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Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line option for non-small-cell lung cancer (NSCLC) harboring active EGFR mutations. The overall survival of patients with advanced NSCLC has improved dramatically with the development of comprehensive genetic profiles and targeted therapies. However, resistance inevitably occurs, leading to disease progression after approximately 10–18 months of EGFR-TKI treatment. Platinum-based chemotherapy is the standard treatment for patients who have experienced disease progression while undergoing EGFR-TKI treatment, but its efficacy is limited. The management of extensively pretreated patients with EGFR-mutant NSCLC is becoming increasingly concerning. New agents have shown encouraging efficacy in clinical trials for this patient population, including fourth-generation EGFR-TKIs, EGFR-TKIs combined with counterpart targeted drugs, and novel agents such as antibody–drug conjugates. We review current efforts to manage extensively pretreated patients with EGFR-mutant NSCLC.

Keywords

non-small-cell lung cancer novel systemic therapy pretreatment targeted therapy

Introduction

Lung cancer is the leading cause of mortality worldwide, and non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers.¹ Among patients with NSCLC, epidermal growth factor receptor (EGFR) mutations are the most prevalent oncogene mutations. Such mutations are observed in about 15% of Caucasian patients and nearly 50% of East Asian patients, and their incidence is particularly higher in women and patients with no smoking history.^2–5 The most common types of sensitizing EGFR mutations are EGFR exon 19 deletion and EGFR L858R point mutation, which account for nearly 90% of EGFR mutations sensitive to EGFR tyrosine kinase inhibitors (TKIs).^6,7 The development of EGFR-TKIs has dramatically improved the survival of patients harboring these mutations. In 2009, the Iressa Pan-Asia Study (IPASS) first demonstrated the promising antitumor activity of first-generation EGFR-TKI gefitinib in patients with NSCLC harboring EGFR mutations.^8,9 Subsequent studies that investigated first-generation [gefitinib, erlotinib, and icotinib (China only)] and second-generation [afatinib and dacomitinib] EGFR-TKIs also showed consistent improvements in treatment efficacy, with objective response rates (ORRs) of 70–75% and median progression-free survival (PFS) of 10–14 months compared with conventional platinum-based chemotherapy as first-line treatment for locally advanced or advanced-stage EGFR-mutant NSCLC.^10–16 In addition, several phase III clinical trials (e.g. CTONG1509, RELAY, and NEJ026) have demonstrated the feasibility of combining erlotinib and angiogenesis for EGFR-mutant NSCLC.^17–20 Combination strategies demonstrated significantly superior PFS and longer overall survival (OS) than EGFR-TKI monotherapy.^18–20 Interestingly, the CTONG1509 trial showed that patients with EGFR L858R mutation or baseline brain metastasis derived greater benefit from combination therapy.¹⁷

The third-generation EGFR-TKI osimertinib has shown superior efficacy, with significant improvements in both PFS (18.9 versus 10.2 months) and OS (38.6 versus 31.8 months) compared with first-generation EGFR-TKIs.^21,22 Subsequent novel third-generation EGFR-TKIs (e.g. lazertinib, almonertinib, furmonertinib, and avitinib) also showed superior benefits, with improved PFS in the second-line setting in patients harboring the EGFR T790M mutation.^23–27 Similarly, almonertinib and furmonertinib have demonstrated efficacy superior to that of first- or second-generation EGFR-TKIs. Thus, the use of third-generation EGFR-TKIs in the front-line setting shows promise,^25,28 and huge therapeutic breakthroughs in patients with EGFR mutations with significant improvement in OS.

However, with the clonal evolution of tumors and resulting heterogeneity in EGFR-driven NSCLC, resistance has inevitably developed and is characterized by a variety of mechanisms after treatment with first- to third-generation EGFR-TKIs.^29–31 When patients experience disease progression, tissue (preferably) or liquid biopsy is recommended to identify the mechanisms underlying the resistance to EGFR-TKIs. The primary resistance mechanisms can generally be classified as on-target (EGFR dependent), off-target (EGFR independent), and unknown. A deeper understanding of these resistance mechanisms is fundamental for the development of precision-targeted strategies that may overcome treatment resistance.³² Many oncological drugs have been investigated for this purpose, and some have shown promising efficacy. We summarize the current data regarding new agents that have been designed to overcome acquired resistance to EGFR-TKIs, as well as broad-spectrum drugs such as novel agent antibody–drug conjugates (ADCs) for use in patients with unknown resistance mechanisms. We mainly focus on the clinical efficacy and safety of emergent drugs for patients with EGFR-mutant NSCLC who have experienced disease progression during treatment with standard EGFR-TKIs.

Current recommendations for TKI-pretreated patients with EGFR-mutant NSCLC

Treatment algorithms vary according to disease progression patterns. The progression patterns after the development of EGFR-TKI resistance can be classified into oligoprogression, intracranial progression, and systemic progression.³³ Oligoprogression is defined as the progression of a limited number of metastatic tumor sites with good control of other tumor dissemination sites. Patients with oligoprogression should continue to receive TKI therapy; other potentially useful treatment options include definitive local therapies such as ablative therapy or stereotactic body radiotherapy, which have a high local control rate and favorable PFS outcome.³⁴ Intracranial progression can be classified into oligoprogressive central nervous system (CNS) disease and disseminated CNS progression. Oligoprogressive CNS disease can be treated with stereotactic radiosurgery or surgical resection.³⁵ However, multifocal CNS progression requires whole-brain radiotherapy or alternative systematic therapies. A change in systematic therapy is warranted for patients with systemic progression. The standard treatment for patients who have experienced disease progression on third-generation EGFR-TKIs or first- or second-generation EGFR-TKIs without EGFR T790M mutation is platinum-based doublet chemotherapy with or without an angiogenesis inhibitor.³⁶ In one study, the response rate with second-line platinum-based chemotherapy in pretreated patients with EGFR mutation-positive lung cancer was about 30%, and the median PFS was about 6 months.³⁷ Although it may provide only modest benefits, chemotherapy is by far the most important treatment for patients with EGFR-mutant NSCLC who have progressed during treatment with third-generation EGFR-TKIs. Biomarker-directed treatment strategies are recommended for patients harboring a definite acquired resistance alteration, such as MET amplification.

Treatment strategies for patients with EGFR-dependent resistance mechanisms

Although third-generation EGFR-TKIs (including osimertinib, lazertinib, almonertinib, and furmonertinib) have shown superior efficacy in patients with activating EGFR mutations with or without T790M alterations (often seen in patients with disease progression on first- or second-generation EGFR-TKIs), few treatment options are available for these patients after the disease has progressed.³⁰ The most common acquired on-target EGFR-TKI resistance mutation is EGFR C797S, accounting for about 15% of patients treated with second-line osimertinib and 7% of patients treated with first-line osimertinib.^38–40 Activation of EGFR C797S can lead to constant activation of the downstream mitogen-activated protein kinase (MAPK) pathway regardless of EGFR-TKI therapy, and no targeted treatment has been approved.⁴⁰ Previous studies showed that rechallenge with a first-generation EGFR-TKI in combination with a third-generation EGFR-TKI led to only brief clinical improvement for patients with concomitant EGFR T790M and C797S in trans, with a median PFS of 1.5–3.0 months.^41,42 Several fourth-generation EGFR-TKIs designed to overcome EGFR C797S resistance recently showed encouraging efficacy for these patients (Figure 1).

Figure 1.

Resistance mechanisms of EGFR-TKIs and their treatment strategies for extensively pretreated patients with non-small-cell lung cancer (NSCLC) harboring EGFR mutations (created with BioRender.com).

BLU-945

BLU-945 is a selective fourth-generation EGFR-TKI designed to target common activating and on-target resistance mutations, such as EGFR C797S and T790M.⁴³ It can suppress EGFR signal activation despite the presence of EGFR T790M and C797S mutations. Preclinical data indicated that BLU-945 had >450-fold higher selectivity for C797S and T790M mutants than the wild-type gene. BLU-945 has shown antitumor activity as monotherapy or in combination with osimertinib in osimertinib-resistant cell-line-derived tumor xenografts and patient-derived xenograft models.^43,44 Based on the pharmacological activity of BLU-945, an ongoing phase I/II first-in-human study (SYMPHONY, NCT04862780) was designed to evaluate the tolerability and antitumor activity of BLU-945 as monotherapy or in combination with osimertinib in patients with osimertinib-resistant EGFR-mutant NSCLC.⁴⁵ As of the 7 January 2022 cutoff, 33 patients were enrolled, and most had received more than three lines of prior therapy. The preliminary analysis indicated that BLU-945 was generally well-tolerated, and no grade 4 or 5 adverse events (AEs) were reported. One patient developed grade 3 transaminitis, but it was relieved after drug interruption. Patients treated with BLU-945 also showed a significant reduction in circulating tumor DNA (ctDNA). Increased doses of BLU-945 were associated with greater tumor shrinkage. These initial results showed safe, promising antitumor activity of BLU-945 in combination with osimertinib in extensively pretreated patients with EGFR-mutant NSCLC. Further explorations in larger samples are ongoing.

BLU-701

BLU-701 is another brain-penetrant, reversible, next-generation EGFR-TKI designed to overcome osimertinib-resistant EGFR C797S mutation. It strongly inhibits both EGFR 19 deletion and L858R mutations with or without the presence of the EGFR C797S resistance mutation. In a preclinical study, BLU-701 showed durable inhibition of EGFR autophosphorylation and tumor reduction.⁴⁶ The HARMONY trial (NCT05153408) is an ongoing phase I/II first-in-human study investigating the safety and antitumor activity of BLU-701 as monotherapy or in combination with osimertinib or chemotherapy in patients with pretreated EGFR-mutant NSCLC.^47,48 This study is currently enrolling patients with metastatic EGFR-mutant NSCLC receiving one or more lines of EGFR-TKIs. Patients undergoing phase I dose escalation will be assigned to three different treatment cohorts: part 1A (BLU-701 monotherapy), part 1B (BLU-701 + osimertinib), and part 1C (BLU-701 + carboplatin and pemetrexed). During phase II monotherapy, patients harboring an acquired EGFR C797S resistance mutation will be treated with BLU-701 as monotherapy.

Another study was conducted to evaluate the antitumor activities of BLU-945 and BLU-701 in an EGFR L858R/C797S-driven Ba/F3 cell-line-derived tumor xenograft subcutaneous tumor model.⁴⁹ The administration of BLU-945 or BLU-701 monotherapy resulted in substantial tumor regression. Furthermore, combining BLU-945 with BLU-701 resulted in more robust antitumor activity and tumor regression because these drugs may cover a broader mutational spectrum of on-target resistance mechanisms.

BBT-176

BBT-176 can specifically and noncovalently inhibit triple EGFR-mutant residues (exon19del or L858R/T790M/C797S). Preclinical data demonstrated promising antitumor efficacy of BBT-176 in EGFR triple-mutant models in Ba/F3 engineered cells and patient-derived xenografts.⁵⁰ A phase I study of BBT-176 was designed to investigate the tolerability and antitumor activity in patients with EGFR mutations who were previously treated with at least one line of EGFR-TKI therapy (NCT04820023).⁵¹ The interim results showed that among 18 enrolled patients, 5 harbored a triple-mutant EGFR gene (exon19del/T790M/C797S or L858R/T790M/C797S). Toxicities were well tolerated, and no treatment discontinuation or dose-limiting toxicity occurred. Two patients with triple EGFR mutations (exon19del/T790M/C797S) showed tumor reduction, with one patient showing up to 30.3% tumor regression. Overall, the interim results of this study demonstrated preliminary antitumor activity of BBT-176 with acceptable toxicity. Further exploration of the recommended phase II dose is ongoing.

Many other fourth-generation EGFR-TKIs are currently under evaluation. We summarize the ongoing trials and the medications investigated in these studies in Table 1.

Table 1.

Ongoing trials and corresponding investigated agents for patients with EGFR-dependent resistance mechanisms.

NCT number	Drug	Phase	Title	Alteration criteria	Sample size
NCT04820023	BBT-176	Phase I/II	Phase I/II Study of BBT-176 in Advanced NSCLC With Progression After EGFR TKI Treatment	EGFR mut; After prior EGFR TKI	168
NCT05153408	BLU-701	Phase I/II	(HARMONY) Study of BLU-701 in EGFR-mutant NSCLC	EGFR mut and/or C797S; After osimertinib	160
NCT04862780	BLU-945	Phase I/II	(SYMPHONY) Phase I/II Study Targeting EGFR Resistance Mechanisms in NSCLC	EGFR mut and/or C797S; After osimertinib	190
NCT05393466	BPI-361175	Phase I/II	BPI-361175 Tablets in Patients With Advanced NSCLC	EGFR mut and/or C797S;	30
NCT05329298	BPI-361175	Phase I/II	A phase I/II Study of BPI-361175 in Subjects With Advanced Solid Tumors	EGFR mut	90
NCT05519293	H002	Phase I/II	Phase I/IIa Study of H002 in NSCLC With Active EGFR Mutation	EGFR mut and/or C797S	76
NCT05552781	H002	Phase I/II	H002 in Patients With EGFR Mutation Locally Advanced or Metastatic NSCLC	EGFR mut and/or C797S	76
NCT05555212	QLH11811	Phase I	To Evaluate the Efficacy of QLH11811 in Advanced NSCLC Patients With EGFR Mutation	EGFR mut and/or C797S	72

EGFR, epidermal growth factor receptor; EGFR mut, EGFR mutation; NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitors.

Unresolved clinical issues and perspective of fourth-generation EGFR-TKIs

Like third-generation EGFR-TKIs, novel agents that target EGFR C797S resistance mutations can eventually benefit patients. The ideal fourth-generation EGFR-TKI should target not only EGFR C797S mutation but also improve the outcomes of patients with EGFR L858R mutation and those with CNS metastases. However, the current data on fourth-generation EGFR-TKIs are limited. Moreover, in addition to EGFR C797S as a resistance mechanism, wild-type EGFR gene amplification has been described as a resistance mechanism after failed treatment with third-generation EGFR-TKIs.^52,53 However, few data on patients with EGFR amplifications have been reported. There is an urgent clinical need for effective treatment in this population.

Treatment strategies for patients with EGFR-independent resistance mechanisms

EGFR-independent resistance (also called off-target resistance) is another primary mechanism after tumor progression during EGFR-TKI therapy. EGFR-independent resistance involves various mutations, including MET amplification, EGFR amplification, and HER2 amplification.³⁰ Generally, patients with off-target resistance are treated with a combination of an EGFR-TKI and other specific drugs that target resistance mutations to inhibit tumor growth.

Treatment strategies for patients with MET amplification

Acquired MET amplification resistance has been observed in 5–15% of patients treated with first- or second-generation EGFR-TKIs and about 20% of patients treated with third-generation EGFR-TKIs.^52,54 One study showed that EGFR-mutant NSCLC progressed during third-generation EGFR-TKI therapy because acquired MET amplification can be inhibited by the combination of EGFR-TKIs and mesenchymal–epithelial transition factor TKIs (MET-TKIs).⁵⁵ Several small-molecule MET-TKIs (including capmatinib, tepotinib, and savolitinib) were designed to target MET amplification in the setting of EGFR-TKI resistance, and all have shown promising results (Figure 2).

Figure 2.

ORRs of patients harboring EGFR mutations with MET dysregulation after disease progression on prior EGFR-TKI therapy under different criteria and treatments.

Capmatinib

Capmatinib (INC280), a highly potent and selective inhibitor of the MET receptor, has shown potent antitumor activity in cancer models with MET alterations.^56,57 Wu et al.⁵⁵ investigated the safety and efficacy of the combination of capmatinib and gefitinib in patients with EGFR mutations and MET dysregulation (including MET amplification and MET overexpression) in the context of EGFR-TKI resistance. The combination of MET-TKI and EGFR-TKI therapy was well tolerated. The most common treatment-related AEs (TRAEs) were nausea (28%), peripheral edema (22%), and decreased appetite (21%). Although the ORR was 29% in the overall population, the ORRs in patients who had tumors with a MET gene copy number (GCN) of >6 and MET overexpression [immunohistochemistry (IHC) 3+] were 47% and 32%, with a median PFS of 5.49 and 5.45 months, respectively. The antitumor activity of capmatinib was stronger in patients with higher MET-amplified and MET overexpression levels. This study was the first to confirm the feasibility and efficacy of combining a MET-TKI with an EGFR-TKI in patients with MET dysfunction who developed disease progression while undergoing EGFR-TKI treatment. The clinical trials of patients with EGFR mutations and MET alterations who progressed on previous EGFR-TKI therapy are summarized in Table 2.

Table 2.

Clinical trials for patients harboring EGFR mutations with MET alterations who experienced disease progression on previous EGFR-TKI therapy.

Author (year), study	Drug	Trial phase (n)	Enrolled criteria	Subgroup (patients)	ORR	PFS
Wu et al. (2018) Wu et al. (2021) (NCT01610336)	Capmatinib + gefitinib	II (100)	After EGFR-TKI<T790 M- MET: GCN ⩾ 5 or IHC 2 +/ 3+; then GCN ⩾ 5 plus IHC 2 +/ 3+; then GCN ⩾ 4 or IHC 3+;	MET GCN <4 (n = 41)	12.0%	mPFS: 3.9 months
				MET 4 ⩽ GCN⩽6 (n = 18)	22.0%	mPFS: 5.4 months
				MET GCN ⩾ 6 (n = 36)	47.0%	mPFS: 5.5 months
				MET IHC2+ (n = 16)	19.0%	mPFS: 7.5 months(MET IHC2+ and GCN >5)
				MET IHC3+ (n = 78)	32.0%	mPFS: 5.5 months
McCoach et al. (2021)(NCT01911507)	Capmatinib + erlotinib	I/II (35)	⩾1 prior EGFR TKI	Cohort A: MET IHC 2/3+ (n = 8)	50.0%	–
Wu et al. (2020)Liam et al. (2022)INSIGHT	Tepotinib + gefitinib	II (55)	After first- or second-generation EGFR-TKI<T790 M-MET: IHC2 +/ 3+ or FISH GCN ⩾ 5; MET/CEP7 ⩾ 2	MET amplification (n = 12)	66.7%	mPFS: 16.6 months
				MET: IHC 3+ (n = 19)	68.4%	mPFS: 8.3 months
				Chemotherapy (n = 24)	33.0%–43.0%	mPFS: 4.2–4.4 months
Mazieres et al. (2022)INSIGHT2	Tepotinib + osimertinib	II (100)	After osimertinibMET: FISH GCN ⩾ 5 and/or MET/CEP7 ⩾ 2 by FISH (tissue)or GCN ⩾ 2.3 by NGS (blood)	FISH (tissue, n = 22, follow-up ⩾ 9 months)	54.5%	–
				NGS (blood, n = 16, follow-up ⩾ 9 months)	50.0%	–
Sequist et al. (2020),Han et al. (2022)TATTON	Savolitinib + osimertinib	Ib (180)	After EGFR-TKIMET: GCN ⩾5 and/or MET/CEP7 ⩾2.2	No previous third-generation EGFR-TKI (N = 111)	62%−67%	mPFS: 9.0–11.1 months
Sequist et al. (2020),Han et al. (2022)TATTON	Savolitinib + osimertinib	Ib (180)	After EGFR-TKIMET: GCN ⩾5 and/or MET/CEP7 ⩾2.2	Previous third-generation EGFR-TKI (N = 69)	33.0%	mPFS: 5.5 months
Yang et al. (2021)(NCT02374645)	Savolitinib + gefitinib	Ib (51)	After EGFR-TKIMET: FISH GCN ⩾ 5 or MET/CEP7 ⩾ 2	All patients (n = 51)	31.0%	mPFS: 4 months
				EGFR T790 M – (n = 20)	52.0%	mPFS: 4.2 months
Yu et al. (2021),ORCHARD(NCT03944772)	Savolitinib + osimertinib	II (20)	After osimertinibNGS MET amplification/MET exon 14 skipping	All patients (n = 20)	41.0%	–
Ahn et al. (2022)SAVANNAH	Savolitinib + osimertinib	II (196)	After osimertinibMET: FISH GCN ⩾ 5 and/or MET/CEP7 ⩾ 2	MET: IHC3+ in ⩾50% tumor cells (N = 196)	32.0%	mPFS: 5.3 months
				MET: IHC3+ in ⩾90% tumor cells and/or FISH GCN ⩾ 10 (n = 108)	49.0%	mPFS: 7.1 months
Camidge et al. (2022)(NCT02099058)	Teliso-V + erlotinib	Ib (35)	After EGFR-TKIMET IHC ⩾ 150	MET scores ⩾225 (n = 19)	52.6%	–
				150 ⩽ MET scores < 225 (n = 16)	12.5%	–

EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; GCN, gene copy number; HR, hazard ratio; MET, mesenchymal–epithelial transition; mPFS, median progression-free survival; NGS, next-generation sequencing; ORR, objective response rate; PFS, progression-free survival; TKI, tyrosine kinase inhibitors.

Tepotinib

Tepotinib is another highly selective type 1b MET inhibitor that has shown strong antitumor activity in tumor models in vitro.^58,59 The phase Ib/II INSIGHT study investigated the safety and efficacy of combining tepotinib with gefitinib in patients with MET dysregulations who had acquired EGFR-TKI resistance.⁶⁰ The results showed that tepotinib was well tolerated when combined with gefitinib. In the overall population, survival outcomes were comparable between the tepotinib plus gefitinib group and the chemotherapy group, with a median PFS of 4.9 versus 4.4 months, respectively [hazard ratio (HR), 0.67; 90% confidence interval (CI), 0.35–1.28]. However, more prolonged PFS and OS were seen in patients with MET amplification with a high GCN in the tepotinib plus gefitinib arm than in the chemotherapy arm (median PFS, 16.6 versus 4.2 months; median OS, 37.3 versus 13.1 months). Similar results were observed in patients with high MET overexpression (IHC 3+) (median PFS, 8.3 versus 4.4 months; median OS, 37.3 versus 17.9 months). Patients with high-level MET overexpression and MET amplification showed increased survival benefits. The most frequent grade ⩾3 TRAEs were elevated levels of amylase (16%) and lipase (13%) in the combination group. These results demonstrated superior survival outcomes for patients with NSCLC harboring EGFR mutation and high-level MET dysregulation in the tepotinib plus gefitinib group compared with the traditional chemotherapy group. Based on the promising efficacy shown in the INSIGHT study, a phase II study (INSIGHT 2) was designed to examine the efficacy of tepotinib in combination with osimertinib in patients with MET-amplified NSCLC who had experienced disease progression on first-line osimertinib.⁶¹ The preliminary results showed an ORR of 54.5% in patients with MET amplification treated with a combination of tepotinib and osimertinib.⁶² Safety was acceptable with a grade ⩾3 AE rate of 23.9%, and the most common TRAEs were diarrhea (40.9%) and peripheral edema (23.9%). In this initial analysis of INSIGHT 2, tepotinib combined with osimertinib was well tolerated and showed promising efficacy for patients who developed disease progression on first-line osimertinib.

Savolitinib

Savolitinib, also known as HMPL-504 or volitinib, is an oral, potent, and highly selective type Ib MET-TKI.⁶³ Savolitinib combined with EGFR-TKI therapy has shown strong antitumor activity in co-occurring EGFR-mutant and MET-amplified NSCLC xenograft models with acquired resistance to EGFR-TKI therapy.⁶⁴ Several clinical trials have proved its efficacy in patients with NSCLC. A phase Ib study (NCT02374645) demonstrated the feasibility and high antitumor activity of savolitinib plus gefitinib in patients with disease progression on prior EGFR-TKI therapy.⁶⁵ Another phase Ib study (TATTON) assessed the efficacy of savolitinib plus osimertinib and revealed an ORR of 33–67% in patients who received this combination; this outcome was dependent on EGFR T790M status and whether patients had previously received a third-generation EGFR-TKI.^66–68 A higher dose of savolitinib was associated with higher toxicity (grade ⩾3 AEs: 57% with savolitinib 600 mg versus 38% with savolitinib 300 mg). The combination of osimertinib and savolitinib shows acceptable safety and encourages antitumor activity.

The SAVANNAH trial is an ongoing global, single-arm phase II trial studying the efficacy of savolitinib plus osimertinib in patients with EGFR-mutant NSCLC with MET overexpression or amplification who experienced disease progression on prior osimertinib therapy.⁶⁹ Patients were treated with savolitinib 300 or 600 mg once daily or 300 mg twice daily in combination with osimertinib. The preliminary results showed that osimertinib combined with savolitinib demonstrated an ORR of 49% (95% CI, 39–59%) among patients with high-level MET overexpression (IHC 3+ in ⩾90% of tumor cells) or MET amplification [fluorescence in situ hybridization (FISH): GCN of ⩾10].⁷⁰ However, the ORR was only 9% (95% CI, 4–18%) in patients whose tumors showed low-level MET expression or MET amplification. A global phase III trial (SAFFRON) evaluating this combination is underway to further confirm its efficacy.⁷¹

Overall, the combination of MET inhibitors (including capmatinib, tepotinib, and savolitinib) with EGFR-TKIs has shown encouraging efficacy for patients with resistance to EGFR-TKIs and harboring MET alterations, especially those with high-level MET dysregulation.

Treatment strategies for patients with alternative resistance pathways

Other bypass-mediated resistance mechanisms, although rare, also cause disease progression during treatment with EGFR-TKIs for EGFR-mutant lung cancer. Such mechanisms include HER2 amplification, KRAS amplification, CCND1 amplification, and BRAF mutations. In one study, HER2 amplification was detected in 2–7% of patients who experienced disease progression on third-generation EGFR-TKIs.³⁸ Acquired HER2 amplification can result in EGFR-TKI resistance through constant activation of downstream pathways such as the MAPK and PI3K pathways.⁷² Some ADCs show promising efficacy for patients with primary HER2 alterations, including HER2 amplification and HER2 mutation in NSCLC; these ADCs include trastuzumab emtansine (TDM1) and trastuzumab deruxtecan (T-DXd, DS-8201).^73,74 As in patients with EGFR-mutant NSCLC with MET amplification, the combination of osimertinib and TDM1 has shown promising efficacy in patients with EGFR-mutant NSCLC with HER2 amplification-mediated resistance.⁷⁵ In addition, a case report showed that the combination of an EGFR-TKI and pyrotinib (a selective HER2-TKI) resulted in a durable response, even when resistance to gefitinib had developed in patients with HER2 missense mutations.^76,77 These results support further studies using this novel drug in the setting of HER2-driven EGFR-TKI resistance.

BRAF V600E mutations, identified in 1–3% of patients who experience disease progression while on EGFR-TKI therapy, also represent a resistant mechanism.^38,39,78 Preclinical and retrospective evidence support the use of EGFR-TKIs in combination with BRAF V600E-specific inhibitors to block bypass signal pathways.^79–81 However, few prospective clinical trial data have been released.

The ongoing phase II ORCHARD trial is a biomarker-directed platform-based study involving patients with advanced NSCLC harboring EGFR mutations who developed disease progression on first-line osimertinib.⁸² In this study, various drug combinations are being administered according to the identified resistance mechanism to front-line osimertinib, including EGFR C797S mutation, MET alterations, EGFR amplification, ALK rearrangement, RET fusions, and unknown resistance mechanisms. The primary objective of this trial is to address challenges faced by patients with extensive prior treatments.

Unmet clinical issues and perspectives regarding MET inhibitors

Although many studies have shown promising efficacy for combinations of MET-TKIs with EGFR-TKIs, there remain some challenges in diagnosing and treating patients with MET amplification. The definitions of MET amplification and MET overexpression remain controversial.⁸³ FISH is the gold standard detection method for MET amplification because it can distinguish true MET amplification from MET polyploidy (duplication of the whole chromosome 7) by calculating the ratio of MET to the centromere on chromosome 7 (MET/CEP7).⁸⁴ However, no criterion has been established to define the threshold of the GCN and MET/CEP7.^85,86 In clinical trials, the cutoff for MET amplification (i.e. MET GCN) ranges from 1.8 to 10, with correspondingly variable clinical efficacies. Overall, better efficacy of MET-TKI therapy has been observed in patients with a high MET GCN.⁸⁷ In addition, with the ability to comprehensively detect all types of mutations in a single analysis, the role of next-generation sequencing (NGS) in identifying MET amplification remains controversial. In a study from China, MET amplification identified by NGS failed to distinguish significant clinical outcomes of MET-TKI treatment.⁸⁸ The concordance rate between NGS and FISH is poor, at only 62.5% (25/40). By contrast, a study using a bioinformatically expanded NGS analysis achieved 91% concordance with the FISH method.⁸⁹ Overall, the clinical role of NGS in identifying MET amplification, particularly low-level MET amplification, remains controversial. Further studies are urgently needed to determine the optimal method to detect MET amplification.

MET protein overexpression, as shown by IHC, is also commonly used as a potential biomarker for MET dysregulation because it is much less expensive and more convenient to perform in clinical practice. Two studies have demonstrated the promising performance of MET overexpression in predicting the efficacy of capmatinib or tepotinib.^55,60 However, previous studies showed a poor relationship between MET overexpression and MET amplification.⁹⁰ FISH and NGS remain the preferred techniques, and the role of MET overexpression in acquired MET-dysregulated NSCLC requires further validation.⁸⁷ Furthermore, the relative efficacy of three small-molecule MET inhibitors (tepotinib, capmatinib, and savolitinib) in patients with MET amplifications remains unknown.⁸³ Further head-to-head trials or meta-analyses comparing these MET inhibitors are warranted. The efficacy of these agents appears to be greater in patients with MET amplification who have a higher GCN and in patients with high-level MET protein expression.^55,60

Despite the considerable therapeutic advances that have been made for patients with MET amplification who have developed resistance to EGFR-TKIs, there is an urgent need for therapy in patients with other off-target resistance mechanisms to EGFR-TKIs.³⁰ However, data on resistance by alternative pathways remain elusive, and the standard of treatment for these patients is limited. Most currently available evidence regarding these rare types of mutation resistance has been obtained from retrospective and preclinical studies. Further randomized controlled trials are required to elucidate the clinical utilization of these strategies.

Emerging drugs for patients with unknown resistance mechanisms

Among patients who develop disease progression while taking third-generation osimertinib, about 30–50% have no identifiable resistance mechanisms. Biomarker-directed treatment strategies are not feasible in these patients; instead, platinum-doublet chemotherapy plus antiangiogenic drugs are recommended.^36,37 Moreover, emerging novel approaches have shown preliminary efficacy for these patients, including ADCs, the bispecific antibody amivantamab, and immune checkpoint inhibitors (ICIs).

Patritumab deruxtecan (HER3-DXd, U3-1402)

Patritumab deruxtecan is a novel HER3-directed ADC consisting of a HER3 antibody attached to the topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. Because HER3 expression was found in 83% of NSCLC tumors, patritumab deruxtecan was shown to be safe and effective in patients pretreated with EGFR-TKIs in a phase I study (NCT03260491).^91,92 The data showed promising results, with an ORR of 39% (95% CI, 26.0–52.4%), disease control rate (DCR) of 72% (95% CI, 59–83%), and median PFS of 8.2 (95% CI, 4.4–8.3) months. Patritumab deruxtecan showed potent CNS activity in patients with CNS metastases with an ORR of 32% and DCR of 80%, similar to its effect in patients without CNS disease. In addition, patritumab deruxtecan showed promising clinical efficacy and a manageable safety profile in patients with a broad range of genomic resistance alterations. Because of the surprising results obtained in the trials, patritumab deruxtecan was designated ‘the most promising clinical candidate’ in the World ADC Awards at the World ADC San Diego 2021 meeting. This reaffirmed DXd-ADC technology as a global breakthrough. Furthermore, comprehensive research into second- or third-line patritumab deruxtecan is currently underway in the HERTHENA-Lung01 and HERTHENA-Lung02 trials. Further explorations of HER3 as a biomarker are needed.

Datopotamab deruxtecan (Dato-DXd, DS-1062)

Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein highly expressed in NSCLC and other solid tumors. TROP2 overexpression can result in poor survival. Datopotamab deruxtecan is a TROP2-directed ADC consisting of a TROP2-directed monoclonal antibody, a novel topoisomerase 1 inhibitor, and a tetrapeptide-based linker. Preclinical studies showed promising antitumor activity of datopotamab deruxtecan in mice with TROP2-positive tumors.⁹³ A phase I study of datopotamab deruxtecan demonstrated an ORR of 26%, a DCR of 70%, a preliminary median PFS of 6.9 (95% CI, 2.7–8.8) months, and a manageable safety profile in patients with NSCLC extensively pretreated with standard therapy (NCT03401385).⁹⁴ Based on the encouraging efficacy of datopotamab deruxtecan, a phase II study involving patients with EGFR-mutant NSCLC who developed disease progression on EGFR-TKI therapy is ongoing (TROPION-Lung05, NCT04484142).^94,95

Telisotuzumab vedotin (ABBV-399, Teliso-V)

Telisotuzumab vedotin, a novel ADC targeting the MET protein, delivers a cytotoxic payload (monomethyl auristatin E) into MET-overexpressing tumor cells.⁹⁶ Overexpression of MET protein is observed in approximately 50% of NSCLCs.⁹⁰ The co-occurrence of MET overexpression and EGFR mutation in NSCLC is the rationale for dual targeting of EGFR and MET alteration. Teliso-V has shown a tolerable safety profile and good antitumor activity as monotherapy for advanced solid tumors.⁹⁷ In phase I/Ib study, Teliso-V plus erlotinib demonstrated antitumor activity in patients with MET-overexpressing, EGFR-activated, EGFR-TKI-pretreated NSCLC.⁹⁸ The ORR was 32.1%, and the median PFS for all efficacy-evaluable patients was 5.9 months (95% CI, 2.8 months to not reached). Among patients with EGFR-mutant cancer, those with high MET overexpression had an ORR of 52.6%. The median PFS was 6.8 months in those who were negative for EGFR T790M mutation. The toxicity was acceptable, with grade ⩾3 AEs occurring in 64% of patients. Teliso-V plus erlotinib showed encouraging antitumor activity and acceptable toxicity in EGFR-TKI-pretreated patients with EGFR-mutant, MET-overexpressing NSCLC.

Amivantamab plus lazertinib

Amivantamab, an EGFR–MET bispecific antibody, can bind to each receptor’s extracellular domain, bypassing resistance at the TKI binding site.⁹⁹ The CHRYSALIS-2 (NCT04077463) study was designed to investigate amivantamab plus lazertinib in patients with EGFR mutation-sensitive NSCLC after disease progression on osimertinib and platinum chemotherapy. Of 50 patients in whom efficacy could be evaluated, the ORR was 36% and the median PFS was 5.1 months.¹⁰⁰ The toxicities were acceptable, with the most common grade ⩾3 TRAEs being infusion-related reactions (7%), acneiform dermatitis (5%), and hypoalbuminemia (4%). Among an unselected population that had acquired resistance to osimertinib and platinum-based chemotherapy, amivantamab and lazertinib demonstrated encouraging antitumor activity. When combining chemotherapy, these strategies showed a higher ORR of 50% (95% CI, 27–73%).¹⁰¹ The ongoing phase III randomized MARIPOSA-2 study is evaluating amivantamab in combination with lazertinib and chemotherapy in the post-osimertinib setting (NCT04988295).

Current data and ongoing clinical trials of immunotherapy

ICIs have demonstrated great success in driver gene-negative NSCLC, and their therapeutic effects in EGFR mutation-positive NSCLC have been raising interest. EGFR-mutant NSCLC has lower programmed cell death-ligand 1 expression and a lower tumor mutation burden, resulting in a suppressive tumor immune microenvironment.¹⁰² The multicenter registered IMMUNOTARGET study revealed that patients harboring driver mutations (e.g. KRAS, EGFR, BRAF, MET) showed a poor outcome to immunotherapy, with an average ORR of 19%.¹⁰³ Among patients with EGFR mutation-positive cancer (n = 125), the ORR was only 12.2% and the median PFS was 2.1 months. A pooled analysis of three large clinical trials involving 186 patients with EGFR-mutant cancer that progressed on previous EGFR-TKI therapy also revealed drastically lower efficacy with immunotherapy than with chemotherapy in this particular population (HR, 1.05; 95% CI, 0.70–1.55).¹⁰⁴ Therefore, patients with EGFR mutations were not included in most first-line immunotherapeutic clinical trials, except for the IMpower150 study.^105–108 This study investigated the efficacy of atezolizumab in 124 patients with EGFR mutation-positive cancer who had received prior EGFR-TKI treatment. Consistent with previous studies, no survival benefit was observed in the immunotherapy plus chemotherapy group. However, in the immunotherapy plus chemotherapy and bevacizumab group, this study was the first to demonstrate the survival benefit of immunotherapy compared with chemotherapy, with a PFS of 10.2 versus 6.9 months, respectively. In the WJOG8515L trial and a subgroup analysis of the IMpower130 trial, negative results were obtained in patients treated with immunotherapy.^109,110 The recent randomized phase III CheckMate772 trial also failed to meet its primary endpoint, with no PFS benefits observed between nivolumab plus chemotherapy and chemotherapy alone for patients with EGFR-mutant cancer who progressed on previous EGFR-TKI therapy. The median PFS was 5.6 and 5.4 months, respectively (HR, 0.75; 95% CI, 0.56–1.00; p = 0.05).¹¹¹ Furthermore, the combination of a CTLA-4 inhibitor (ipilimumab) plus nivolumab failed to show a survival benefit in patients with EGFR-mutant NSCLC, with a median PFS of only 1.22 months.¹¹²

Antiangiogenic agents appear to contribute to survival benefits in patients with EGFR mutation. Several translational studies have shown that antiangiogenic agents can boost the immune system by limiting NF-κB activation in immature dendritic cells.¹¹³ This finding was further supported by the recent phase III ORIENT-31 trial, which evaluated the efficacy and safety of sintilimab plus chemotherapy with or without IBI305 compared with chemotherapy for patients with EGFR-mutant NSCLC who had developed disease progression after receiving EGFR-TKIs.¹¹⁴ The results favored the sintilimab plus IBI305 plus chemotherapy group over the chemotherapy alone group, with a significantly longer median PFS (6.9 versus 4.3 months; HR, 0.46; p < 0.001). However, a modest PFS benefit was observed in the sintilimab plus chemotherapy group compared with the chemotherapy group, with a median PFS of 5.5 versus 4.3 months (HR, 0.723; 95% CI, 0.552–0.948).¹¹⁵

One study investigated the safety and practicability of CRISPR-engineered T cells in patients with refractory NSCLC. Adoptive transfer of engineered T cells resulted in durable efficacy. The median PFS was 7.7 weeks, and the median OS was 42.6 weeks.¹¹⁶ However, more data and trials on CRISPR gene editing are warranted.

Overall, the efficacy of ICIs is modest in patients with EGFR-mutant NSCLC. However, with the addition of antiangiogenic agents, immunotherapy has shown improved efficacy over chemotherapy alone, indicating the crucial role of antiangiogenic agents in patients with EGFR mutations. ICI therapy combined with chemotherapy and antiangiogenic agents has become a treatment option for these extensively pretreated patients with EGFR-mutant NSCLC. Several large clinical trials examining combination strategies of chemotherapy and immunotherapy are ongoing in patients with EGFR-mutant NSCLC who progressed on previous EGFR-TKI therapy (Table 3).

Table 3.

Clinical trials of ICIs in patients with advanced EGFR-mutated NSCLC.

Study	Phase	EGFRm (n)	Line	Treatment	ORR	PFS and/or OS
CheckMate 057	3	82	⩾2	Nivolumab	11%	PFS HR 1.46 (0.90–2.37)OS HR 1.18 (0.69–2.02)
KEYNOTE 010	2/3	87	⩾2	Pembrolizumab	NA	PFS HR = 1.79 (0.94–3.42)OS HR = 0.90 (0.51–1.58)
POPLAR	2	18	⩾2	Atezolizumab	NA	OS HR = 0.99 (0.29–3.40)
OAK	3	85	⩾2	Atezolizumab	5%	OS = 10.5 months
ATLANTIC	2	102	⩾3	Durvalumab	PD-L1 > 25%: 12.2%PD-L1 < 25%: 3.6%	mPFS PD-L1 > 25%: 1.9 month; PD-L1 < 25%: 1.9 monthsmOS PD-L1 > 25%: 13.3 months; PD-L1 < 25%: 9.9 months
IMpower150	3	124	⩾2	Chemotherapy ± atezolizumab ± bevacizumab	ABCP group: 71%ACP group: 36%BCP group: 42%	mPFS ABCP group: 10.2 mo; ACP group: 6.9 months; BCP group: 6.9 months
NCT03513666	2	40	⩾2	Toripalimab + chemotherapy	50%	mPFS = 7.0 months
TATTON	1b	23	⩾2	Durvalumab + osimertinib	43%	–
ORIENT-31 (NCT03802240)	3	600	⩾2	Chemotherapy ± Sintilimab ±IBI305	Sintilimab + IBI305 + chemotherapy: 48.1%;Sintilimab + chemotherapy: 34.8%;Chemotherapy: 29.4%	mPFS Sintilimab + IBI305 + chemotherapy: 7.2 months;Sintilimab + chemotherapy: 5.5 months;chemotherapy: 4.3 months
CheckMate 722 (NCT02864251)	3	580	⩾2	Nivolumab + chemotherapy/ipilimumab	Nivolumab + chemotherapy: 31%Chemotherapy: 27%	mPFS Nivolumab + chemotherapy: 5.6 months;chemotherapy: 5.4 months
KEYNOTE 789 (NCT03515837)	3	480	⩾2	Pembrolizumab + chemotherapy	Ongoing	–
NCT03924050	3	350	⩾2	Toripalimab + chemotherapy	Ongoing	–
ILLUMINATE (NCT03994393)	2	100	⩾2	Durvalumab + tremelimumab	Ongoing	–
NCT03786692	2	117	⩾2	Atezolizumab + chemotherapy + bevacizumab	Ongoing	–

ABCP, atezolizumab plus bevacizumab plus carboplatin plus paclitaxel; ACP, atezolizumab plus carboplatin plus paclitaxel; BCP, bevacizumab plus carboplatin plus paclitaxel; EGFRm, EGFR mutation; HR, hazard ratio; ICIs, immune checkpoint inhibitors; Mo, months; mPFS, median progression-free survival; NSCLC, non-small-cell lung cancer; ORR, objective response rate; OS, overall survival.

Strategies for CNS metastasis

CNS metastasis in patients with lung cancer occurs more frequently in those with EGFR mutations, and most EGFR-TKI treatment failures can be attributed to CNS progression. CNS metastases include brain metastasis and leptomeningeal metastasis (LM), and the clinical outcome of LM is dismal. The BRAIN study revealed intracranial activity of icotinib in patients with EGFR-mutant NSCLC and multiple brain metastases, indicating that EGFR-TKIs are a promising first-line therapeutic option in this setting.¹¹⁷ Furthermore, the third-generation EGFR-TKI osimertinib demonstrated favorable efficacy in the CNS as both front-line and second-line therapy in the FLAURA and AURA3 trials.^21,118 Two other third-generation EGFR-TKIs, aumolertinib and furmonertinib, also showed prominent CNS activity in first-line treatment.^119,120 In the ANEAS trial, the ORR of aumolertinib in evaluable CNS lesions was 85.7%, and the median CNS-PFS was 29.0 months. In the FURLONG study of furmonertinib, the ORR of measurable CNS lesions was 91%, and the duration of response was 100%. These studies consolidated the role of third-generation EGFR-TKIs in the front-line setting of patients with multiple brain metastases.

Among patients with LM, double-dose osimertinib resulted in an ORR of 62% and a median OS of 11 months.^121,122 The LM antitumor activity of standard-dose osimertinib was further confirmed in a pooled analysis of AURA series studies.¹²³ Another drug, zorifertinib (AZD3759), showed potent penetration of the blood–brain barrier and promising clinical CNS activity in a phase I study, and the findings of the randomized phase III study assessing its CNS activity will be published in the American Society of Clinical Oncology 2023 meeting proceedings.¹²⁴ However, CNS progression was still frequent in patients with EGFR-mutant NSCLC, and subsequent therapy after third-generation EGFR-TKIs for LM was limited. A recent retrospective study indicated that 72.7% of patients (16/22) with matched targeted therapy had a clinical response based on the resistance mechanisms of LM, and showed that continuing osimertinib combined with intensification therapy could prolong survival in patients without matched therapies.¹²⁵ Local treatments such as radiotherapy, neurosurgery, and intrathecal injection have effectively relieved patients’ neurological symptoms. A recent phase I/II clinical trial involving 30 patients with LM showed that the clinical response rate of intrathecal pemetrexed was 84.6%, the median OS was 9 months (95% CI, 6.6–11.4), and the safety profile was tolerable.¹²⁶

Treating CNS progression remains an unmet need in patients with EGFR-mutant disease; however, few trials have included patients with active CNS disease. Further explorations of EGFR-TKI therapy plus anti-angiogenesis drugs or radiotherapy are needed. Furthermore, treatment strategies based on the mechanisms of CNS metastases or biomarkers of the therapeutic response may be promising.

Expert insights

EGFR-TKIs have been the standard front-line treatment option for patients with NSCLC harboring EGFR active mutations since IPASS study. The clinical outcomes of advanced NSCLC have dramatically improved. However, after extensive treatment with EGFR-TKIs or chemotherapy, patients experience further challenges because of the lack of standard therapies. Improving patients’ quality of life and survival has been a central focus for decades. New agents have shown encouraging efficacy for patients who progressed to standard treatments, including fourth-generation EGFR-TKIs designed to overcome EGFR C797S resistance, EGFR-TKIs combined with their counterpart target drugs to tackle off-target resistance mechanisms, and novel ADCs and ICIs to offset unknown resistance alterations. Clinical trials involving these new drugs or combined strategies are ongoing. Therefore, patients are recommended to participate in clinical trials, which will provide another treatment option, further accelerate the development of novel drugs, and eventually benefit patients. The ORCHARD trial, a biomarker-directed platform study focusing on patients who underwent failed treatment with osimertinib, was designed to explore effective post-progression combination strategies based on specific resistance mechanisms.⁶⁹ Because of the widespread application of NGS, optimal therapies after progression to standard EGFR-TKIs must be chosen according to the resistance mechanisms, including EGFR-dependent and EGFR-independent alternative pathways.

MET inhibitors, ADCs, and ICIs appear to be particularly efficacious. Several phase II clinical trials have demonstrated the superior efficacy and tolerable safety of combining MET inhibitors and EGFR-TKIs for patients who have EGFR-mutant NSCLC with acquired MET amplification.^55,60 Further data from the phase III study are anticipated. A specific resistance mechanism is not identified in a majority of patients (about 30–50%) who develop disease progression during treatment with osimertinib.³⁰ Therefore, future explorations should concentrate on overcoming EGFR treatment resistance and developing new agents, such as ADCs and bispecific antibody drugs for patients with unknown resistance mechanisms. Approaches focusing on the specific resistant gene for each patient may narrow the treatment scope to some extent. Therefore, broad-spectrum drugs such as ADCs, which can overcome multiple resistance mechanisms of EGFR-TKIs, may play an essential role in extensively pretreated EGFR-mutant NSCLC. The encouraging preliminary results of patritumab deruxtecan and datopotamab deruxtecan suggest that ADCs may be promising novel agents for extensively pretreated patients with EGFR-mutant NSCLC. In addition, as demonstrated in two randomized phase III studies (ORIENT31 and CheckMate772), the efficacy of immunotherapy is modest in patients with EGFR-mutant NSCLC. The combination of immunotherapy and platinum-based chemotherapy with anti-angiogenesis therapy may be a treatment option.

In the future, we should focus on the prevention of drug resistance. There is an urgent need to identify patients who may be prone to resistance and administer appropriate therapy to delay or prevent resistance. For example, more radical therapies such as the combination of EGFR-TKIs and chemotherapy may be suggested for patients with EGFR mutations concomitant with genetic alterations of TP53 and RB1, which may lead to small-cell transformation. Because the third-generation EGFR-TKIs osimertinib, aumolertinib, and furmonertinib have dramatic CNS activity and can reduce or delay CNS progression, they should be front-line options for patients with a high risk of CNS metastasis. Furthermore, ctDNA is essential in performing comprehensive genomic profiling, monitoring resistance, and predicting the prognosis.¹²⁷ Therefore, patients should undergo ctDNA monitoring, if available, to gain access to potentially effective precision strategies that will help overcome the resistance to EGFR-TKIs. In addition, it is critical to identify specific resistance mechanisms for patients treated with EGFR-TKIs and determine an appropriate treatment strategy.¹²⁸ Some preclinical studies have shown that targeting CD70 and CD24 may be essential in EGFR-TKI resistance.^129,130 Targeting these molecules can improve treatment outcomes in patients with acquired EGFR-TKI resistance.

Conclusion

Significant progress is being made in overcoming EGFR-TKI resistance in experimental settings because of the growing understanding of resistance mechanisms. Fourth-generation EGFR-TKIs show the potential to overcome EGFR-dependent resistance. EGFR-TKIs combined with their counterpart target drugs, such as MET inhibitors, are designed to treat off-target alterations. Moreover, novel agents such as ADCs are under exploration to treat patients without specific resistance mechanisms. Our goal is to improve patient quality of life and OS. It is essential to prevent or delay the occurrence of EGFR-TKI resistance and develop more broad-spectrum agents for extensively pretreated patients with NSCLC.

Footnotes

Acknowledgements

None.

Declarations

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Novel systemic therapies in the management of tyrosine kinase inhibitor-pretreated patients with epidermal growth factor receptor-mutant non-small-cell lung cancer

Abstract

Keywords

Introduction

Current recommendations for TKI-pretreated patients with EGFR-mutant NSCLC

Treatment strategies for patients with EGFR-dependent resistance mechanisms

BLU-945

BLU-701

BBT-176

Unresolved clinical issues and perspective of fourth-generation EGFR-TKIs

Treatment strategies for patients with EGFR-independent resistance mechanisms

Treatment strategies for patients with MET amplification

Capmatinib

Tepotinib

Savolitinib

Treatment strategies for patients with alternative resistance pathways

Unmet clinical issues and perspectives regarding MET inhibitors

Emerging drugs for patients with unknown resistance mechanisms

Patritumab deruxtecan (HER3-DXd, U3-1402)

Datopotamab deruxtecan (Dato-DXd, DS-1062)

Telisotuzumab vedotin (ABBV-399, Teliso-V)

Amivantamab plus lazertinib

Current data and ongoing clinical trials of immunotherapy

Strategies for CNS metastasis

Expert insights

Conclusion

Footnotes

Acknowledgements

Declarations

References