Dacomitinib for EGFR-L858R-mutated non-small cell lung cancer following acquired resistance to third-generation EGFR-TKIs: a retrospective real-world study

Introduction

Globally, lung cancer remains the leading cause of cancer-related mortality and ranks as the second most commonly diagnosed malignancy (1). Non-small cell lung cancer (NSCLC) is the most common histological subtype of lung cancer, accounting for about 85% of all patients (2). Epidermal growth factor receptor (EGFR) is one of the most common mutations in NSCLC, accounting for about 50% of cases. Notably, within this subset, 85–90% of mutations comprise deletions in exon 19 (19del) and the p.L858R point mutation in exon 21 (21-L858R), collectively termed common EGFR mutations (3,4). Patients harboring the EGFR 21-L858R mutation exhibit a distinct molecular profile compared to those with the EGFR 19del mutation. This profile is characterized by a higher frequency of concurrent genetic alterations (5) and an elevated tumor mutation burden (TMB) (6), both of which significantly compromise clinical prognosis. Currently, tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for patients with locally advanced or metastatic NSCLC harboring EGFR mutations (7). Third-generation EGFR-TKIs, such as osimertinib, effectively inhibit the prevalent EGFR-activating mutations (exon 19 deletion or L858R) as well as the T790M mutation, thereby extending patient survival after the first or second generation of EGFR-TKI resistance (8,9). Third-generation EGFR-TKIs are initially effective in the treatment of NSCLC with an initial response rate of 80% and a median progression-free survival (mPFS) of 19 months, but patients eventually develop drug resistance (10,11). Drug resistance drives disease progression (PD), severely limits subsequent treatment options, and significantly shortens survival duration. Currently, the late treatment options for patients with third-generation EGFR-TKIs resistance are extremely limited and uncertain, and systematic and efficient coping strategies are urgently needed. In long-term clinical practice, we have observed that the second-generation irreversible EGFR-TKI dacomitinib may have significant efficacy in these patients, but its efficacy and safety in later-line treatment have not been systematically studied and verified. Although the subgroup analysis of the ARCHER 1050 trial showed that dacomitinib could significantly prolong PFS and overall survival (OS) in patients with 21-L858R mutation in first-line treatment (12-14), the drug failed to reach the main research endpoint in later-line treatment (such as ARCHER 1009, ARCHER 1028 and BR.26 studies) (15-17). It is worth noting that these studies did not specifically analyze patients with third-generation EGFR-TKI resistance, and lacked real-world evidence to support the application value of dacomitinib in such populations.

More than 30% of NSCLC patients with EGFR mutations develop brain metastases (18,19). The premise of successful treatment of brain metastases is that the drug needs to effectively penetrate the blood-brain barrier (BBB). The permeability of BBB is regulated by multiple factors, including the affinity of drugs to ATP-binding cassette efflux transporters [such as permeable glycoprotein P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)]-these transporters are involved in the clearance of endotoxin, drugs and chemotherapeutic agents in the central nervous system (CNS) (20,21). It is worth noting that traditional chemotherapeutic drugs and macromolecular monoclonal antibodies are generally difficult to cross the BBB (22,23). Dacomitinib is significantly superior to other EGFR-TKIs in brain tissue distribution characteristics: its brain-blood distribution coefficient reached 0.612, which is much higher than that of gefitinib (0.0358) and afatinib (0.254) (24). The key mechanism is that dacomitinib is not a pharmacological substrate for P-gp/ABCB1 or BCRP/ABCG2, and drugs such as gefitinib and erlotinib are used as such transporter substrates, which are actively effluxed to the blood circulation at the BBB (25). Due to the extremely low proportion of patients with brain metastases (only about 2%) included in previous dacomitinib prospective studies (16), and active or untreated brain metastases are often listed as exclusion criteria for EGFR-TKI trials, clinical evidence on the efficacy of dacomitinib in the treatment of CNS metastases is significantly limited.

Based on real-world clinical practice, this study systematically evaluated the efficacy and safety of dacomitinib in patients with EGFR-sensitive mutations (21-L858R mutation) who developed acquired resistance to third-generation EGFR-TKIs. The results will provide an important reference for clinical practice and provide a new treatment option, but it still needs to be further verified by large sample prospective clinical trials. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0153/rc).

Methods

Patients

From November 2020 to March 2024, consecutive patients with advanced EGFR exon 21 L858R-mutated NSCLC who developed acquired resistance to third-generation EGFR-TKIs and subsequently received dacomitinib at Shandong Cancer Hospital were retrospectively enrolled in this study. During the study period, 389 patients at our center developed acquired resistance to third-generation EGFR-TKIs; of these, 42 patients who received dacomitinib were included in the present study, whereas the remaining 347 patients who did not receive dacomitinib were not included. The decision to administer dacomitinib was made according to routine clinical practice at the discretion of the treating physicians, taking into account the patient’s performance status, disease burden, prior treatment history, drug accessibility, and patient preference. Dacomitinib was initiated at either 45 or 30 mg once daily according to routine clinical practice. In cases of grade 3 or higher treatment-related adverse events (TRAEs), or persistent grade 2 adverse events lasting beyond one treatment cycle, dose reduction was permitted. Information on starting dose, dose reduction, reasons for dose modification, and treatment discontinuation due to toxicity was retrospectively collected from the medical records. Effectiveness assessment was performed every 6 weeks (±3 days). The inclusion criteria for patients included: (I) age ≥18 years; (II) histologically or cytologically confirmed advanced-stage (IIIB–IV) NSCLC, a genetic test that revealed EGFR mutations; (III) following resistance to third-generation EGFR-TKIs. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Shandong Cancer Hospital and Institute (No. SDTHEC2024001033). Informed consent was taken from all patients.

Data collection and follow-up

We collected baseline characteristics and clinical data of patients, including age, sex, smoking status, Eastern Cooperative Oncology Group performance status (ECOG PS), tumor stage, number and type of previous treatment regimens, number of metastatic organs, major metastatic sites (including brain, bone, and liver metastases), survival status, and subsequent treatments received after dacomitinib discontinuation or PD. ECOG PS was assessed at the initiation of dacomitinib treatment and recorded as the baseline performance status for analysis. According to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, patients had at least one evaluable lesion. Patients were followed up via electronic medical records and telephone calls until March 31, 2025, with survival time calculated in months.

Study endpoints

Extracranial tumor response and progression were evaluated according to the RECIST v1.1, while intracranial tumor response and progression were assessed using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. All imaging examinations are independently reviewed and assessed by two experienced physicians; in the event of a discrepancy in the assessment, a senior physician will conduct a further review and make the final determination.

Tumor imaging was systematically evaluated at 2–3 months intervals throughout the treatment period. Treatment response was categorized into complete remission (CR), partial remission (PR), stable disease (SD), and PD. Overall response rate (ORR) represented the percentage of patients achieving complete or PR across any metastatic sites, including brain and extracranial lesions. Disease control rate (DCR) was defined as the proportion of patients demonstrating CR, PR, or SD. Intracranial ORR and DCR were specifically calculated based on brain lesion assessments. Intracranial progression-free survival (iPFS) was measured from the initiation of dacomitinib treatment until intracranial lesion progression, patient death, or the final imaging date. Overall PFS commenced with dacomitinib treatment and concluded at the point of intracranial or extracranial progression, patient death, or the last imaging evaluation. OS was defined as the time from the first administration of dacomitinib to the last follow-up or death. TRAEs were evaluated and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Statistical analysis

Statistical analysis was conducted using SPSS 27.0 and GraphPad Prism 9.0 software. Measurement data were presented as mean ± standard deviation or median (Md), while categorical data were reported as case numbers. A univariate Cox proportional hazards model evaluated the correlation between various subgroups and OS/PFS, expressing results as hazard ratio (HR) with 95% confidence interval (CI). Statistical significance was defined as a bilateral P value <0.05.

Results

Study population and clinical characteristics

Totally, 42 EGFR-L858R-mutated NSCLC patients were included: 14 males (33.3%) and 28 females (66.7%), with a median age of 57 (range, 40–88). Baseline features are listed in Table 1. Five patients (11.9%) had a smoking history. Forty patients (95.2%) had adenocarcinoma. Patients with ECOG PS 0–1 and 2 accounted for 85.7% (36/42) and 14.3% (6/42), respectively; no patient had ECOG PS ≥3. ECOG PS was assessed at the initiation of dacomitinib treatment. Seventeen patients (40.5%) had documented acquired T790M mutation during prior EGFR-TKI treatment. Genetic testing at the time of progression on third-generation EGFR-TKIs was available in 30 of 42 patients (71.4%). Among these 30 patients, 14 (46.7%) had EGFR-dependent (on-target) resistance mechanisms, 3 (10.0%) had EGFR-independent (off-target) resistance mechanisms, and 13 (43.3%) had no identifiable candidate resistance mechanism. For the remaining 12 patients (28.6%), molecular testing information at progression could not be retrieved. Following resistance to third-generation EGFR-TKIs, patients continued with dacomitinib: 22 (52.4%) as third-line or below and 20 (47.6%) as fourth-line or beyond. Fifteen (35.7%) received 30 mg dacomitinib, while 27 (64.3%) received 45 mg. Thirty (71.4%) had resistance to first/second-generation TKIs, then developed resistance to third-generation TKIs. In terms of metastatic burden, 25 patients (59.5%) had metastases involving ≥3 organs. The major metastatic sites were brain, bone, and liver, which were present in 33 (78.6%), 20 (47.6%), and 5 (11.9%) patients, respectively. Among patients with brain metastases, 31 (73.8%) had parenchymal brain metastases and 7 (16.7%) had meningeal metastases.

Overall efficacy

The median follow-up period was 16.3 months (range, 3.0–35.0 months). Among the 42 patients harboring the 21-L858R mutation, efficacy evaluation showed 14 cases (33.3%) with PR (Table 2), 19 cases (45.2%) with SD, and 9 cases (21.4%) with PD, resulting in an overall ORR of 33.3% and a DCR of 78.6% (Figure 1). The mPFS was 5.7 months (95% CI: 4.4–6.9) and the median OS (mOS) was 26.5 months (95% CI: 15.2–37.8) (Figures 1,2). We conducted univariate and multivariate Cox regression analyses to explore subgroup-specific associations between prognostic factors and PFS/OS in advanced EGFR-mutant NSCLC patients treated with dacomitinib. Variables with P values less than 0.10 in the univariate analysis were included in the multivariate analysis. In univariate Cox analysis, ECOG PS, T790M mutation status, and the treatment line of dacomitinib were associated with PFS, with P values of <0.001, 0.04, and 0.09, respectively (Table 3). For OS, ECOG PS (P<0.001), T790M mutation (P=0.03), treatment line of dacomitinib (P=0.02), metastatic organs (P=0.08), and bone metastases (P=0.03) were associated with outcome (Table 3). In multivariate analysis, ECOG PS remained independently associated with both PFS (HR =0.010, 95% CI: 0.001–0.092, P<0.001) and OS (HR =0.003, 95% CI: 0.000–0.038, P<0.001). In the multivariate model for OS, the treatment line of dacomitinib also remained significant (HR =0.161, 95% CI: 0.033–0.781, P=0.02), whereas metastatic organ number (HR =0.164, 95% CI: 0.020–1.318, P=0.09) and T790M mutation status (HR =0.106, 95% CI: 0.009–1.253, P=0.07) showed borderline associations (Table S1).

Figure 1 Survival outcomes and treatment responses: (A) OS, (B) PFS, and (C) waterfall plot of non-CNS response. CI, confidence interval; CNS, central nervous system; OS, overall survival; PFS, progression-free survival.

Figure 2 Swimlane diagram: (A) OS; (B) PFS. OS, overall survival; PFS, progression-free survival.

Treatment following dacomitinib discontinuation or PD primarily includes chemotherapy regimens (such as pemetrexed/platinum-based, albumin-bound paclitaxel combined with carboplatin, or docetaxel), anti-angiogenic therapy (such as bevacizumab or anlotinib), other targeted therapies or EGFR-TKI re-treatment, local radiotherapy or pleural intervention, and participation in clinical trials. Therefore, the relatively prolonged OS observed in this study may at least partially be influenced by subsequent treatments after dacomitinib therapy.

Intracranial efficacy

Among 30 patients with measurable intracranial lesions, 8 patients (19.0%) achieved PR, 19 patients (45.2%) achieved SD, and 3 patients (7.1%) had PD (Figure 3). The intracranial ORR was 19.0%, and the DCR was 64.3%. The median iPFS was 12.9 months (95% CI: 8.7–17.1). The 12-month iPFS rate was 50.2% (95% CI: 33.5–75.4%), and the 18-month iPFS rate was 41.9% (95% CI: 24.4–71.9%) (Figure 3). A representative case further illustrated the potential clinical benefit of dacomitinib in symptom management. A 55-year-old male patient with lung adenocarcinoma harboring the EGFR 21-L858R mutation and brain metastases presented with chest wall traction pain. After initiation of dacomitinib at 45 mg once daily, his brain metastasis (BM)-related symptoms significantly improved by the first follow-up visit at 1 week, and brain MRI and chest CT performed at 8 weeks demonstrated marked shrinkage of metastatic lesions (Figure 4).

Figure 3 Intracranial efficacy outcomes: (A) intracranial PFS, and (B) waterfall plot of intracranial response. CI, confidence interval; PFS, progression-free survival.

Figure 4 Intracranial response to dacomitinib: comparison of brain MRI at baseline and after 8 weeks of treatment with dacomitinib 45 mg/day. MRI, magnetic resonance imaging.

Safety

In this study, TRAEs were observed in 92.9% (39/42) of patients and were predominantly grade 1–2 in severity (Table 4), with no grade 5 TRAEs reported. The overall incidence of grade ≥3 TRAEs was 14.3% (6/42), and no new unexpected safety signals were identified. Overall, 9 of 42 patients (21.4%) required dose reduction because of intolerable TRAEs. All dose reductions occurred in patients who started dacomitinib at 45 mg once daily, corresponding to a dose-reduction rate of 33.3% (9/27) in the 45 mg starting-dose group, whereas no dose reductions were observed in the 30 mg starting-dose group (0/15). The main reasons for dose modification were rash (3/9, 33.3%), diarrhea (3/9, 33.3%), and paronychia (2/9, 22.2%); one additional patient (1/9, 11.1%) underwent dose reduction because of persistent grade 2 interstitial lung disease. No patient permanently discontinued dacomitinib because of TRAEs, and all patients who underwent dose reduction were able to continue treatment thereafter.

Discussion

At present, chemotherapy combined with anti-angiogenic drugs or immunotherapy is recommended for patients who are resistant to TKI treatment and lack alternative targeted therapy (26-28). Nevertheless, the therapeutic outcomes remain suboptimal. Dacomitinib is a potent irreversible inhibitor that effectively targets all active kinase members within the ErbB family, specifically EGFR/HER1, HER2, and HER4 (29). Dacomitinib demonstrates superior in vitro sensitivity compared to gefitinib, erlotinib, afatinib, and osimertinib in cells with the EGFR 21-L858R mutation (30). While prior research has suggested dacomitinib’s potential efficacy for patients with EGFR 21-L858R mutation, compelling evidence remains scarce regarding its effectiveness and safety in advanced NSCLC exhibiting resistance to third-generation EGFR-TKIs.

Notably, patients harboring the 21-L858R mutation demonstrate reduced responsiveness to initial third-generation EGFR-TKI treatments. The FLAURA study substantiated this observation, confirming that while osimertinib can extend mPFS and mOS in 21-L858R mutation carriers, its therapeutic efficacy remains significantly inferior to 19del patients, with a mPFS of 14.4 versus 21.4 months (11). Secondly, the 21-L858R mutation induces conformational changes in the EGFR protein, which significantly diminishes EGFR-TKI binding affinity and accelerates drug resistance (31,32). Moreover, this mutation is linked to increased genomic complexity, frequently co-occurring with mutations in TP53, RB1, or PIK3CA (5,33,34). These co-mutations can further impair the efficacy of TKIs by activating alternative signaling pathways or inhibiting apoptosis. In summary, these unique molecular characteristics significantly increase the risk of resistance to third-generation TKIs in 21-L858R patients, highlighting the great challenges of post-drug resistance treatment in this group.

When interpreted in the context of previous reports of EGFR-TKI rechallenge or dacomitinib treatment after 3rd-generation TKIs resistance, the efficacy observed in our cohort appears numerically favorable. In the MSKCC phase II pilot study, Choudhury et al. reported an ORR of 17% and a median PFS of 1.8 months with dacomitinib after first-line osimertinib (35). In the Japanese multicenter retrospective TOPGAN2020-02 study, Tanaka et al. reported an ORR of 25.5%, a median PFS of 4.3 months, and a median OS of 10.5 months in patients receiving dacomitinib rechallenge (36). Notably, patients with EGFR exon 21 L858R achieved a longer median PFS than those with exon 19 deletion (5.8 vs. 4.1 months, P=0.02). Likewise, in a prospective exploratory study, Morimoto et al. showed limited efficacy of first- or second-generation EGFR-TKI rechallenge after osimertinib resistance, with an ORR of 6.9% and a median PFS of 1.9 months (37). By comparison, our study showed an ORR of 33.3% and a median PFS of 5.7 months, with a relatively prolonged median OS of 26.5 months. Several factors may partly explain these differences. First, our cohort consisted exclusively of patients with NSCLC harboring the EGFR exon 21 L858R mutation; in contrast, previous studies enrolled a more heterogeneous population of patients with EGFR mutations. The relatively favorable prognosis observed in the present study may, therefore, partially reflect the clinical heterogeneity existing among different mutational subtypes. In addition, all patients in our study received active subsequent treatment after dacomitinib progression, which may also have contributed to the relatively prolonged OS observed in our cohort. Therefore, cross-study comparisons should be interpreted with caution, given differences in mutation subtype, study population, metastatic burden, prior treatment history, and post-progression management. Future prospective studies are warranted to further clarify the factors associated with long-term survival in this setting.

With the continuous expansion of treatment options after osimertinib resistance, amivantamab-based regimens and antibody-drug conjugates (ADCs) have emerged as important therapeutic strategies in advanced EGFR-mutated NSCLC. In the phase III MARIPOSA-2 study, amivantamab plus chemotherapy improved PFS and iPFS versus chemotherapy after progression on osimertinib, and at the prespecified second interim OS analysis, the median OS was 17.7 months in the amivantamab plus chemotherapy group versus 15.3 months in the chemotherapy group (HR =0.73, 95% CI: 0.54–0.99; nominal P=0.04), although the final OS analysis has not yet been formally tested (38,39). In the CHRYSALIS-2 Cohort A study, amivantamab plus lazertinib after progression on osimertinib and platinum-based chemotherapy achieved a median OS of 14.8 months (40). Among ADCs, patritumab deruxtecan demonstrated a median OS of 11.9 months in HERTHENA-Lung01 (41), whereas sacituzumab tirumotecan in the phase III OptiTROP-Lung04 trial showed a significant OS benefit over chemotherapy, with median OS not reached versus 17.4 months, respectively (HR =0.60, 95% CI: 0.44–0.82; two-sided P=0.001) (42). Although these new drugs represent significant advances in treatment following osimertinib therapy, the median OS observed in our cohort was 26.5 months, suggesting that dacomitinib may still have clinical efficacy in some patients. In particular, it may remain a reasonable option for patients with EGFR L858R-mutated disease, for those who are not ideal candidates for intensive intravenous combination therapy, for those who prefer an oral regimen with manageable toxicity, or for patients with brain metastases in whom intracranial activity is of particular clinical interest (24,43,44).

In the progression of NSCLC, up to 40% of patients had BM, and EGFR mutation cases showed a significantly higher tendency of brain diffusion [odds ratio (OR) =3.83, 95% CI: 1.72–8.55; P=0.001] (45,46). Moreover, the management of TKI-resistant BM remains challenging, with limited efficacy data for EGFR-mutant populations. We conducted an exploratory analysis of BM subgroups. There was no significant difference in median PFS and OS between the two groups (mPFS: 5.4 vs. 6.2 months, P=0.29; mOS: 18.1 vs. 26.5 months, P=0.73), which may indicate that dacomitinib may have the potential to improve the long-term survival of patients with BM. This phenomenon may be attributed to dacomitinib’s unique pharmacological properties, particularly its superior brain penetration compared to other EGFR-TKIs. Specifically, dacomitinib demonstrates a higher brain/blood partition coefficient (0.612) than gefitinib (0.0358) and afatinib (0.254), indicating its enhanced ability to cross the BBB and potentially exert therapeutic effects within the CNS (24). Moreover, dacomitinib does not serve as a pharmacokinetic substrate for P-gp (ABCB1) or BCRP (ABCG2), which are known to transport substrates like gefitinib and erlotinib back across the BBB (25). A pre-clinical study demonstrated that systemic dacomitinib administration effectively inhibits glioblastoma brain xenograft growth, further evidencing its ability to penetrate the BBB (47). These results highlight dacomitinib’s promising intracranial anti-tumor potential.

Dacomitinib showed sustained efficacy of intracranial metastasis control in the drug-resistant population of this study. The 12-month and 18-month iPFS were 50.2% (95% CI: 33.5–75.4%) and 41.9% (95% CI: 24.4–71.9%), respectively. The intracranial DCR was 64.3%. Interestingly, although this intracranial control rate was significantly lower than that of dacomitinib in newly diagnosed NSCLC patients with EGFR mutation [12 months iPFS 78.6% (95% CI: 64.8–95.4%), 18 months iPFS 70.4% (95% CI: 54.9–90.1%)] (44), this difference can be attributed to the increased biological complexity of tumors after acquired resistance (such as bypass activation, enhanced BBB adaptability) and the effect of changes in the intracranial microenvironment on drug penetration and efficacy. However, in the context of post-drug resistance treatment, the intracranial control ability of dacomitinib still has important clinical value. Compared with the ORIENT31 four-drug combination regimen (Cim + IBI305 + chemotherapy), although it reported a longer mPFS (7.2 months) (48,49), it did not specifically evaluate the efficacy of patients with BM. The intracranial DCR and iPFS data provided in this study provided direct evidence for this high-risk population. In addition, compared with the high ORR (55%) and mPFS (11.1 months) reported by SKB264 in specific populations (50), dacomitinib has a lower ORR (33.3%), but its intracranial ORR (17.4%) and DCR (58.7%) provide important treatment options for patients with BM that may not be fully covered by SKB264. At the same time, the 12-month iPFS rate of >50% observed in this study was significantly better than the survival time of patients receiving platinum-based chemotherapy after osimertinib resistance reported by White et al. (51) [median treatment duration was only 3.9 months (95% CI: 1.9–7.8), mOS 12.8 months (95% CI: 6.9–19.5)], indirectly suggesting that its intracranial control effect is better than chemotherapy drugs.

The safety profile of dacomitinib in this study was consistent with previous reports (13,52), with no new safety signals identified. Most TRAEs were grade 1–2, the overall rate of dose reduction was 21.4% (9/42), and no patient permanently discontinued treatment because of toxicity. Notably, all dose reductions occurred in the 45 mg starting-dose group, whereas no dose reductions were required among patients who started at 30 mg. The main reasons for dose modification were rash, diarrhea, and paronychia, indicating that the observed toxicities were largely predictable and manageable in routine clinical practice. From a clinical perspective, these findings suggest that the antitumor activity of dacomitinib was achieved with generally acceptable tolerability, and that dose adjustment allowed treatment to be maintained in most patients.

This study has several limitations that should be acknowledged. First, given the retrospective, single-center, real-world design and the relatively limited sample size, the findings should be interpreted with appropriate caution, and further confirmation in larger prospective studies is warranted. Second, the absence of a concurrent control group precludes direct comparison with other post-resistance treatment strategies and limits the strength of causal inference regarding the efficacy of dacomitinib. Third, selection bias is unavoidable in retrospective clinical practice. During the study period, 389 patients at our center developed resistance to third-generation EGFR-TKIs. Of these, 42 received dacomitinib treatment and were included in this study, while the remaining 347 did not receive dacomitinib treatment. In routine clinical practice, treatment selection is based on physician judgment, patient performance status, disease burden, prior treatment history, drug availability, and patient preference. Therefore, the enrolled population may have enriched patients with relatively good clinical conditions, which could affect the observed results. Finally, genetic testing at PD was only available in a subset of patients. Of the 30 patients with available test results, 14 (46.7%) had EGFR-dependent targeting mutations, 3 (10.0%) had EGFR-independent bypass/off-target resistance mechanisms, and 13 (43.3%) had no identifiable candidate resistance mechanisms. Therefore, while these data support the biological heterogeneity of resistance after third-generation EGFR-TKI treatment, the incomplete test coverage and the limited number of patients with specific off-target mechanisms prevent further analysis of the relationship between resistance subtypes and dacomitinib efficacy. Despite these limitations, this study still provides preliminary real-world evidence supporting the potential clinical activity and manageable safety of dacomitinib in this specific clinical setting, and also provides a rationale for future prospective clinical trials to further validate these findings and better define the patients most likely to benefit from this treatment strategy.

Conclusions

In conclusion, our research demonstrates that dacomitinib exhibits promising efficacy and favorable safety profiles in patients harboring EGFR-L858R-mutations who have developed resistance to third-generation EGFR-TKIs, particularly in late-line treatment scenarios. It is worth noting that dacomitinib was also observed to be effective in patients with brain metastases. Nevertheless, further prospective clinical investigations are warranted to validate these preliminary findings.

Acknowledgments

We thank all enrolled patients and their families for supporting our work. We are also grateful to all participating medical centers.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0153/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0153/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0153/prf

Funding: This study was funded by the National Natural Science Foundation of China (No. 82272845) and the Shandong Provincial Natural Science Foundation (No. ZR2023LZL001).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0153/coif). All authors report funding from the National Natural Science Foundation of China and the Shandong Provincial Natural Science Foundation. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Shandong Cancer Hospital and Institute (No. SDTHEC2024001033). Informed consent was taken from all patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer Statistics, 2021. CA Cancer J Clin 2021;71:7-33. [Crossref] [PubMed]
2. Testa U, Castelli G, Pelosi E. Lung Cancers: Molecular Characterization, Clonal Heterogeneity and Evolution, and Cancer Stem Cells. Cancers (Basel) 2018;10:248. [Crossref] [PubMed]
3. Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014;9:154-62. [Crossref] [PubMed]
4. Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169-81. [Crossref]
5. Hong S, Gao F, Fu S, et al. Concomitant Genetic Alterations With Response to Treatment and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With EGFR-Mutant Advanced Non-Small Cell Lung Cancer. JAMA Oncol 2018;4:739-42. [Crossref] [PubMed]
6. Offin M, Rizvi H, Tenet M, et al. Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers. Clin Cancer Res 2019;25:1063-9. [Crossref] [PubMed]
7. Ettinger DS, Wood DE, Aisner DL, et al. NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021. J Natl Compr Canc Netw 2021;19:254-66. [Crossref] [PubMed]
8. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med 2017;376:629-40. [Crossref] [PubMed]
9. Yang JC, Ahn MJ, Kim DW, et al. Osimertinib in Pretreated T790M-Positive Advanced Non-Small-Cell Lung Cancer: AURA Study Phase II Extension Component. J Clin Oncol 2017;35:1288-96. [Crossref] [PubMed]
10. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543-50. Erratum in: Nature 2014;514:262 Erratum in: Nature 2018;559:E12.
11. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25. [Crossref] [PubMed]
12. Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 2017;18:1454-66. [Crossref] [PubMed]
13. Cheng Y, Mok TS, Zhou X, et al. Safety and efficacy of first-line dacomitinib in Asian patients with EGFR mutation-positive non-small cell lung cancer: Results from a randomized, open-label, phase 3 trial (ARCHER 1050). Lung Cancer 2021;154:176-85. [Crossref] [PubMed]
14. Mok TS, Cheng Y, Zhou X, et al. Updated Overall Survival in a Randomized Study Comparing Dacomitinib with Gefitinib as First-Line Treatment in Patients with Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations. Drugs 2021;81:257-66. [Crossref] [PubMed]
15. Ellis PM, Shepherd FA, Millward M, et al. Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial. Lancet Oncol 2014;15:1379-88. [Crossref] [PubMed]
16. Ramalingam SS, Jänne PA, Mok T, et al. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Lancet Oncol 2014;15:1369-78. [Crossref] [PubMed]
17. Ramalingam SS, O'Byrne K, Boyer M, et al. Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trials. Ann Oncol 2016;27:423-9. [Crossref] [PubMed]
18. Mujoomdar A, Austin JHM, Malhotra R, et al. Clinical Predictors of Metastatic Disease to the Brain from Non-Small Cell Lung Carcinoma: primary tumor size, cell type, and lymph node metastases. Radiology 2007;242: [Crossref]
19. Heon S, Yeap BY, Britt GJ, et al. Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res 2010;16:5873-82. [Crossref] [PubMed]
20. Garg P, Dhakne R, Belekar V. Role of breast cancer resistance protein (BCRP) as active efflux transporter on blood-brain barrier (BBB) permeability. Mol Divers 2015;19:163-72. [Crossref] [PubMed]
21. Elmeliegy MA, Carcaboso AM, Tagen M, et al. Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation. Clin Cancer Res 2011;17:89-99. [Crossref] [PubMed]
22. Bartolotti M, Franceschi E, Brandes AA. EGF receptor tyrosine kinase inhibitors in the treatment of brain metastases from non-small-cell lung cancer. Expert Rev Anticancer Ther 2012;12:1429-35. [Crossref] [PubMed]
23. Lampson LA. Monoclonal antibodies in neuro-oncology: Getting past the blood-brain barrier. MAbs 2011;3:153-60. [Crossref] [PubMed]
24. Kim M, Laramy JK, Mohammad AS, et al. Brain Distribution of a Panel of Epidermal Growth Factor Receptor Inhibitors Using Cassette Dosing in Wild-Type and Abcb1/Abcg2-Deficient Mice. Drug Metab Dispos 2019;47:393-404. [Crossref] [PubMed]
25. Fan YF, Zhang W, Zeng L, et al. Dacomitinib antagonizes multidrug resistance (MDR) in cancer cells by inhibiting the efflux activity of ABCB1 and ABCG2 transporters. Cancer Lett 2018;421:186-98. [Crossref] [PubMed]
26. Reck M, Shankar G, Lee A, et al. Atezolizumab in combination with bevacizumab, paclitaxel and carboplatin for the first-line treatment of patients with metastatic non-squamous non-small cell lung cancer, including patients with EGFR mutations. Expert Rev Respir Med 2020;14:125-36. [Crossref] [PubMed]
27. Cavanna L, Citterio C, Orlandi E. Immune checkpoint inhibitors in EGFR-mutation positive TKI-treated patients with advanced non-small-cell lung cancer network meta-analysis. Oncotarget 2019;10:209-15. [Crossref] [PubMed]
28. Chen RL, Chen HJ, Jiang BY, et al. Bevacizumab plus chemotherapy for patients with advanced pulmonary adenocarcinoma harboring EGFR mutations. Clin Transl Oncol 2018;20:243-52. [Crossref] [PubMed]
29. Gonzales AJ, Hook KE, Althaus IW, et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor. Mol Cancer Ther 2008;7:1880-9. [Crossref] [PubMed]
30. Kobayashi Y, Mitsudomi T. Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy. Cancer Sci 2016;107:1179-86. [Crossref] [PubMed]
31. Eck MJ, Yun CH. Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer. Biochim Biophys Acta 2010;1804:559-66. [Crossref] [PubMed]
32. Furuyama K, Harada T, Iwama E, et al. Sensitivity and kinase activity of epidermal growth factor receptor (EGFR) exon 19 and others to EGFR-tyrosine kinase inhibitors. Cancer Sci 2013;104:584-9. [Crossref] [PubMed]
33. Stockhammer P, Grant M, Wurtz A, et al. Co-Occurring Alterations in Multiple Tumor Suppressor Genes Are Associated With Worse Outcomes in Patients With EGFR-Mutant Lung Cancer. J Thorac Oncol 2024;19:240-51. [Crossref] [PubMed]
34. Guo Y, Song J, Wang Y, et al. Concurrent Genetic Alterations and Other Biomarkers Predict Treatment Efficacy of EGFR-TKIs in EGFR-Mutant Non-Small Cell Lung Cancer: A Review. Front Oncol 2020;10:610923. [Crossref] [PubMed]
35. Choudhury NJ, Makhnin A, Tobi YY, et al. Pilot Study of Dacomitinib for Patients With Metastatic EGFR-Mutant Lung Cancers With Disease Progression After Initial Treatment With Osimertinib. JCO Precis Oncol 2021;5:PO.21.00005.
36. Tanaka H, Sakamoto H, Akita T, et al. Clinical efficacy of dacomitinib in rechallenge setting for patients with epidermal growth factor receptor mutant non-small cell lung cancer: A multicenter retrospective analysis (TOPGAN2020-02). Thorac Cancer 2022;13:1471-8. [Crossref] [PubMed]
37. Morimoto K, Yamada T, Takeda T, et al. Clinical Efficacy and Safety of First- or Second-Generation EGFR-TKIs after Osimertinib Resistance for EGFR Mutated Lung Cancer: A Prospective Exploratory Study. Target Oncol 2023;18:657-65. [Crossref] [PubMed]
38. Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol 2024;35:77-90. [Crossref] [PubMed]
39. Popat S, Reckamp KL, Califano R, et al. LBA54 Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutated, advanced non-small cell lung cancer after disease progression on osimertinib: Second interim overall survival from MARIPOSA-2. Ann Oncol 2024;35:S1244-5.
40. Besse B, Goto K, Wang Y, et al. Amivantamab Plus Lazertinib in Patients With EGFR-mutant NSCLC After Progression on Osimertinib and Platinum-based Chemotherapy: Results From CHRYSALIS-2 Cohort A. J Thorac Oncol 2025;20:651-64. [Crossref] [PubMed]
41. Yu HA, Goto Y, Hayashi H, et al. HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy. J Clin Oncol 2023;41:5363-75. [Crossref] [PubMed]
42. Fang W, Wu L, Meng X, et al. Sacituzumab Tirumotecan in EGFR-TKI-Resistant, EGFR-Mutated Advanced NSCLC. N Engl J Med 2026;394:13-26. [Crossref] [PubMed]
43. Dacomitinib antagonizes multidrug resistance MDR Source Cancer Lett 2018;
44. Jung HA, Park S, Lee SH, et al. Dacomitinib in EGFR-mutant non-small-cell lung cancer with brain metastasis: a single-arm, phase II study. ESMO Open 2023;8:102068. [Crossref] [PubMed]
45. Magnuson WJ, Lester-Coll NH, Wu AJ, et al. Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis. J Clin Oncol 2017;35:1070-7. [Crossref] [PubMed]
46. Shin DY, Na II, Kim CH, et al. EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol 2014;9:195-9. [Crossref] [PubMed]
47. Zahonero C, Aguilera P, Ramírez-Castillejo C, et al. Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma. Mol Cancer Ther 2015;14:1548-58. [Crossref] [PubMed]
48. Lu S, Wu L, Jian H, et al. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2022;23:1167-79. [Crossref] [PubMed]
49. Lu S, Wu L, Jian H, et al. Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Respir Med 2023;11:624-36. [Crossref] [PubMed]
50. Zhao S, Cheng Y, Wang Q, et al. Sacituzumab tirumotecan in advanced non-small-cell lung cancer with or without EGFR mutations: phase 1/2 and phase 2 trials. Nat Med 2025;31:1976-86. [Crossref] [PubMed]
51. White M, Neal JW, Gardner RM, et al. 141P Chemotherapy with or without immunotherapy or bevacizumab for EGFR-mutated lung cancer after progression on osimertinib. J Thorac Oncol 2021;16:S773-4.
52. Wang S, Liu J, Wang Y, et al. Efficacy and safety of dacomitinib as first-line treatment for advanced non-small cell lung cancer patients with epidermal growth factor receptor 21L858R mutation: A multicenter, case-series study in China. Chin J Cancer Res 2024;36:398-409. [Crossref] [PubMed]