Efficacy and safety of third-generation EGFR-TKI rechallenge therapy in advanced non-small cell lung cancer patients with EGFR mutation: a retrospective cohort study

Introduction

Non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations represents a distinct molecular entity that has seen a paradigm shift in management. The Phase III FLAURA trial established the third-generation tyrosine kinase inhibitor (TKI), osimertinib, as the preferred first-line standard of care due to its superior efficacy and favorable intracranial penetration (1). However, despite these advances, acquired resistance to osimertinib is inevitable and remains the principal cause of treatment failure (2-4). Once the initially used third-generation TKI loses efficacy, subsequent treatment options become severely limited. For patients lacking actionable resistance alterations, platinum-based chemotherapy with or without antiangiogenic therapy remains the current standard of care, as the benefit of immune checkpoint inhibitors appears to be limited in this population. Although several novel therapeutic strategies have recently emerged, including amivantamab-based combinations (5) and novel antibody-drug conjugates (ADCs) like patritumab deruxtecan (6,7), their real-world application is often hindered. Many patients at this advanced stage exhibit a declining Eastern Cooperative Oncology Group (ECOG) performance status or face limited access to repeated genomic profiling, rendering intensive regimens clinically unfeasible or intolerable. This exhaustion of tolerable options highlights a substantial unmet need for effective, low-toxicity salvage therapies. Historically, clinical trials evaluating the rechallenge of prior-generation TKIs (8-14) demonstrated modest but reproducible efficacy, with objective response rates (ORRs) ranging from 14.3% to 64.3% and disease control rates (DCRs) exceeding 50%. These observations suggest that an EGFR-TKI-free interval, coupled with intervening systemic therapy, may partially restore sensitivity to EGFR inhibition through dynamic changes in tumor clonal composition. Building upon this rationale, several retrospective studies have investigated third-generation EGFR-TKI rechallenge after osimertinib failure, which reported a median progression-free survival (mPFS) ranging from 3.4 to 8.95 months (15-19).

However, despite these encouraging findings, the role of third-generation EGFR-TKI rechallenge remains controversial. Most available evidence is derived from retrospective single-center studies with limited sample sizes and substantial heterogeneity in patient selection, treatment lines, interval therapies, resistance mechanisms, and rechallenge strategies. Several fundamental clinical questions therefore remain unanswered, including which patients are most likely to benefit from rechallenge, the optimal timing for treatment re-administration, and whether intervening therapies influence subsequent treatment efficacy. As a result, current international guidelines have not recommended third-generation EGFR-TKI rechallenge as a standard therapeutic strategy, underscoring the need for additional real-world evidence.

To address this critical knowledge gap, this study systematically evaluated the clinical efficacy and safety profile of third-generation EGFR-TKI rechallenge in a real-world cohort of heavily pretreated patients. Unlike most previously published cohorts, our study specifically focused on patients who had received multiple prior systemic therapies, representing a population with particularly limited therapeutic options in routine clinical practice. Furthermore, we explored clinical factors associated with survival outcomes to better characterize patients who may derive benefit from this salvage strategy, with the aim of providing clinically relevant evidence to support individualized treatment decision-making in late-line EGFR-mutated NSCLC. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0596/rc).

Methods

Patients

A retrospective study was performed at Jinling Clinical Medical School, Nanjing Medical University from December 2019 to August 2025. Patients with EGFR-mutated NSCLC who received third-generation EGFR-TKI rechallenge after disease progression following previous third-generation EGFR-TKI therapy were retrospectively identified through the hospital electronic medical record system. Follow-up information was obtained from the institutional electronic medical record system, outpatient and inpatient visit records, telephone follow-up, and the provincial mortality registry. Eligible patients met all of the following criteria:

• age ≥18 years;
• histologically or cytologically confirmed advanced NSCLC;
• documented EGFR mutations (including exon 19 deletion, L858R, or uncommon mutations);
• previous treatment with at least one third-generation EGFR-TKI;
• radiologically confirmed disease progression following third-generation EGFR-TKI therapy;
• receipt of third-generation EGFR-TKI rechallenge therapy.

Patients without histological or cytological confirmation of NSCLC or with concomitant malignancies that could interfere with efficacy or survival evaluation, or with incomplete core clinical data were excluded. Baseline clinical data were extracted from the electronic medical records, including demographic characteristics, ECOG performance status, clinicopathological features, molecular characteristics, and treatment history. Data were independently reviewed by two investigators to ensure accuracy and completeness, with any discrepancies resolved by consensus. Patients were routinely followed until disease progression, death, or the data cutoff date. Chest CT was routinely performed every 6–8 weeks or earlier when disease progression was clinically suspected. Radiological tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (20). ORR was defined as the proportion of patients achieving complete response (CR) or partial response (PR). DCR was defined as the proportion of patients achieving CR, PR, or stable disease (SD). Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (21). Treatment-related adverse events (TRAEs) of all grades and grade 3–4 adverse events were summarized. For patients with multiple episodes of the same adverse event, the highest recorded grade was used for analysis. No human subjects were prospectively enrolled, no interventions were performed, and no biological samples were collected for the purposes of this study. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Jinling Hospital (No. 2024DZKY-100-01). Informed consent was waived in this retrospective study.

Statistical analysis

Progression-free survival (PFS) was defined as the interval from initiation of third-generation EGFR-TKI rechallenge to radiologically confirmed disease progression or death from any cause. Overall survival (OS) was defined as the time from treatment initiation to death from any cause, or to last follow-up for censored cases. Patients who had not experienced disease progression or death at the data cutoff were censored at the date of the last follow-up. DCR was defined as the proportion of patients with CR, PR, or SD. Continuous variables are presented as the median (range), and categorical variables are summarized as frequencies and percentages. Kaplan-Meier survival curves were generated to estimate PFS and OS, and median survival times with 95% confidence intervals (CIs) were calculated. Survival differences between groups were compared using the log-rank test. Univariate Cox proportional hazards regression analyses were performed to identify factors associated with PFS and OS. Candidate variables included demographic characteristics, clinicopathological features, molecular characteristics, and treatment-related variables. All statistical tests were two-sided, and a P value <0.05 was considered statistically significant. To reduce selection bias, all consecutive eligible patients treated during the study period were included. Baseline clinical information was independently reviewed by two investigators to minimize information bias. Nevertheless, because treatment allocation was based on physician discretion rather than randomization, residual confounding by indication could not be completely eliminated. Statistical analyses were performed using R software (version 4.5.1; R Foundation for Statistical Computing, Vienna, Austria).

Results

Patient characteristics

A total of 29 patients who received third-generation EGFR TKI rechallenge following failure of prior third-generation EGFR TKI therapy and subsequent intervening treatments were included. The median age was 61 years (range, 45–84 years), with a female predominance (58.6%, 17/29). Most patients were never smokers (89.7%, 26/29) and presented with stage IV adenocarcinoma (93.1%, 27/29). All patients had histologically confirmed lung adenocarcinoma. Prior to rechallenge, 16 patients (55.2%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2, whereas 13 patients (44.8%) presented with an ECOG PS of 3–4.

All patients received intervening therapies before the initiation of rechallenge. The median interval time between initial third-generation EGFR TKI progression and rechallenge therapy was 10.0 months (range, 1.0–29 months). Patients had a median of 5 (range, 3–12) total lines of systemic therapy prior to rechallenge, including a median of 2 (range, 1–6) lines of systemic therapy in the interval between initial and rechallenge treatment. 26 (89.7%) received chemotherapy-based regimens, two (6.9%) received first-generation EGFR-TKIs, and one (3.4%) received immunotherapy monotherapy. Within the chemotherapy-based cohort, a combination of chemotherapy and immunotherapy was the most frequent regimen (55.2%, 16/29), followed by chemotherapy monotherapy (34.5%, 10/29). Carboplatin plus pemetrexed was the most common chemotherapy regimen; alternative regimens included single-agent pemetrexed, carboplatin plus gemcitabine, paclitaxel, and docetaxel. Regarding primary EGFR mutation status, exon 19 deletion was the most frequent alteration (55.2%, 16/29), followed by the L858R mutation (27.6%, 8/29) and uncommon EGFR mutations (17.2%, 5/29). At the time of rechallenge, EGFR T790M positivity was detected in 8 patients (27.6%), whereas 21 patients (72.4%) were T790M-negative. Co-occurring genetic alterations were identified in 51.7% (15/29) of patients, predominantly including TP53 mutation (34.5%, 10/29) and MDM2 amplification (6.9%, 2/29), along with other low-frequency alterations including MET amplification, BRCA2 mutation, and NCOA4-RET mutation (n=1 each). No co-occurring alterations were detected in the remaining 14 patients (48.3%). For prior target therapy, Osimertinib was the most commonly administered third-generation EGFR TKI (55.2%, 16/29), followed by aumolertinib (37.9%, 11/29) and furmonertinib (6.9%, 2/29). For rechallenge treatment, furmonertinib was the most frequently utilized agent (37.9%, 11/29), followed by aumolertinib (34.5%, 10/29) and osimertinib (27.6%, 8/29). Rechallenge was predominantly administered as a fifth-line or later therapy (65.5%). Comprehensive baseline characteristics are presented in Table 1.

Efficacy assessment and survival analysis

As of the data cutoff date on August 30, 2025, 29 patients were included in this study cohort, and 20 death events were recorded. The median PFS following third-generation EGFR-TKI rechallenge was 6.0 months (95% CI: 4.0–9.0; Figure 1A), and the median OS was 12.0 months (95% CI: 10.0–NA) (Figure 1B). No patients achieved a CR or PR. The DCR was 20.7% (95% CI: 8.0–39.7%), with six patients achieving SD. Individual treatment sequences and clinical milestones are detailed in Figure 2.

Figure 1 Kaplan-Meier curves for progression-free survival and overall survival. (A) PFS in the overall population (n=29). (B) OS in the overall population (n=29). Number at risk tables are provided below each panel. CI, confidence interval; NA, not available; OS, overall survival; PFS, progression-free survival.

Figure 2 Swimmer plot of treatment sequences and clinical outcomes for individual patients (n=29). Each horizontal bar represents an individual patient, with the x-axis indicating the duration of follow-up in months from the initiation of first-line therapy. The color-coded segments represent different treatment regimens, including various generations of EGFR-TKIs, chemotherapy, immunotherapy, and combination therapies as defined in the legend. Black squares indicate the time of death, while right-pointing arrows denote patients who were still alive and receiving ongoing treatment at the time of data cutoff. EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

We subsequently conducted an analysis of PFS across different subgroups. Figure 3 shows PFS in each subgroup. ECOG performance status was significantly associated with PFS; patients with an ECOG score of 0–2 demonstrated a median PFS of 7.0 months (95% CI: 4.0–20.0) compared to 5.0 months (95% CI: 2.0–NA) in the ECOG 3–4 cohort (P=0.04) (Figure 3A). Similarly, patient sex was a statistically significant prognostic factor, with female patients exhibiting a prolonged median PFS compared to male patients (8.0 months, 95% CI: 5.0–20.0 vs. 3.0 months, 95% CI: 2.0–NA; P=0.02) (Figure 3B). Furthermore, patients receiving a chemo-containing regimen achieved a significantly longer median PFS compared to those receiving a non-chemo regimen (7.5 months, 95% CI: 4.0–9.0 vs. 2.0 months, 95% CI: 1.0–NA; P=0.02) (Figure 3C). Other evaluated baseline characteristics did not show statistically significant associations with PFS. Specifically, no significant differences were observed regarding smoking history (never vs. ever: 5.5 vs. 7.0 months, P=0.41), duration of prior TKI PFS (<6 vs. ≥6 months: 4.0 vs. 7.0 months, P=0.35), or T790M mutation status (negative vs. positive: 5.5 vs. 7.0 months, P=0.89).

Figure 3 Subgroup analyses of PFS using Kaplan-Meier survival curves. Kaplan-Meier estimates of PFS were stratified according to various baseline clinical and molecular characteristics: (A) ECOG performance status (0–2 vs. 3–4); (B) sex (male vs. female); (C) interval regimen (non-chemo vs. chemo-containing); (D) smoking history (never vs. ever); (E) prior TKI PFS (<6 vs. ≥6 months); and (F) T790M mutation status (negative vs. positive). The median PFS and 95% CIs for each subgroup are detailed within the respective panels. Statistical differences between groups were evaluated using the log-rank test. Vertical tick marks on the survival curves indicate censored events. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; NA, not available; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

Consistent with the PFS findings, Kaplan-Meier analysis of OS identified ECOG performance status and sex as significant prognostic factors (Figure 4). Patients in the ECOG 0–2 group achieved a median OS of 25.0 months (95% CI: 17.0–NA) versus 10.0 months (95% CI: 8.0–NA) in the ECOG 3–4 group (P=0.005). Female patients demonstrated a median OS of 20.0 months (95% CI: 11.0–NA) compared to 8.0 months (95% CI: 7.0–NA) for male patients (P=0.009). In contrast to its significant impact on PFS, the chemo-containing regimen demonstrated no statistically significant OS benefit over the non-chemo regimen (median OS: 12.0 months, 95% CI: 9.0–NA vs. 20.0 months, 95% CI: 12.0–NA; P=0.76). A history of smoking showed a trend toward poorer OS, albeit without reaching statistical significance (never vs. ever: 18.5 months, 95% CI: 10.0–NA vs. 10.0 months, 95% CI: 8.0–NA; P=0.07). Similarly, long-term OS was not significantly affected by either prior TKI PFS (<6 vs. ≥6 months: 9.0 months, 95% CI: 8.0–NA vs. 18.5 months, 95% CI: 12.0–NA; P=0.10) or T790M mutation status (negative vs. positive: 12.0 months, 95% CI: 8.0–NA vs. 17.0 months, 95% CI: 10.0–NA; P=0.73).

Figure 4 Subgroup analyses of OS using Kaplan-Meier survival curves. Kaplan-Meier estimates of OS were stratified according to various baseline clinical and molecular characteristics: (A) ECOG performance status (0–2 vs. 3–4); (B) sex (male vs. female); (C) interval regimen (non-chemo vs. chemo-containing); (D) Smoking history (never vs. ever); (E) prior TKI PFS (<6 vs. ≥6 months); and (F) T790M mutation status (negative vs. positive). The median OS and 95% CIs for each subgroup are detailed within the respective panels. Statistical differences between groups were evaluated using the log-rank test. Vertical tick marks on the survival curves indicate censored events. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; NA, not available; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

Safety assessment

Among the 29 patients, eight (27.6%) experienced at least one TRAE, as detailed in Table 2. A total of ten TRAEs were documented in these patients, of which three (10.3%) were grade ≥3. Specifically, the grade ≥3 TRAEs included one case of grade 3 rash, one case of grade 3 interstitial pneumonia, and one case of grade 4 myelosuppression. The remaining seven TRAEs occurred in six patients (20.7%), consisting of one case of grade 1 myelosuppression (3.4%), one case of grade 1 interstitial pneumonia (3.4%), two cases of grade 2 myelosuppression (6.9%), and three grade 2 non-hematologic events (one rash, one diarrhea, and one ALT/AST elevation).

Discussion

Currently, chemotherapy combined with anti-angiogenic agents or immunotherapy is recommended for patients with EGFR-mutated NSCLC who experience disease progression on TKIs and lack alternative targeted therapies. Following progression on osimertinib, amivantamab plus chemotherapy has emerged as a viable option based on the MARIPOSA-2 trial; however, the mPFS was limited to 6.3 months (5). ADCs provide additional therapeutic alternatives in this setting. For instance, datopotamab deruxtecan received accelerated US FDA approval in June 2025, supported by the TROPION-Lung05 study which reported a comparable mPFS of 5.8 months (7). Other ADCs have also demonstrated efficacy: patritumab deruxtecan yielded a median overall survival (mOS) of 11.9 months in the HERTHENA-Lung01 trial (22), and sacituzumab tirumotecan significantly improved OS compared to chemotherapy in the phase III OptiTROP-Lung04 trial (23). Despite these advancements, the modest PFS benefits and potential toxicities associated with current salvage therapies highlight an ongoing clinical need for efficacious and well-tolerated options. Herein, we report our institutional experience with third-generation EGFR-TKI rechallenge. In this real-world retrospective study of 29 patients, third-generation EGFR-TKI rechallenge demonstrated a DCR of 20.7% and an mPFS of 6.0 months, accompanied by a favorable safety profile characterized by a 10.3% incidence of grade ≥3 TRAEs.

Existing studies on third-generation TKI rechallenge show varied efficacy. Wang et al. reported a longer mPFS of 8.95 months with furmonertinib (19). Similarly, Levine et al. observed a 53% DCR and an 8.9-month median OS with osimertinib retreatment (24). In a Japanese multicenter retrospective observational study by Araki et al., EGFR-TKI rechallenge yielded an ORR of 23.1%, a DCR of 53.9%, and a median PFS of 3.4 months (15). In comparison, our cohort showed relatively limited efficacy, which may be attributable to a combination of interrelated clinical and biological factors. Although most patients had a relatively long TKI-free interval, this alone may not have been sufficient to restore EGFR-TKI sensitivity. Given the advanced disease stage and extensive prior treatments, acquired resistance mechanisms and tumor heterogeneity may have contributed to reduced sensitivity to rechallenge therapy (25). In addition, differences in drug pharmacology among third-generation TKIs (such as varying potency against heterogeneous resistance mutations and distinct kinase binding affinities) may lead to variable clinical efficacy in heavily pretreated settings (26). Furthermore, treatment decisions were made in routine clinical practice without predefined selection criteria, and 20 patients died during the follow-up period. Collectively, these confounding variables may explain the relatively lower DCR observed in our heavily pretreated population.

Interestingly, the duration of the TKI-free interval, defined using a ten-month cutoff, did not significantly influence clinical outcomes in our extensively pretreated cohort (Figures S1,S2). Instead, exploratory analyses suggested a potential trend toward improved PFS with chemotherapy-containing interval regimens; however, the marked imbalance in group sizes (26 vs. 3 patients) severely limits the statistical power, precluding any definitive conclusions. Additionally, baseline ECOG PS was associated with both PFS and OS. Patients with an ECOG PS of 0–2 were observed to have longer survival compared to the ECOG 3–4 cohort. This survival advantage may be multifactorial. On one hand, a better performance status might reflect a relatively lower baseline disease burden or less aggressive tumor biology. On the other hand, adequate physiological reserve may allow these patients to better tolerate treatment-related toxicities, maintain treatment intensity, and reduce the likelihood of early treatment discontinuation. However, because this study lacks a control arm—such as a cohort receiving best supportive care or standard chemotherapy—our findings cannot definitively prove that third-generation EGFR-TKI rechallenge itself conferred a survival benefit. Moreover, female sex was associated with improved PFS in univariable analysis; however, this finding should be interpreted cautiously given the small sample size and potential residual confounding. The biological basis underlying this association remains unclear.

Intriguingly, traditional prognostic biomarkers—specifically T790M and TP53 status—did not exhibit the anticipated predictive power in our late-line setting. Although these mutations are well-known indicators of genomic instability and poor trajectory in earlier lines of therapy (27,28), neither demonstrated a clear as lacks a control sociation with survival outcomes in our cohort (Figures S3-S6). These findings suggest that single-gene stratification alone may be insufficient for robust prognostic prediction. Consequently, future risk-stratification models should incorporate comprehensive, multi-gene genomic profiling to better guide precision oncology strategies.

Our findings underscore a pragmatic shift in clinical evaluation. Given the logistical and financial hurdles of performing sequential, comprehensive next-generation sequencing (NGS) in the real world, macroscopic clinical phenotypes frequently guide management decisions. Our analyses indicate that baseline ECOG PS and chemotherapy-containing interval regimens may serve as surrogate markers for assessing physiological reserve and tolerance to tumor burden. When molecular profiling is incomplete or highly complex, ECOG PS represents a reliable clinical parameter to guide patient selection for third-generation TKI rechallenge, helping to identify patients with adequate functional reserve who may derive clinical benefit from salvage therapy.

Several limitations of this study should be acknowledged. First, the small sample size limited the statistical power, particularly for subgroup analyses, while the single-center design may restrict the generalizability of our findings. Therefore, these results require validation in larger, multicenter cohorts. Second, the absence of a comparator group limited our ability to determine the relative efficacy of third-generation EGFR-TKI rechallenge compared with other available salvage strategies. Third, owing to the retrospective real-world nature of this study, treatment decisions were not standardized as in prospective clinical trials. Furthermore, our clinical dataset cannot provide direct mechanistic insights into why certain subgroups, such as female patients or those receiving interval chemotherapy, experienced better outcomes. In addition, comprehensive longitudinal genomic profiling was not uniformly available across the cohort. Consequently, we were unable to fully characterize dynamic molecular evolution or identify potential resistance mechanisms, such as MET amplification or HER2 alterations, particularly among patients without detectable resistance alterations. Finally, the retrospective design may have introduced selection bias and limited the completeness of clinical data collection. Future prospective studies incorporating serial ctDNA-based molecular monitoring are warranted to better elucidate the mechanisms underlying response and resistance to third-generation EGFR-TKI rechallenge and to identify biomarkers that may guide patient selection.

Conclusions

In conclusion, third-generation EGFR-TKI rechallenge represents a feasible and well-tolerated salvage strategy for heavily pretreated patients with EGFR-mutant NSCLC. ECOG PS at rechallenge was associated with survival outcomes, and patients who received chemotherapy-containing regimens during the TKI-free interval showed a trend toward more favorable outcomes. These findings suggest that functional status and prior treatment history may help inform patient selection, which requires further prospective validation.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0596/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0596/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0596/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0596/coif). The authors have no 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. The study was approved by the Institutional Review Board of Jinling Hospital (No. 2024DZKY-100-01). Informed consent was waived in this retrospective study.

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/.

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