Abstract
Background:
Dacomitinib has demonstrated superior efficacy compared with first-generation tyrosine kinase inhibitors (TKIs) in patients with epidermal growth factor receptor (EGFR) exon 21-mutated non-small-cell lung cancer (NSCLC). However, the standard 45 mg dose often leads to a high incidence of grade 3 and 4 toxicities, limiting its clinical application. This study aimed to evaluate the preliminary efficacy and safety of a proactive low-dose dacomitinib strategy as first-line treatment.
Methods:
This retrospective cohort study analyzed data from 31 patients with EGFR exon 21-mutated advanced NSCLC consecutively enrolled between August 2019 and April 2023, who initiated dacomitinib at 15 or 30 mg/d. A comparative cohort of 35 patients receiving first-generation EGFR-TKIs was also included. Initial dose selection was based on clinical judgment regarding patient age, comorbidities, and performance status. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline.
Results:
The objective response rate (ORR) in the low-dose dacomitinib group was 67.7%, higher than that observed in the first-generation EGFR-TKI group (P = .009). Subgroup analysis showed ORRs of 75% and 60% in the 15 mg and 30 mg cohorts, respectively (P = .389). The median progression-free survival (PFS) in the low-dose dacomitinib group was 14.2 months (95% confidence interval [CI] = 12.4-15.9 months). Compared with first-generation EGFR-TKIs, low-dose dacomitinib was associated with significantly prolonged PFS (HR = 0.43, 95% CI = 0.25-0.72; P = .001). No significant difference in PFS was observed between the 15 mg and 30 mg groups (HR = 0.81, 95% CI = 0.37-1.76; P = .594). While grade 1 and 2 toxicities were common, the 15 mg group exhibited a significantly lower incidence of grade 3 and 4 rash compared with the 30 mg group (0% vs 33.3%).
Conclusions:
Initial low-dose dacomitinib demonstrated promising efficacy with an improved safety profile in patients with EGFR exon 21-mutated NSCLC. These findings support the feasibility of a dose-optimization strategy, although further prospective studies are warranted.
Introduction
Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, accounting for approximately 80% to 85% of all lung cancer cases. 1 Notably, patients harboring activating mutations in the epidermal growth factor receptor (EGFR) gene derive significant clinical benefit from targeted therapy with tyrosine kinase inhibitors (TKIs). Exon 19 deletions and the L858R point mutation in exon 21 represent the most prevalent genomic drivers. These alterations trigger constitutive activation of the EGFR pathway, thereby promoting tumor cell proliferation and survival.2,3 Advances in targeted agents, including gefitinib, erlotinib, and dacomitinib, have markedly improved the prognosis for patients with EGFR-mutant NSCLC, offering superior clinical outcomes compared to conventional chemotherapy.4-6
Dacomitinib, a second-generation irreversible pan-human epidermal growth factor receptor (HER) TKI targeting EGFR, HER2, and HER4, has demonstrated clinical superiority over first-generation inhibitors, particularly in extending progression-free survival (PFS) and overall survival (OS).7,8 This efficacy was prominently showcased in the landmark phase III ARCHER 1050 trial, where dacomitinib significantly outperformed gefitinib in the first-line treatment of advanced EGFR-mutant NSCLC. 9 In the Asian subpopulation, dacomitinib achieved a median PFS of 16.5 months and a median OS of 37.7 months, representing the first head-to-head phase III trial to show a significant OS benefit between 2 EGFR-TKIs. Nevertheless, the clinical utility of the standard 45 mg/d regimen is frequently constrained by a high incidence of adverse events (AEs), primarily diarrhea, dermatitis, acneiform rash, and paronychia.10-14 Notably, dose reductions to 30 mg or 15 mg were required in 66% to 85% of patients to manage these toxicities. Although post-hoc analyses indicated that efficacy was maintained following such dose modifications, these AEs often adversely affect patient quality of life (QoL) and treatment adherence.
To mitigate these dacomitinib-associated toxicities, there is an intensifying clinical interest in dose-optimization strategies aimed at reducing adverse reactions without sacrificing therapeutic potency. Optimizing the initial dose may improve patient compliance and safety, especially in vulnerable populations such as elderly patients or those with pre-existing comorbidities who are predisposed to severe toxicities.14,15 Accordingly, the present study was designed to evaluate the clinical efficacy and safety of an initial low-dose dacomitinib regimen (15 or 30 mg/d) as a first-line intervention for patients harboring the EGFR exon 21 L858R mutation.
Herein, we systematically assessed whether this reduced-dose approach could yield comparable efficacy to standard-of-care EGFR-TKIs. By characterizing the safety landscape and clinical utility of this strategy, we aim to establish a refined, viable first-line treatment paradigm for EGFR-mutant NSCLC. Such an approach holds the potential to bridge the gap between potent EGFR inhibition and patient tolerability, ultimately enhancing both long-term oncological outcomes and overall QoL.
Methods
Patient Selection
For this retrospective study, a total of 31 patients with EGFR exon 21-mutated advanced NSCLC, who were treated with low-dose dacomitinib between August 2019 and April 2023 at The Tenth Affiliated Hospital, Southern Medical University (Dongguan People’s Hospital) and Huizhou Third People’s Hospital, Guangzhou Medical University, were consecutively enrolled to minimize potential selection bias. In addition, another 35 cases receiving first-generation EGFR-TKIs were recruited as a comparative cohort to evaluate the efficacy and toxicities of different targeted therapies. Patient identities were meticulously protected through de-identification in accordance with ethical standards to maintain strict confidentiality.
The reporting of this study complies with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines. 16 The present study was approved by the Ethics Committee of The Tenth Affiliated Hospital, Southern Medical University (Dongguan People’s Hospital) and was conducted according to the Declaration of Helsinki. Informed written consent was not necessary owing to its retrospective nature according to the national regulations.
Given the retrospective observational design of this study, treatment assignment was not randomized, and initial dosing was determined by clinical discretion. The initial dose selection (either 15 mg or 30 mg/d) was determined by the treating physicians based on clinical judgment, primarily considering baseline factors such as advanced age (⩾65 years), the presence of underlying comorbidities, and the Eastern Cooperative Oncology Group (ECOG) performance status.
The inclusion criteria were as follows: patients aged 18 to 75 years; initially diagnosed with stage IIIb or IV lung adenocarcinoma per the International Association for the Study of Lung Cancer 8th edition of Tumor Node Metastasis staging; patients harboring EGFR-sensitive mutation, specifically exon 21 mutation, as confirmed by genetic testing and having at least 1 measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria; and patients treated with either first-generation EGFR-TKIs or dacomitinib. Furthermore, all included patients had adequate organ function.
The exclusion criteria were as follows: previously treated advanced NSCLC, patients with squamous cell carcinoma or small cell lung cancer, including mixed small cell lung cancer and NSCLC; patients with active brain metastases, carcinomatous meningitis, spinal cord compression, or brain or leptomeningeal disease detected by computed tomography or magnetic resonance imaging; pregnant or breastfeeding women; patients with conditions significantly affected oral drug absorption, such as inability to swallow, chronic diarrhea, or intestinal obstruction; patients with confirmed EGFR wild-type, exon 19 deletion, T790M mutation, or other genetic abnormalities, such as ALK, ROS1, c-MET, or RET alterations (fusion or mutation); patients with any other uncured active malignancies, excluding cured basal cell carcinoma, cervical carcinoma in situ, or superficial bladder cancer; and patients with any condition that the investigator deemed to potentially interfere with the study’s conduct or outcomes.
Treatment Schedule
This retrospective study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committees. Herein, dacomitinib was administered using a dose-escalation strategy, with the initial dose being low and gradually increasing based on patient response and tolerability. Treatment was commenced with an initial dacomitinib dose of 15 or 30 mg/d. If the disease exacerbated (without progression), the dose was increased to 30 or 45 mg/d. In the case of unacceptable side effects such as grade 3 or higher diarrhea, paronychia, dermatitis, acneiform, and stomatitis in 30 mg/d group, the dose was reduced to 15 mg/d to manage treatment-related toxicity. If a patient could not tolerate the dose of 15 mg/d, treatment was discontinued. For grade 3 or higher toxicity, treatment was interrupted until recovered to grade 2 or baseline. Treatment was continued until the disease progressed, intolerable toxicity was observed, or the patient voluntarily withdrew from the study. Toxicities were recorded and categorized per the National Cancer Institute Common Terminology Criteria for adverse events (NCI-CTCAE) version 3.0.
In clinical practice, dose adjustments during treatment were performed at the discretion of the treating physicians based on patient tolerance and AEs. However, due to the retrospective nature of this study, detailed longitudinal data regarding the frequency and patterns of dose modifications were not consistently available for all patients.
Data Collection
The clinical data of patients with EGFR exon 21 mutant NSCLC were recorded carefully at baseline. Additionally, tumor responses were evaluated based on the RECIST criteria, where disease control was defined as complete response (CR), partial response (PR), or stable disease (SD) without progression. The PFS was defined as the time from the initiation of EGFR-targeted therapy to either disease progression or death, with patients who were alive and without progression at the time of the last follow-up being censored. The cutoff date for PFS analysis was March 2025. Treatment-related toxicities were recorded in detail according to the NCI-CTCAE version 4.0. The relationship between toxicities and the administered treatment was assessed. Throughout the study period, all clinical data were meticulously monitored to ensure accuracy and completeness.
Statistical Analysis
Statistical analyses were conducted using the Statistical Package for Social Sciences 26.0 software. Overall response rates (ORRs) and their 95% confidence intervals (CIs) were calculated separately for each treatment group. Differences in PFS between treatment groups were analyzed using the Kaplan-Meier survival curves, with comparisons performed using log-rank tests. Additionally, univariable Cox proportional hazards regression analyses were performed to explore potential factors associated with PFS. Multivariable Cox regression was not conducted due to the relatively small sample size and limited number of events to avoid model overfitting and unstable estimates. All tests were 2-sided, and P-values < .05 were considered statistically significant.
Results
Baseline Clinicopathologic Characteristics
The baseline clinicopathologic characteristics of patients included in this study are summarized in Table 1. The median ages were similar between the dacomitinib group and the first-generation EGFR-TKI group. Patients aged ⩾65 years accounted for 51.6% of the dacomitinib group and 45.7% of the first-generation EGFR inhibitors group. All patients had adenocarcinoma histology, with most presenting with stage IV disease at diagnosis (96.8% in the dacomitinib group vs 94.3% in the first-generation EGFR inhibitors group). Notably, brain metastases were present in 32.3% of patients in the dacomitinib group and 40% of those in the first-generation EGFR inhibitors group, respectively. None of these patients had prior treatment of brain metastases, such as surgery or radiotherapy. All patients harbored sensitive EGFR mutations, predominantly exon 21 L858R mutations (96.8% in the dacomitinib group and 97.1% in the first-generation EGFR-TKI group). Patients treated with low-dose dacomitinib received an initial dose of 15 or 30 mg/d, whereas those receiving first-generation EGFR inhibitors were treated with standard doses of gefitinib, erlotinib, or icotinib.
Clinicopathologic Characteristics of Patients Diagnosed With Advanced Lung Adenocarcinoma Harboring EGFR Exon 21 Mutation.
ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; PS, performance status.
In addition, baseline characteristics were compared between the 15 mg and 30 mg dacomitinib subgroups. Overall, the 2 groups were generally comparable with respect to key clinical variables, including age, sex, smoking status, and the presence of brain metastases. Specifically, the proportion of patients with brain metastases was similar between the 2 groups (31.3% vs 33.3%). Although a numerical difference in ECOG performance status was observed, this may be related to the limited sample size rather than a clear systematic imbalance.
Efficacy
The efficacy results of first-line treatment for patients with EGFR exon 21-mutated advanced NSCLC are summarized in Table 2. Among the 31 patients receiving low-dose dacomitinib, the objective response rate (ORR) was 67.7% (95% CI = 50.3-85.2). Specifically, the ORRs were 75% (95% CI = 51.2-98.8) and 60% (95% CI = 31.9-88.1) in the 15 and 30 mg/d groups (P = .389). In comparison, the ORR among patients treated with first-generation EGFR-TKIs was only 48.6% (95% CI = 31.2-66.0).
Efficacy Results of First-Line Treatment for Patients Diagnosed With Advanced Lung Adenocarcinoma Harboring EGFR Exon 21 Mutation.
The P-value of response rates: low dose of dacomitinib vs first-generation TKIs is 0.119. 15 mg group vs 30 mg group is 0.389. The P-value of median PFS: low dose of dacomitinib vs first-generation TKIs is 0.001. 15 mg group vs 30 mg group is 0.592. EGFR, epidermal growth factor receptor; PFS, progression-free survival; PR, partial response; SD, stable disease; TKIs, tyrosine kinase inhibitors.
The median PFS for the low-dose dacomitinib group was 14.2 months (95% CI = 12.4-15.9 months), which was significantly longer than the 7.9 months (95% CI = 5.0-10.8 months) observed in the first-generation EGFR-TKI group (P = .001) (Figure 1). Univariable Cox regression analysis further confirmed that treatment with low-dose dacomitinib was significantly associated with prolonged PFS (HR = 0.43, 95% CI = 0.25-20.7) (Supplementary Table S1). In the subgroup analysis of dacomitinib cohorts, although the median PFS in the 15 mg/d group (14.6 months; 95% CI = 13.7-15.4 months) was numerically higher than that in the 30 mg/d group (13.2 months; 95% CI = 7.9-18.5 months). However, no statistically significant difference was detected (HR = 0.81, 95% CI = 0.37-1.76; P = .594). This suggests that both low-dose regimens offered comparable clinical efficacy in this patient population, as indicated by the lack of a statistically significant difference between the 2 groups (Figure 2).
Kaplan-Meier curves for progression-free survival (PFS) of patients treated with low-dose dacomitinib and first-generation TKIs.
Kaplan-Meier curves for progression-free survival (PFS) of patients treated with 15 mg and 30 mg dacomitinib.
Treatment-Related Toxicities
The treatment-related toxicities are summarized in Table 3. The most common toxicities associated with low-dose dacomitinib were rash, pruritus, diarrhea, and fatigue. Most of these events were grade 1 and 2 and clinically manageable. The incidence of grade 1 and 2 rash, pruritus, and diarrhea in the low-dose dacomitinib group (38.7%, 29%, and 25.8%, respectively) was comparable to that observed in the first-generation EGFR-TKI group (34.3%, 20%, and 22.9%, respectively). Other AEs, including anorexia, anemia, fatigue, nausea, and elevated aminotransferase levels, occurred at similar frequencies across both treatment cohorts.
Treatment-Related Toxicities.
Notably, the 15 mg/d dacomitinib group exhibited a significantly better safety profile with respect to severe dermatologic toxicities, with no grade 3 and 4 rash observed in the 15 mg/d group, whereas the incidence reached 33.3% (5/15) in the 30 mg/d group. Grade 3 and 4 toxicities were overall rare in the total low-dose dacomitinib population, with only 5 cases of rash (16.1%), 2 cases of anemia (6.5%), and 1 case of diarrhea (3.2%). In the 15 mg/d cohort, only 1 case of grade 3 and 4 anemia (6.3%) was recorded, with no instances of severe rash or diarrhea. Overall, these data demonstrated that initial low-dose dacomitinib, particularly at 15 mg/d, provides a favorable safety profile with a markedly reduced toxicity burden compared with historical standard-dose data.
Discussion
The therapeutic efficacy of dacomitinib as a first-line intervention for advanced EGFR-mutated NSCLC was initially established in the phase II ARCHER 1042 study and subsequently corroborated by the phase III ARCHER 1050 trial.17-19 We acknowledge that third-generation EGFR-TKIs, particularly osimertinib, are now widely used as the standard first-line treatment for EGFR-mutant NSCLC.20,21 However, dacomitinib remains clinically relevant for several reasons. In the Asian subgroup analysis of ARCHER 1050, dacomitinib significantly improved both PFS and OS compared with gefitinib, and benefit was also observed in patients harboring exon 21 L858R mutations. 22 Importantly, OS was maintained in patients who underwent dose reduction, supporting the feasibility of dose-optimization strategies.
In addition, dacomitinib has been recognized as an important first-line option in EGFR-mutated NSCLC when toxicities can be appropriately managed. 23 From a real-world perspective, treatment selection is influenced not only by efficacy but also by accessibility, cost, and tolerability. 24 Pharmacoeconomic analyses have suggested that dacomitinib may be cost-effective or more economical than osimertinib in certain healthcare systems. 25 Therefore, rather than challenging the current standard role of third-generation TKIs, the present study aimed to explore whether a low-dose dacomitinib strategy could preserve clinical benefit while improving tolerability in patients with EGFR exon 21-mutated NSCLC. Although dacomitinib demonstrated significant improvements in both PFS and OS compared to gefitinib, its clinical utility is often hampered by a substantial toxicity burden associated with the standard 45 mg starting dose. 26 In the ARCHER 1050 trial, a considerable proportion of patients required dose modifications, specifically, in the Asian subpopulation, approximately 67.6% of patients necessitated dose reductions to 30 mg or 15 mg to manage treatment-emergent AEs. In the Japanese subset, this figure was even higher, with 85.0% of patients requiring dose de-escalation due to toxicities such as dermatitis acneiform, paronychia, and diarrhea. 17
Evidence from the ARIA study and recent Asian real-world cohorts suggests that initiating treatment at a reduced dose (15 or 30 mg) does not compromise clinical outcomes. These findings are supported by the unique pharmacological and pharmacokinetic profiles of dacomitinib. As a second-generation irreversible pan-HER inhibitor, dacomitinib facilitates potent, covalent binding to the ATP-binding site of the EGFR kinase domain, ensuring sustained target inhibition even at reduced systemic concentrations.9,27 Quantitative PK analyses indicate that dacomitinib exhibits dose-proportional increases in systemic exposure within the 15 to 60 mg dose range, characterized by an extended elimination half-life (approximately 70 hours) that maintains stable steady-state plasma levels. Preclinical models further confirm that its high binding affinity with IC50 values in the low nanomolar range. This combination of irreversible binding and a long half-life suggests that a 15-mg daily dose provides sufficient systemic exposure to exceed the threshold required for the sustained inhibition of EGFR, particularly in exon 21-mutated subtypes. 28
In the ARCHER 1050 Asian population, post-hoc analyses revealed that OS was robustly maintained in patients who underwent dose reductions. Notably, the median OS for the dose-reduction group in the Asian cohort was “Not Reached” (95% CI = 39.5-NR), compared to 37.7 months in the overall Asian dacomitinib arm. 10 Our study aligns with these observations, demonstrating that initial low-dose dacomitinib yields superior efficacy compared with first-generation EGFR-TKIs. In this context, our objective was not to replace the current standard first-line therapy but to evaluate whether dose optimization could improve the therapeutic index of a clinically active second-generation EGFR-TKI in a real-world setting. These outcomes are consistent with the therapeutic benefits reported in standard-dose trials, reinforcing the validity of proactive dose optimization.14,15 Crucially, our subgroup analysis indicated that the efficacy of the 15 mg/d dose was comparable to that of the 30 mg/d dose. This observation was further supported by univariable Cox regression analysis, which demonstrated no significant difference in PFS between the 2 dosing strategies. These findings collectively suggest that a lower starting dose may achieve similar clinical benefit while improving tolerability.
Several limitations of this study should be acknowledged. First, the relatively small sample size may limit the statistical power of the analysis and increase the risk of type II error. Therefore, the absence of a statistically significant difference between the 15 mg and 30 mg groups should be interpreted with caution. Second, as a retrospective study, potential selection bias cannot be fully excluded. Accordingly, our findings should be considered exploratory and hypothesis-generating rather than definitive, and further validation in larger prospective cohorts is warranted.
Conclusion
In conclusion, our findings suggest that initial low-dose dacomitinib (15 or 30 mg/d) may represent a feasible and potentially safer dose-optimization strategy for patients with EGFR exon 21 L858R-mutated advanced NSCLC. This strategy offers comparable clinical efficacy in terms of ORR and PFS when compared to standard-dose historical data while significantly reducing the incidence of high-grade toxicities compared with first-generation EGFR-TKIs. Although these results demonstrate preliminary feasibility, particularly for patients with poor tolerability profiles, large-scale prospective randomized controlled trials are warranted to definitively validate the long-term impact of this dose-optimized approach.
Supplemental Material
sj-docx-1-onc-10.1177_11795549261454548 – Supplemental material for Initial Low-Dose Dacomitinib for First-Line Treatment of Patients With EGFR Exon 21-Mutated Non-Small-Cell Lung Cancer
Supplemental material, sj-docx-1-onc-10.1177_11795549261454548 for Initial Low-Dose Dacomitinib for First-Line Treatment of Patients With EGFR Exon 21-Mutated Non-Small-Cell Lung Cancer by Ke-Jun Liu, Lin-Xuan Huang, Guan-Ming Jiang, Ning-Ning Guo, Qing-Lin Tan, Yan-Min Cai, Shi-Yuan Chen, Wei Du, Nian-Xin Fang and Jun Jia in Clinical Medicine Insights: Oncology
Footnotes
Acknowledgements
The authors thank the doctors, nurses, patients, and their family members for their support. The authors also thank their colleagues for their technical assistance, psychological support, and valuable guidance during this study. The abstract was previously published in the 2021 ASCO Annual Meeting under the DOI: 10.1200/JCO.2021.39.15_suppl.e21083.
Ethical Considerations
The present study was approved by the Ethics Committee of The Tenth Affiliated Hospital, Southern Medical University (Dongguan People’s Hospital) (approval no KYKT2021-032) at November 18, 2021, and was conducted according to the Declaration of Helsinki.
Consent to Participate
Informed written consent was not necessary owing to the retrospective nature of the study, according to national regulations.
Author Contributions
Jun Jia, Nian-Xin Fang, and Wei Du designed the investigation and supervised the study. Qing-Lin Tan, Yan-Min Cai, and Shi-Yuan Chen performed the investigation. Guan-Ming Jiang and Ning-Ning Guo provided essential assistance and analyzed data. Ke-Jun Liu and Lin-Xuan Huang designed and performed the research, analyzed data, and wrote the article. All authors read and approved the final manuscript and agreed to be accountable for all aspects of the work presented in the manuscript.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the Guangdong Basic and Applied Basic Research Foundation, China (grant no. 2021B1515140031).
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
The datasets generated or analyzed during the current study are available from the first author upon reasonable request.
Supplemental Material
Supplemental material for this article is available online.
References
Supplementary Material
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