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Abstract

Background:

While developments in targeted therapy have marked a new epoch for non-small cell lung cancer (NSCLC) patients harboring actionable genomic alterations, the management of individuals resistant to epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains a formidable challenge.

Objectives:

This study was designed to evaluate the comparative efficacy and safety of available therapeutic regimens and to identify the optimal treatment strategy for patients with disease progression following EGFR-TKI therapy.

Design:

This is a systematic review and Bayesian network meta-analysis.

Data sources and methods:

Databases including PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov, along with conference proceedings from January 1, 2020, to June 1, 2025, were searched. Randomized controlled trials (RCTs) assessing treatment options for advanced NSCLC patients resistant to EGFR-TKIs were eligible. We identified the optimal therapeutics through comparison of the surface under the cumulative ranking curves (SUCRA).

Results:

Overall, 19 RCTs involving 4,039 participants were identified. Meta-analysis indicated that sacituzumab tirumotecan (Sac-TMT) significantly improved progression-free survival (PFS; hazard ratio [HR] 0.20, 95% credible interval [CI] 0.13–0.30) and overall survival (OS; HR 0.36, 95% CI 0.20–0.66) compared to conventional chemotherapy as evidenced by its superior SUCRA values (0.997 for PFS and 0.946 for OS). Datopotamab deruxtecan (Dato-DXd) also demonstrated clinically meaningful efficacy outcomes. Specifically, Sac-TMT showed statistically superior PFS benefits relative to nearly all comparator regimens, including immune checkpoint inhibitor (ICI)-based and bispecific antibody (bsAb)-based strategies (all p < 0.05). Amivantamab in combination with lazertinib and chemotherapy (SUCRA = 0.816) and ivonescimab combined with chemotherapy (SUCRA = 0.779) both exhibited capabilities in prolonging PFS. Notably, the triplet regimen was associated with the highest incidence of severe-grade AEs compared to all other treatment options.

Conclusion:

Sac-TMT, Dato-DXd, and bsAbs-based regimens were identified as the most efficacious options with manageable toxicity for advanced NSCLC patients who progressed after EGFR-TKIs. These findings underscore the pivotal role of innovative therapeutic agents, illuminating potential treatment avenues for this difficult-to-treat refractory population.

Trial registration:

This study was registered as INPLASY202510014.

Plain language summary

ADCs May Be Better Than Immunotherapy in NSCLC Progressed After EGFR-TKIs

This network meta-analysis was conducted to select the optimal treatment option for NSCLC patients resistant to EGFR-TKIs. We thoroughly searched databases including PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov along with conference proceedings from January 1, 2020 to June 1, 2025 for eligible RCTs assessing treatment options for advanced NSCLC patients resistant to EGFR-TKIs. We identified the optimal therapeutics through comparison of SUCRA values. Overall, 19 RCTs involving 4,039 participants were identified. Meta-analyses indicated that sacituzumab tirumotecan (Sac-TMT) and datopotamab deruxtecan (Dato-DXd) significantly improved PFS and OS compared to conventional chemotherapy. Specifically, Sac-TMT showed statistically superior PFS benefits relative to nearly all comparator regimens, including ICI-based and bsAb-based strategies. Moreover, the toxicity of Sac-TMT was moderate. In conclusion, ADCs and bsAbs-based regimens were identified as the most efficacious options with manageable toxicity for advanced NSCLC patients progressed after EGFR-TKIs.

Keywords

antibody-drug conjugate bispecific antibody epithelial growth factor receptor tyrosine kinase inhibitor immunotherapy network meta-analysis non-small cell lung cancer

Introduction

A pivotal therapeutic target in non-small cell lung cancer (NSCLC) is the epithelial growth factor receptor (EGFR) gene mutation, which varies geographically in prevalence, and is notably higher in East Asia (38%–50%) compared to the Americas (24%) and Europe (14%).¹ EGFR tyrosine kinase inhibitors (EGFR-TKIs) are endorsed as the preferred first-line treatment for patients harboring EGFR mutations.^2–4 Nonetheless, the development of resistance to these medications poses a formidable clinical and scientific challenge.^5–8 The predominant mechanism of resistance to first- and second-generation EGFR-TKIs is the acquisition of the EGFR T790M mutation. Despite the promising preclinical efficacy of second-generation TKIs in inhibiting T790M kinase activity, clinical data have revealed a rather limited effectiveness in patients with acquired resistance to first-generation TKIs.^9–11 Furthermore, while third-generation EGFR-TKIs demonstrate anti-tumor activity in patients who have progressed on previous EGFR-TKI treatment, the development of additional complex resistance mechanisms presents a considerable challenge, marked by a paucity of specific therapeutic options.^12,13

A substantial body of literature has explored the efficacy of immune checkpoint inhibitor (ICI) monotherapies and ICI-based combination regimens in patients with advanced EGFR-mutated NSCLC who had progressed on third-generation or earlier EGFR-TKIs.^14–27 However, these studies yielded inconsistent findings. For patients with actionable genomic alterations in the IMpower151 trial, the median PFS for ABCP arm (atezolizumab plus bevacizumab plus platinum-based doublet chemotherapy) was 8.5 months, compared to 8.3 months for BCP arm (bevacizumab plus platinum-based doublet chemotherapy) (hazard ratio (HR) 0.86, 95% credible interval [CI] 0.61–1.21), indicating no statistically significant difference.²⁸ In contrast, the IMpower150 study demonstrated a significant improvement of ABCP over BCP in PFS (HR 0.62, 95% CI 0.45–0.86).¹⁷ A recent published network meta-analysis²⁹ based on immunotherapy has confirmed the outstanding efficacy of ICI-antiangiogenic-chemotherapy combination strategy, which represents a new breakthrough in the treatment of NSCLC patients with EGFR-TKI resistance. Recently, bispecific antibodies (bsAbs)^30,31 and antibody-drug conjugates (ADCs)^27,32–34 have shown significant promise in the management of EGFR-TKI-resistant NSCLC, offering novel therapeutic avenues for patients refractory to targeted therapies.

This network meta-analysis and systematic review is conducted to address the inconclusive nature of subsequent treatment strategies for patients with advanced EGFR-mutated NSCLC who have progressed on EGFR-TKIs. Given that recent studies have highlighted the potential of bsAbs and ADCs, the objective is to comprehensively evaluate the comparative efficacy and safety of all existing treatment modalities, thereby furnishing a clinically relevant reference.

Methods

Eligibility criteria

Eligible studies encompassed phase II or phase III randomized controlled trials (RCTs) involving patients with histologically or cytologically confirmed advanced (stage III, IV, or recurrent) EGFR-mutated NSCLC who exhibited resistance to EGFR-TKIs. Patients were classified as resistant if their disease progressed on first/second-generation EGFR-TKIs with a verified negative T790M mutation status or if they progressed on first-line third-generation EGFR-TKIs. These studies also need report at least one efficacy or safety outcome of interest, such as progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events (AEs) of any-grade or severe-grade (grade higher than or equal to 3). Studies that did not meet these inclusion criteria were excluded, as were trials that assessed EGFR mutations as a subgroup without providing separate outcome statistics. The study protocol was registered as INPLASY202510014. All analyses were performed in strict adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.³⁵

Data sources and extraction

Digital databases, including PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov, were comprehensively searched to identify potential clinical trials. Additionally, we reviewed presentations and abstracts from major international conferences held between January 1, 2020, and June 1, 2025, as well as reference lists of relevant reviews to avoid omission. The detailed search strategy is provided in Table S2.

Data extracted encompassed study information (phase, registered ID, publication year, and sample size per arm), demographic characteristics (sex, age, ethnicity, and smoking status), treatment arms, and outcomes (HRs with corresponding 95% CIs) for PFS and OS, as well as the number of individuals with objective response, and any-grade or severe-grade AEs). The literature search and data extraction were completed by two independent reviewers (Y.Y.C. and Y.J.D.), with any discrepancies resolved through consultation with a senior investigator (H.H.D.)

Risk of bias assessment

The Cochrane risk of bias tool for RCTs³⁶ was utilized to evaluate the risk of bias across included trials based on a comprehensive assessment of the randomization process and masking, deviations from intended interventions, missing outcome data, outcome measurement, and selectively reported outcomes.

Statistical analysis

We performed the data analysis using R software (version 4.4.2). PFS was designated as the primary outcome, with secondary outcomes encompassing OS, ORR, any-grade AEs, and severe-grade AEs. Summary estimate statistics were reported as HRs for survival endpoints (PFS and OS) or odds ratios (ORs) for binary variables (ORR, any-grade AEs, and severe-grade AEs), accompanied by their 95% Cls. The Markov chain Monte Carlo simulation technique³⁷ was employed to conduct the network meta-analysis, enabling comparisons between any two therapeutic regimens in the included trials by concurrently synthesizing direct and indirect evidence. We opted for the Bayesian framework over the frequentist framework, considering its capability of integrating existing knowledge and managing uncertainty. The Bayesian approach^38,39 is particularly advantageous in dealing with sparse data, estimation bias, and over-confident conclusions, which are common in network meta-analyses. Sample iterations and number of burn-ins were properly adjusted for each endpoint. The shape of posterior distributions and Gelman-Rubin diagnostics were used for estimation of convergence.⁴⁰ The fixed-effect consistency model was employed, as all the direct evidence was derived from a single trial.³⁸ Treatment rankings were determined using the surface under the cumulative rank (SUCRA) value, which is based on probabilities of superiority and ranges from 0 (the most noneffective or unsafe treatment) to 1 (contrary to 0 value). Global inconsistency of network meta-analyses was assessed by comparing consistency with inconsistency models according to the suitability of model fit, while local inconsistency of direct and indirect results was judged by comparing estimates from network meta-analyses and pairwise meta-analyses. We further performed pairwise meta-analyses of treatment strategies containing immunotherapy for head-to-head comparisons involving at least two trials. Heterogeneity was evaluated based on the I² statistics and Q-test,^41,42 with the fixed-effect model being adopted when statistical heterogeneity was inconsiderable (I² < 50% or Q-test p > 0.10); otherwise, a random-effects model was adopted.

Control for multiple testing

Given the multiple pairwise comparisons (k = 15) conducted in this network meta-analysis, a multiple testing correction was essential. We prioritized controlling the False Discovery Rate (FDR), the expected proportion of falsely rejected null hypotheses among all significant findings, using the Benjamini-Hochberg (BH) procedure. This approach is more powerful (i.e., less conservative) than controlling the family-wise error rate (e.g., with Bonferroni correction) when the number of comparisons is moderate or large, as it is more tolerant of identifying multiple true positive effects, which is a plausible scenario in this therapeutic context.⁴³ For completeness and transparency, we also applied the more stringent Bonferroni correction (significance level set at α = 0.05 / k). All active interventions compared against the common reference (chemotherapy) for the primary outcomes (PFS and OS) were subjected to these corrections. Results are presented with unadjusted, BH-adjusted, and Bonferroni-adjusted p-values to allow for a comprehensive and nuanced interpretation.

Assessment of certainty of evidence (GRADE)

The certainty of evidence for the findings from the network meta-analysis (NMA) was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework for NMA.⁴⁴ Given the large number of interventions in the network, which would theoretically yield a vast number of pairwise comparisons (n = 100 pairs), performing a full GRADE evaluation for all comparisons was deemed neither feasible nor likely to yield interpretable information for clinicians. Therefore, a focused, pragmatic strategy was employed to prioritize the most clinically relevant comparisons for formal GRADE assessment.

On the one hand, evidence profiles (Summary of Findings tables) were created for the comparison of every active intervention regimen against the common comparator (chemotherapy). On the other hand, the top three ranking interventions were selected based on the surface under the cumulative ranking curve (SUCRA) values for PFS and OS. All pairwise comparisons between these top-ranked regimens were evaluated. For all other pairwise comparisons not included in the lists, effect estimates are available in the league table provided, while not undergoing formal GRADE rating. It should be noted that almost all these comparisons are based solely on indirect evidence, affecting their certainty.

Results

A literature retrieval of databases yielded 4396 records, from which 19 RCTs ultimately fulfilled the inclusion criteria, with no additional studies from conference proceedings included. The study selection process is shown in the PRISMA flowchart (Figure 1).

Figure 1.

PRISMA flow chart of study selection process.

Characteristics of included trials and risk of bias assessment

These RCTs encompassed a total of 4039 patients harboring EGFR mutations and evaluated distinct therapeutic regimens containing the innovative bsAb and ADC, among which 10 immunotherapy-based treatment strategies were assessed. The distribution of women and never smokers was generally balanced across the different treatment groups, as per the reported baseline characteristics (Table 1). Among the trials included, 15 RCTs were deemed high risk of bias, primarily attributed to inadequate blinding control arising from open-label study designs (Figure S1). A total of 19 randomized controlled trials were incorporated into the overall network meta-analysis, with 16 trials, respectively, providing statistics on PFS and OS, along with 14 trials reporting outcomes of ORR and 10 trials reporting toxicity outcomes (Figure S2). Details of analysis models are shown in Table S3.

Table 1.

Characteristics of included trials.

Female (%)	Never smoker(%)	Asian(%)	Intervention arm(s) [category]	Comparator arm(s) [category]	Reported Outcomes
Median age (year)	Never smoker(%)	Asian(%)	Intervention arm(s) [category]	Comparator arm(s) [category]	Reported Outcomes
63/60 64/64	64/63	60/61	Patritumab Deruxtecan (HER3-DXd)	Platinum-based chemotherapy [chemo]	PFS, OS, ORR, Any-grade and severe-grade AEs
58/52 57/55	53/65	100/100	Sacituzumab tirumotecan (Sac-TMT)	Docetaxel [chemo]	PFS, OS, ORR, Any-grade and severe-grade AEs
64/62/60 61/62/62	67/69/64	50/51/48	Amivantamab + lazertinib + carboplatin-pemetrexed Amivantamab + carboplatin-pemetrexed	Carboplatin-pemetrexed [chemo]	PFS, OS, ORR, Any-grade and severe-grade AEs
39/31* 63/64*	20/17*	38/39*	Datopotamab deruxtecan (Dato-DXd)	Docetaxel [chemo]	PFS, OS, ORR
52/51 60/59	70/71	100/100	Ivonescimab + carboplatin-pemetrexed [ICI-antiangio-chemo]	Carboplatin-pemetrexed [chemo]	PFS, OS, ORR, Any-grade and severe-grade AEs
58/63 64/61	61/63	94/93	Nivolumab + cisplatin/carboplatin-pemetrexed [ICI-chemo]	Cisplatin/carboplatin-pemetrexed [chemo]	PFS, OS, ORR, Any-grade and severe-grade AEs
62/61 62/64	66/66	61/61	Pembrolizumab + cisplatin/carboplatin-pemetrexed [ICI-chemo]	Cisplatin/carboplatin-pemetrexed [chemo]	PFS, OS, ORR, Any-grade and severe-grade AEs
59/59/60 59/58/56	70/69/71	100/100/100	Sintilimab + IBI-305 + cisplatin-pemetrexed [ICI-antiangio-chemo] Sintilimab + cisplatin-pemetrexed [ICI-chemo]	Cisplatin-pemetrexed [chemo]	PFS, OS, ORR, Any-grade and severe-grade AEs
57/54* 63/61*	63/62*	100/100*	Atezolizumab + bevacizumab + carboplatin-paclitaxel (ABCP) [ICI-antiangio-chemo]	Carboplatin/cisplatin-pemetrexed [chemo]	PFS, OS, ORR, Any-grade and severe-grade AEs
41/41* 61/61*	54/49*	100/100*	Atezolizumab + bevacizumab + carboplatin-pemetrexed/paclitaxel (ABCP) [ICI-antiangio-chemo]	Bevacizumab + carboplatin-pemetrexed/paclitaxel (BCP)	PFS
30/31* 69/70*	19/23*	100/100*	Nivolumab + docetaxel [ICI-chemo]	Nivolumab [ICI]	PFS, OS, ORR
54/62 71/67	56/56	100/100	Nivolumab [ICI]	Carboplatin-pemetrexed [chemo]	PFS, OS, ORR, Any-grade and severe-grade AEs
47/62/55 64/63/62	59/64/46	35/44/41	Aatezolizumab + bevacizumab + carboplatin-paclitaxel (ABCP) [ICI-antiangio-chemo] Atezolizumab + carboplatin-paclitaxel (ACP) [ICI-chemo]	Bevacizumab + carboplatin-paclitaxel (BCP)	PFS, OS, ORR, Any-grade and severe-grade AEs
50/27 59/71	81/80	100/100	Nivolumab + ipilimumab [ICI]	Nivolumab [ICI]	ORR
52/66* 50/62*	43/45*	0/0*	Pembrolizumab + docetaxel [ICI-chemo]	Docetaxel [chemo]	PFS, OS, ORR
39/39* 63/64*	20/17*	20/22*	Atezolizumab [ICI]	Docetaxel [chemo]	OS
38/39* 63/62*	18/20*	21/21*	Pembrolizumab [ICI]	Docetaxel [chemo]	PFS, OS
35/47* 62/62*	19/20*	0/0*	Atezolizumab [ICI]	Docetaxel [chemo]	OS
48/42* 61/64*	20/21*	3/3*	Nivolumab [ICI]	Docetaxel [chemo]	PFS, OS

Data for all patients, including those without EGFR mutations.

AE, adverse events; Chemo, chemotherapy; ICI, immune checkpoint inhibitor; ICI-antiangio-chemo, ICI plus antiangiogenesis plus chemotherapy; ICI-chemo, ICI plus chemotherapy; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

We have created Summary of Findings tables (Supplemental Material 2) using the GRADEpro GDT software for efficacy outcomes (PFS and OS). These tables present the estimated effects alongside their corresponding certainty ratings (High, Moderate, Low, or Very Low) for all key comparisons.

Assessment of efficacy

Sacituzumab tirumotecan (Sac-TMT) demonstrated the most favorable PFS profile among all treatments, with a SUCRA value of 0.997 (Figure S3). It exhibited statistically significant superiority over nearly all comparator regimens except for Datopotamab deruxtecan (Dato-Dxd), where no significant difference was observed. Dato-Dxd also showed substantial PFS benefits (Figure S3), with significant advantages over atezolizumab plus carboplatin-pemetrexed/docetaxel (ACP; HR 0.27, 95% CI 0.12–0.62), bevacizumab plus carboplatin-pemetrexed/docetaxel (BCP; HR 0.43, 95% CI 0.21–0.86), chemotherapy (HR 0.35, 95% CI 0.21–0.59), nivolumab with (HR 0.20, 95% CI, 0.11–0.36) or without chemotherapy (HR 0.49, 95% CI 0.27–0.88), pembrolizumab with (HR 0.20, 95% CI 0.09–0.45) or without chemotherapy (HR 0.44, 95% CI 0.25–0.77), and sintilimab plus chemotherapy (HR 0.49, 95% CI 0.27–0.88). However, the improvements of Dato-Dxd over the two ICI-antiangio-chemo strategies, ABCP (HR 0.58, 95% CI 0.31–1.09) and sintilimab-IBI305-chemotherapy (HR 0.69, 95% CI 0.38–1.24), were of no statistical significance (Figure 2). Additionally, amivantamb-lazertinib-chemotherapy (SUCRA = 0.864), along with ivonescimab-chemotherapy (SUCRA=0.823), demonstrated promising PFS benefits (Figure S3), with efficacy comparable to Dato-Dxd. In contrast, patritumab deruxtecan (HER3-DXd) lagged behind Sac-TMT (HR 3.85, 95% CI 2.43–6.09), Dato-DXd (HR 2.20, 95% CI 1.26–3.87), amivantamab plus chemotherapy with (HR 1.75, 95% CI 1.29–2.39) or without lazertinib (HR 1.61, 95% CI 1.13–2.28), ivonescimab-chemotherapy (HR 1.68, 95% CI 1.17–2.41), and sintilimab-IBI305-chemotherapy (HR 1.51, 95% CI 1.08–2.11).

Figure 2.

League tables of efficacy and safety comparisons in network meta-analysis. Data are pooled HR (95% credible interval) for A-B and OR (95% credible interval) for C-E. Bold data indicate a significant difference. (a) Progression-free survival (green), (b) Overall survival, (c) Objective response rate, (d) Any-grade adverse events, (e) Severe-grade adverse events.

Sac-TMT demonstrated the highest probability of superior OS (SUCRA = 0.946), followed by Dato-DXd (SUCRA = 0.790) and amivantamab plus chemotherapy (SUCRA=0.629) (Figure S3). Statistically significant benefits in OS was observed for Sac-TMT versus amivantamab plus chemotherapy with (HR 0.38, 95% CI 0.16–0.87) or without lazertinib (HR 0.47, 95% CI 0.23–0.95), Sac-TMT versus chemotherapy (HR 0.36, 95% CI 0.20–0.66), Sac-TMT versus nivolumab alone (HR 0.40, 95% CI 0.18–0.86) or combing chemotherapy (HR 0.44, 95% CI 0.23–0.86), Sac-TMT versus HER3-DXd (HR 0.37, 95% CI 0.19–0.70), Sac-TMT versus pembrolizumab-chemotherapy (HR 0.43, 95% CI 0.23–0.81), and Sac-TMT versus sintilimab-IBI305-chemotherapy (HR 0.37, 95% CI 0.19–0.72). Dato-Dxd also showed significant advantages over chemotherapy (HR 0.65, 95% CI 0.56–0.75), pembrolizumab-chemotherapy (HR 0.77, 95% CI 0.60–0.99), and sintilimab-IBI305-chemotherapy (HR 0.66, 95% CI 0.47–0.93) (Figure 2). No statistically significant differences were observed among the other comparable treatment strategies. Dato-Dxd, amivantamab plus chemotherapy, and the combination of nivolumab and ipilimuab excelled in increasing the ORR (Figure S3).

The primary findings for PFS and OS remain significant not only under the conventional threshold but also after FDR correction. Tables S7 and S8 provide complete results for all comparisons, including hazard ratios, 95% confidence intervals, and both unadjusted, Bonferroni-adjusted, and FDR-adjusted p-values for PFS and OS, respectively.

Assessment of safety

The ABCP regimen demonstrated a significantly higher risk of any-grade AEs compared to chemotherapy, nivolumab, nivolumab-chemotherapy, pembrolizumab-chemotherapy, and sintilimab-chemotherapy. Notably, the amivantamab-lazertinib-chemotherapy combination was associated with the most substantial risk of both any-grade AEs and severe-grade AEs among all treatments, as reflected by SUCRA rankings and comparative results. Sintilimab-chemotherapy, nivolumab, and chemotherapy alone were at the forefront in reducing severe toxic events (Figure S3). Encouragingly, Sac-TMT exhibited a moderate risk of any-grade AEs and a favorable low-risk profile for severe-grade AEs (Figure S3).

Comparisons within immunotherapy-based strategies

In the pairwise meta-analysis of survival outcomes, comparisons were made between ICI versus chemotherapy, ICI plus chemotherapy (ICI-chemo) versus chemotherapy, along with ICI plus anti-angiogenesis agents and chemotherapy (ICI-antiangio-chemo) versus chemotherapy (Figure S4). ICI-antiangio-chemo was superior to chemotherapy in prolonging PFS (HR 0.51, 95% CI 0.43–0.61, I² = 0%) with no significant improvements in OS (HR 0.98, 95% CI 0.72–1.33, I² = 0%). ICI-chemo also showed promising improvements in PFS (HR 0.76, 95% CI 0.66–0.88, I² = 0%) and OS (HR 0.84, 95% CI 0.71–0.98, I² = 0%). However, ICI monotherapy appeared to be inferior to chemotherapy in terms of PFS (HR 1.72, 95% CI 1.30–2.29, I² = 0%).

A dedicated series of network meta-analyses was conducted among immunotherapy-based treatment strategies, composed of three different categories of strategies within the 15 RCTs included: ICI-antiangio-chemo, ICI-chemo, and ICI (Table 1). Ivonescimab (AK112/SMT112), a humanized tetravalent bispecific antibody, was categorized into the ICI-antiangio-chemo group for its great binding affinity to both PD-1 and VEGF.²¹ Both efficacy and safety endpoints were rigorously evaluated. The ivonescimab-chemotherapy combination emerged as the top strategy for prolonging PFS, with a SUCRA value of 0.952, followed by sintilimab-IBI305-chemotherapy (SUCRA = 0.898) and the ABCP regimen (SUCRA = 0.784) (Figure S5). No substantial differences in OS outcomes were identified among the treatment strategies (Figure S6). Furthermore, combination therapies including nivolumab-ipilimumab (SUCRA = 0.914), the ABCP regimen (SUCRA = 0.877), and sintilimab-IBI305-chemotherapy (SUCRA = 0.790) demonstrated the capacity to enhance tumor response (Figure S5). In contrast, nivolumab monotherapy did not appear to be a favorable option for ORR (SUCRA = 0.010). Considering toxicity, ACP (SUCRA = 0.951) and sintilimab-chemotherapy (SUCRA = 0.927), respectively, outperformed other therapeutic regimens in reducing the incidence of any-grade and severe-grade adverse events, respectively (Figure S5).

Discussion

This meta-analysis provides a comprehensive evaluation of the efficacy and safety of available treatment strategies for advanced NSCLC patients following progression on EGFR-TKIs, incorporating novel therapeutic agents, ICI monotherapy, and ICI-based combination regimens. Key findings from our pooled analyses suggest that recent innovations in lung cancer treatment confer clinically meaningful improvements in both PFS and OS, particularly Sac-TMT, Dato-DXd, ivonescimab, and amivantamab. While these novel agents did not show significant superiority over ICI-antiangio-chemo combinations, their therapeutic potential remains noteworthy. Sac-TMT emerged as a particularly promising option with optimal efficacy alongside a favorable safety profile, a critical consideration for treatment selection. Amivantamab-lazertinib-chemotherapy, while efficacious, was associated with the highest incidence of grade ⩾ 3 AEs, necessitating careful risk-benefit assessment. The addition of antiangiogenic therapy and chemotherapy to ICI monotherapy achieved the most substantial survival benefits in survival outcomes amongst all comparable immunotherapy-based strategies. Notably, each ICI-based regimen, whether monotherapy or combination, demonstrated distinct therapeutic advantages, highlighting the importance of personalized treatment selection based on efficacy priorities and safety tolerability.

Multitarget antitumor therapeutic agents, such as ADCs and bsAbs, are emerging as a significant advancement in the field of precise cancer treatment.^45,46 ADCs are sophisticated engineered to deliver a cytotoxic payload via a linker attached to a specific monoclonal antibody that homes in on a tumor-associated antigen. Upon antigen binding, the ADC is internalized into the cancer cell, triggering linker degradation and the subsequent release of the cytotoxic payload. This precise delivery mechanism enables the payload to exert its anti-tumor effects selectively within the cancer cells, thereby maximizing anti-tumor activity and minimizing damage to surrounding healthy tissues.^47–49 Recent studies have highlighted the potential applicability of ADCs targeting HER2, HER3, and TROP-2 in NSCLC patients.^32,50,51 Elevated HER3 is prevalent in EGFR-mutated NSCLC,⁵² and the overexpression of these two genes contributes to aberrantly activated downstream signaling pathways associated with tumorigenesis and tumor progression.⁵³ ADC targeted at both EGFR and HER3 has been reported to be effective in tumors harboring various genomic alterations linked to EGFR-TKI resistance.⁵⁴ Trop-2 is another highly-expressed gene identified in NSCLC, making it a suitable target for efficacious and safe payload delivery.³⁴ Encouraging improvements in tumor response and survival extension, along with acceptable toxicity, has been observed in sacituzumab tirumotecan (SKB264/sac-TMT) and sacituzumab govitecan (IMMU-132/SG), two novel ADCs targeted at Trop-2.^55,56 The exceptional performance of ADCs in EGFR-TKI-resistant NSCLC will be further validated in future phase III RCTs where prognostic biomarker can be explored.

Simultaneous blocking of at least two receptors or pathways involved in tumor development potentially inhibits tumor progression more comprehensively and lessens the risk of drug resistance. BsAbs represent another category of multitarget drugs that have emerged in recent years, capable of enhancing efficacy and mitigating toxic events compared to traditional drug combinations.⁵⁷ Different types of bsAbs exhibit distinct mechanisms of action, such as immune cell engagement, payload delivery, and signal blockade.⁵⁸ Ivonescimab is a novel tetravalent anti-PD-1/VEGF bispecific antibody that displays unique cooperative binding to each of its intended targets, resulting in increased in vitro functional bioactivities compared to bevacizumab or PD-1 inhibitors alone.⁵⁹ Its core mechanism of action is primarily reflected in its dual targeting effect and the synergistic combining effect, which achieve a more significant toxicity reduction and efficacy enhancement through its unique tetravalent structure, thus demonstrating outstanding efficacy in the field of treatment after EGFR-TKI resistance. Amivantamab is a fully humanized bsAb designed to target EGFR mutations and MET mutations or amplifications, which are pivotal genomic alterations associated with EGFR-TKI resistance.⁶⁰ It functions by blocking ligand binding to both EGFR and MET, thereby inhibiting downstream signaling pathways and effectively suppressing tumor cell growth and metastasis.^58,61–63 Notably, amivantamab has demonstrated antitumor activity against a spectrum of activating and resistant EGFR mutations, positioning it as a potentially valuable therapeutic option for patients resistant to EGFR-TKIs.⁶⁴ With the modification of the agent structure to increase tumor selectivity and optimize target selection, the efficacy and safety will be further improved.⁶⁵

As per the current guidelines, patients harboring EGFR mutations should receive EGFR-TKI as the standardized first-line treatment, and subsequent treatment after progression is guided by molecular profiling. Patients who are T790M positive are recommended to go on with next-generation TKI, while those T790M-negative patients require alternative strategies, a key focus of this study. It is strongly recommended that patients undergo next-generation sequencing (NGS) following first-line treatment failure to identify actionable targets. However, unlike PD-L1 expression and tumor mutation burden (TMB) for ICIs, predictive biomarkers for ADCs and bsAbs remain limited. Recent preclinical evidence suggests that elevated PD-L1 expression in tumor and immune cells, along with increased density of tumor-infiltrating lymphocytes within the tumor immune microenvironment following acquired resistance to conventional EGFR-TKIs,^66–68 may serve as potential biomarkers. Other candidate biomarkers for ADC efficacy include expression levels of synergistic targets, normalized membrane ratio (NMR), and so on. Unfortunately, biomarker exploration in this context remains constrained by limited statistics. Further translational studies and prospective clinical trials are urgently needed to validate and identify robust predictive biomarkers.

Beyond efficacy outcomes, toxicity profiles represent a critical determinant in optimizing therapeutic strategies for advanced NSCLC. Based on the outcomes released on ASCO 2025, the rates of any-grade AEs of Sac-TMT were similar to those of chemotherapy and patients receiving Sac-TMT were less likely to develop grade ⩾ 3 AEs. With hematological toxicity being the most common event, drug-related interstitial lung disease (ILD) cases were notably absent in the Sac-TMT group. Meanwhile, according to the pooled results of TROPION-Lung01 and TROPION-Lung05 disclosed at ESMO Asia 2024,⁶⁹ the incidence of grade ⩾3 treatment-related adverse events (TRAEs) and events leading to discontinuation arising from Dato-Dxd treatment was low. No grade 4–5 drug-related ILD was reported during the study, nor were there any treatment-related mortality.^50,56,69 In parallel, our network meta-analyses indicated that the risk of any-grade and severe-grade AEs was relatively higher with amivantamab-chemotherapy, amivantamab-lazertinib-chemotherapy, and ABCP combinations, despite that they ranked among the top in terms of efficacy. Fortunately, toxicities reported were manageable with proper supportive care.^21,31,50 Clinicians should better strike a balance between efficacy and safety when determining treatment strategies to optimize clinical outcomes.

The majority of patients will receive platinum-based chemotherapy with or without an immune checkpoint inhibitor (ICI) and antiangiogenic therapy following disease progression on EGFR-TKI.^16,70 The subgroup analysis primarily concentrated on the clinical efficacy and safety of immunotherapy-based treatment regimens, where ICI-antiangio-chemo demonstrated a favorable HR for PFS compared with other therapeutic strategies, possibly due to several potential mechanisms. ICIs, exemplified by anti-PD-1/PD-L1 and anti-CTLA-4 monoclonal antibodies, restore immune cell functions, aiding the body’s “ecological environment” in regaining balance.^71–73 Furthermore, chemotherapy not only directly eliminates tumor cells but also positively modulates the immune system, altering the local tumor microenvironment. Hopefully, the combination of chemotherapy with immunotherapy can enhance the efficacy of immunotherapy and mitigate immune-related toxicity as well.^74,75 Both anti-angiogenic therapies and immunotherapy target the tumor microenvironment, and mounting evidence^76,77 suggests that these two approaches can interact functionally, exhibiting potential synergistic anti-tumor effects.

Strengths and limitations

To the best of our knowledge, this study represents the first comprehensive comparison between contemporary treatment regimens, ICI-based combination therapies, and traditional chemotherapy in the context of advanced EGFR-mutated NSCLC patients who have progressed on EGFR-TKIs. Our findings corroborate previous studies that underscore the synergistic benefits of ICI-based combination therapies, especially the combination of ICI, antiangiogenetic agent and chemotherapy.^29,78,79 Notably, we excluded retrospective studies, single-arm studies and non-randomized controlled trials, focusing solely on phase II and phase III RCTs, which provided a higher hierarchy of evidence and enabled us to draw reliable conclusions. Moreover, previous meta-analyses typically compared the pooled results of each category of treatment strategies. We performed a dedicated network meta-analysis of all currently available regimens and found that while ABCP, along with sintilimab-IBI305-chemotherapy, stood out in improving PFS, other ICI monotherapy or ICI-chemo strategies were relatively safer. Additionally, we included up-to-date statistics, and the promising survival improvements observed with bsAbs and ADCs answered the question whether the innovative therapeutic agents outperform traditional treatment,⁸⁰ thus offering a compelling rationale for their use in NSCLC patients with EGFR-TKI resistance. The application of multiplicity corrections has rendered several initial findings non-significant, particularly under the conservative Bonferroni approach. Our conclusions are therefore weighted toward findings that remain robust after FDR correction, which provides a more balanced approach between type I and type II errors in this exploratory context. This conservative interpretation enhances the validity of our remaining significant findings.

However, it is imperative to acknowledge the limitations inherent in this meta-analysis. First of all, the analysis of patients resistant to EGFR-TKIs as a subgroup in some of the included trials^14,15,18,20 resulted in a relatively low number of participants for certain treatment strategies, potentially compromising the robustness of our results. Secondly, the comparator was not consistently applied, as some trials utilized platinum-based doublet chemotherapy while others employed docetaxel monotherapy. Acknowledging the potential difference between regimens, we added a granular analysis by separating docetaxel monotherapy from platinum-based doublet chemotherapy and presented the results in Figures S8 and S9, which suggest an insignificant difference between platinum-doublet and docetaxel alone. In light of these findings and in alignment with a recently published high-profile network meta-analysis,²⁹ we ultimately combined these chemotherapy regimens into a common control group for the primary analysis. Nonetheless, we acknowledge that further investigation through prospective head-to-head clinical trials directly comparing these chemotherapy backbones is warranted to provide more definitive guidance tailored to specific patient scenarios. Third, the survival outcomes were deemed immature due to the limited duration of follow-up, suggesting that the results may need to be updated. Thus, the potential superiority of ADCs in extending OS should be interpreted with caution and awaits validation through longer-term follow-up and updated survival analyses. The correlation between PFS extension and OS benefit needs to be substantiated in future studies. Moreover, variations in the number and types of prior treatment regimens among the enrolled patients across trials, coupled with limited available data, impeded stratified subgroup analysis. More detailed investigations in future studies are warranted. Lastly, the accessibility of efficacy data for novel therapeutic agents such as bsAbs and ADCs was constrained, and the vast majority of comparisons between the novel intervention regimens are not informed by direct evidence but are derived from indirect comparisons via the NMA. Many statistically significant findings also come from single trials. Only five of the included RCTs reported clinical outcomes for these emerging therapies, as the majority of research on bsAbs and ADCs consisted of single-arm or cohort studies reporting survival benefits. This substantially limits the confidence in these relative effect estimates; they should be interpreted cautiously as exploratory and hypothesis-generating for future clinical trials rather than definitive conclusions. There is an urgent need for future well-designed, adequately powered, head-to-head randomized controlled trials to directly compare these novel combination regimens to validate these findings and provide high-certainty evidence to inform clinical practice guidelines.

Conclusion

The management of individuals exhibiting resistance to EGFR-TKIs poses a significant challenge in clinical practice. Such resistance complicates treatment protocols and necessitates a comprehensive understanding of underlying molecular mechanisms, as well as the exploration of alternative therapeutic strategies to improve patient outcomes. The study indicated that Sac-TMT, Dato-Dxd, and bsAbs-based regimens represent the most efficacious treatment options for patients with advanced NSCLC who have progressed after EGFR-TKIs. The reported adverse events were manageable with appropriate supportive care. Clinicians are encouraged to conduct a thorough evaluation of the efficacy and safety profiles associated with various treatment strategies aimed at optimizing clinical outcomes for NSCLC patients with EGFR-TKI resistance. Our findings underscore the pivotal role of innovative therapeutic agents, illuminating potential treatment avenues for this difficult-to-treat refractory population.

Supplemental Material

sj-doc-1-tam-10.1177_17588359251405044 – Supplemental material for Antibody-drug conjugates outperform chemotherapy in EGFR-TKI-resistant NSCLC: a Bayesian network meta-analysis

Supplemental material, sj-doc-1-tam-10.1177_17588359251405044 for Antibody-drug conjugates outperform chemotherapy in EGFR-TKI-resistant NSCLC: a Bayesian network meta-analysis by Yueying Chen, Yanjun Du, Juan Ni, Dong Wang, Ping Zhan, Yong Song, Hedong Han and Tangfeng Lv in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-docx-2-tam-10.1177_17588359251405044 – Supplemental material for Antibody-drug conjugates outperform chemotherapy in EGFR-TKI-resistant NSCLC: a Bayesian network meta-analysis

Supplemental material, sj-docx-2-tam-10.1177_17588359251405044 for Antibody-drug conjugates outperform chemotherapy in EGFR-TKI-resistant NSCLC: a Bayesian network meta-analysis by Yueying Chen, Yanjun Du, Juan Ni, Dong Wang, Ping Zhan, Yong Song, Hedong Han and Tangfeng Lv in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Yueying Chen

Dong Wang

Ping Zhan

Tangfeng Lv

Supplemental material

Supplemental material for this article is available online.

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