 4G EGFR inhibitors are currently being investigated in early-phase clinical trials.

Other specific inhibitors

Molecular aberrations other than C797S and MET gene alterations have also been identified following osimertinib resistance. Changes in downstream signaling pathways (i.e. RAS/MAPK/ERK, PI3K/AKT and JAK/STAT3), oncogenic fusion genes, alterations in other tyrosine kinase receptors and cell cycle genes are regarded as resistance mechanisms to osimertinib (Fig. 1) that are potentially targetable. However, each of these is a rare fraction detected in <10% of cases (53–61). Specific inhibitors targeting these mechanisms are currently being investigated in early-phase clinical trials. The ongoing clinical trials of these agents are summarized in Table 2. It is still being undetermined whether these specific inhibitors will be implemented in practice, as limited evidence has suggested their efficacy; therefore, the progress of clinical trials of individual agents should be monitored closely.

Chemoimmunotherapy combination

Immune oncology combinatorial treatment (chemo-IO) with a VEGF inhibitor may be a possible treatment option in the clinic following 1L osimertinib resistance. The potential applicability of chemo-IO for EGFR-mutated patients was first reported in a subgroup analysis of EGFR- and ALK-positive patients in the IMpower150 trial, showing survival benefits in terms of both PFS and OS in the atezolizumab, bevacizumab, paclitaxel and carboplatin groups compared with the bevacizumab, paclitaxel and carboplatin groups (110,111).

The chemo-IO ± VEGF inhibitor strategy for patients with EGFR mutations is being investigated in ongoing prospective trials. The CheckMate 722 (NCT02864251) and KEYNOTE-789 (NCT03515837) trials investigated chemo-IO in patients previously treated with EGFR TKIs. Both trials were recently reported to have failed to show the PFS benefit of chemo-IO over platinum chemotherapy (112,113). On the other hand, the ORIENT-31 trial (NCT03802240) that is investigating combination therapy of sintilimab (anti-PD-1 antibody), IBI305 (a bevacizumab biosimilar), and platinum-based chemotherapy in EGFR TKI-treated patients demonstrated significantly improved PFS in the sintilimab + IBI305 + chemotherapy arm compared with chemotherapy alone [median PFS, 6.9 vs. 4.3 months; HR (95% CI), 0.464 (0.337–0.639); P < 0.0001] (114). These results suggest a potential role for VEGF inhibitors combined with chemo-IO for EGFR-mutated patients.

Discussion and conclusion

This review discussed potential treatment strategies for EGFR-mutated advanced NSCLC based on clinical trials. Osimertinib monotherapy is currently the preferred therapeutic option in this population based on favorable efficacy and safety data from the AURA3 and FLAURA trials. However, since resistance to osimertinib would hinder persistent effectiveness for patients, strategies beyond osimertinib in 1L and later-line settings need to be provided.

In the 1L setting, strategies combining EGFR TKI and platinum-based chemotherapy or VEGF inhibitors are being investigated to surpass osimertinib monotherapy. In addition, the beyond PD osimertinib-based combination strategy is also being investigated, expecting to control CNS involvements. An encouraging data on combination strategies from clinical trials before the FLAURA era supports the feasibility of combining osimertinib with these anticancer agents. The results of the ongoing randomized trials of osimertinib-based combination therapy could set a new landmark in 1L therapy for EGFR-mutated NSCLC soon.

In later-line settings after osimertinib resistance, various novel therapeutic strategies have been challenged to address acquired resistance, linked to information on resistance mechanisms, with molecular profile testing gaining a better understanding in recent years. Drugs with a novel class of action, such as ADCs and EGFR-MET bispecific antibodies, have also shown specific clinical activity in osimertinib-resistant patients regardless of the resistance mechanism. The C797S mutation and MET amplification are important therapeutic targets in this setting. Several agents targeting a relatively rare fraction of resistance mechanisms are currently being investigated in early-phase clinical trials. Chemo-IO plus VEGF inhibitors may be an option for 1L osimertinib-resistant patients. However, most of these therapies still need to be investigated in clinical trials and are unavailable in practice. Therefore, performing a re-biopsy at relapse is necessary to expand the possibilities of available trial platforms for individual patients, which would facilitate enrollment in ongoing clinical trials.

In conclusion, the pharmacotherapeutic management of EGFR-mutated advanced NSCLC has been rapidly updated to a new phase with the advent of genomic medicine. Upfront combination strategies aimed at preventing or postponing the emergence of resistance are currently being evaluated. Strategies using antibody agents with novel mechanisms of action during a relapse should be implemented clinically. In addition, there is a growing need for repeated proactive re-biopsies for molecular profile testing. A greater understanding of osimertinib resistance mechanisms will contribute to further progress in the ongoing clinical trials discussed in this review, establishing new therapeutic evidence in this setting. Ultimately, this will maximize survival outcomes in patients with relapsed disease.

Funding

This research was supported by the research fund of National Cancer Center Japan (Grant number: 2023-J-03).

Conflicts of interest statement

No author has any conflicts of interest related to this article. Hidehito Horinouchi reports research funding from MSD, Abbvie, AstraZeneca, BMS, Ono, Merck Biopharma, Daiichi-Sankyo, Janssen, Genomic Helath, Chugai, Roche, Novartis; personal fees as speakers' bureau from AstraZeneca, MSD, Eli Lilly, Ono, BMS, Chugai, Roche, Amgen; personal fees as advisory role from AstraZeneca, Eli Lilly, Chugai, Roche, ONO, BMS, outside the submitted work. Yuichiro Ohe reports research funding from AstraZeneca, Chugai, Lilly, ONO, BMS, Kyorin, Dainippon-Sumitomo, Pfizer, Taiho, Novartis, Takeda, Kissei, Daiichi-Sankyo, Janssen, LOXO; personal fees as expert testimony from AstraZeneca, Chugai, ONO, BMS, Kyorin, Celltrion, Amgen, Nippon Kayaku, Boehringer Ingelheim, AnHeart Therapeutics Inc; personal fees as speakers' bureau from AstraZeneca, Chugai, Eli Lilly, Ono, BMS, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho, Nippon Kayaku, Kyowa Hakko Kirin, outside the submitted work.