Efficacy of dacomitinib in patients with non-small cell lung cancer carrying complex EGFR mutations: a real-world study

Introduction

The most common mutations on the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) are called “common mutations”, and include exon 19 deletion (19Del) (49–72%) and L858R (28–43%) (1). They have shown a remarkable response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) which include first-generation TKI (gefitinib, erlotinib), second generation TKI (afatinib, dacomitinib), and third-generation TKI (osimertinib), while other mutations (10–20%) on EGFR are called “uncommon mutations” or “rare mutations”, with a significant heterogenic response to EGFR-TKIs (1-5). Some uncommon mutations, including G719X, S768I, and L861Q, are also called “major uncommon mutations” and are sensitive to different generations of TKIs, especially afatinib. In comparison, T790M and exon 20 insertion mutations are insensitive to most listed TKIs (except for osimertinib) (2,6-8). Compound mutations are defined as the coexistence of two or more EGFR mutations, regardless of these being common or uncommon mutations, and they are associated with poor prognosis in patients that carry them (9). With the improvement of molecular detection technologies, the proportion of the identified compound mutations has been increased significantly up to 26% (9,10). However, studies on compound mutations are limited due to the numerous permutations between common and uncommon mutations and the variety of uncommon mutation types. These studies are primarily retrospective and have divergent findings, thus leading to a lack of clinical data to confirm and help physicians make decisions for clinical practice (4,5).

As an irreversible, highly selective, second-generation EGFR-TKI, dacomitinib can inhibit signaling from all members of the human EGFR family. The ARCHER 1,050 study demonstrated significantly improved progression-free survival (PFS) [14.7 vs. 9.2 months, hazard ratio (HR) 0.59; 95% confidence interval (CI), 0.47–0.74; P<0.0001] of dacomitinib over gefitinib, leading to its approval as a new standard first-line treatment in patients with EGFR-positive NSCLC (11). In addition, a few published studies have indicated that dacomitinib has potential applications in patients harboring uncommon mutations (12,13), although no conclusive evidence has been presented thus far.

Therefore, to evaluate the efficacy of dacomitinib, we retrospectively analyzed 18 patients with NSCLC harboring complex EGFR mutations by focusing only on complex mutations that include a common mutation and an uncommon mutation. We present the following article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-21-1841/rc).

Methods

Patient eligibility and data collection

Patients were enrolled from the outpatient department of the Chinese PLA General Hospital and the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, and the Peking Union Medical College. Eligible patients met the following requirements: (I) cytologically or histologically confirmed diagnosis of NSCLC; (II) unresectable stage III patients who refused to receive chemoradiotherapy or stage IV patients; (III) harbored common EGFR mutations (19del or L858R, set as C group) or complex EGFR mutations (including a common mutation and an uncommon mutation, set as C+U group) excluding exon 20 insertion mutations and T790M; and (IV) tumor tissue or cell-free DNA were available from plasma, pleural effusion, or cerebrospinal fluid samples and were tested using next-generation sequencing (NGS) which was performed by qualified third-party genetic testing companies that had been accredited by the College of American Pathologists (CAP) before dacomitinib treatment. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Research Ethics Boards of the Chinese PLA General Hospital and the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital (No. 18-070 and 1648). The Research Ethics Boards waived the need for informed consent as this was a retrospective study.

Treatment and efficacy/toxicity evaluation

All patients were treated with dacomitinib alone in a multi-line setting. The physician determined the starting dose based on the patient’s condition. In general, the starting dose was 45 mg for patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 and weight ≥60 kg; 30 mg for patients with a PS of 1 and weight ≤60 kg; 30 mg for patients with a PS of 1 and weight ≥60 kg, with an increase to 45 mg if the patient had a good tolerance; and 15 mg for patients with PS ≥2. Imaging evaluation included chest computed tomography (CT) scans and brain magnetic resonance imaging (MRI), performed every 1–2 months after drug administration. Objective tumor response was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) guidelines (14). The objective response was divided into two categories: complete response (CR) and partial response (PR), while disease control included CR, PR, and stable disease (SD) combined. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Statistical analysis

Categorical variables were reported as numbers and percentages. The chi-square test was used for comparison between different groups. The data cut-off date was September 21, 2021, when the disease status of the patients was confirmed. PFS was defined as the time from dacomitinib administration to disease progression or death from any cause. Overall survival (OS) was defined as the time from dacomitinib administration to death from any cause. Patients who were lost to follow-up were judged to be censored and the last determinable time of survival was used as the time of termination of follow-up. The relationship between various variables and survival was evaluated using the Kaplan-Meier method. Differences between survival curves were tested for statistical significance using log-rank tests. To reduce the effect of confounding factors, stratified analyses of clinical characteristics that differed significantly between the two groups were conducted. Significant prognostic predictors for patients identified by univariate analyses were further assessed by multivariate analyses using the Cox proportional hazards regression model. Statistical analyses were performed, and analytic graphs were created using GraphPad Prism 8 software (GraphPad Software, San Diego, CA, USA). An α value of 0.05 was used as the examination standard.

Results

Baseline characteristics

In total, 72 patients with NSCLC harboring complex EGFR mutations (C+U group, n=18) or common EGFR mutations (C group, n=54), who were treated with dacomitinib, were enrolled in two medical centers between August 2019 and August 2021. The baseline characteristics of the two cohorts are displayed in Table 1. For the C+U group, there were 12 women (66.7%) and 6 men (33.3%), with a median age of 68 years (range, 50–81 years). More than 70% of the patients were non-smokers, and adenocarcinoma was the histologic type detected in all patients. More than half of the patients (55.6%, 10/18) received dacomitinib as the first-line treatment, and nearly 70% of patients received it at a dosage of 30 mg. The L858R was the most frequent mutation (88.9%, 16/18) in complex EGFR mutations (Table 1). The ECOG PS of the 18 patients ranged from 0 to 2, and most patients (77.8%, 14/18) had PS ≤1. Except for the application line of dacomitinib, no significant statistical differences between the C and C+U groups were found in other characteristics, including age, sex, smoking history, histology, disease stage, and common mutation status (Table 1). More patients in the C+U group received dacomitinib as the first-line treatment than those in the C group (55.6% vs. 25.9%, P=0.039).

Genetic profiling

Tumor tissue or cell-free DNA from plasma, pleural effusion, or cerebrospinal fluid samples before dacomitinib treatment were tested using the NGS method in all patients. Figure 1 shows the three-dimensional distribution of uncommon mutations in complex mutations and the corresponding number of cases of the C+U group. Figure 2 shows the details of uncommon mutations, common mutations, and accompanying mutations. Sixteen patients (88.9%) harbored L858R co-existing with rare mutations located in exon 18 to exon 25 of EGFR (mostly E709X in exon 18), and two harbored 19del co-existing with G724S or K754E. The most common concomitant mutations were detected in TP53 (tumor protein p53), CDK4/6 (cyclin-dependent kinase 4/6), and STK11 (serine/threonine kinase 11) genes (Figure 2). In the C group, the most common mutation was also L858R (75.9%, 41/54), and the most common accompanying mutations were TP53, PI3KCA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) point mutations, MET (MET proto-oncogene, receptor tyrosine kinase), and EGFR amplification (Figure S1).

Figure 1 Three-dimensional distribution of uncommon mutations in the C+U group and corresponding number of cases (n=18). We labeled all the uncommon mutation sites co-existing with L858R (A) or 19del (B) carried by the patients in the C+U group in the spatial structure of epidermal growth factor receptor-kinase domain (PDB:4I23). The graph was remodeled in PyMOL software. C+U, common mutations combined with uncommon mutations.

Figure 2 Best change in total target lesion size, genetic profile, and progression-free survival in the C+U group by patient (n=15). (A) Treatment responses of dacomitinib in 15 evaluable patients are shown in the waterfall plot. Patients with brain metastases are marked with black triangles. *, this patient also received whole brain radiotherapy. Dashed lines represent 20% progression (progressive disease) and 30% tumor regression (partial response). (B) The genetic profile (left panel) and progression-free survival (right panel) in the C+U group by patient (n=18) were displayed. The case numbers in Figure 1 and Figure 2 correspond to each other. C+U, common mutations combined with uncommon mutations. amp, amplication; PFS, progression-free survival.

Efficacy/toxicity evaluation

Among the 15 evaluable patients (3 patients could not be evaluated due to lack of target lesions) in the C+U group, 6 (40%), 5 (33.3%) and 4 (26.7%) had PR, SD, and de novo resistance to dacomitinib with PD as the best response, respectively. The objective response rate (ORR) was 40% (6/15) and the disease control rate (DCR) was 73.3% (11/15) (Figure 2A). At the data cut-off date, the median PFS (mPFS) was 7.5 months (95% CI, 4.4–10.6 months), and the median follow-up duration was 8.6 months (95% CI, 3.4–13.8 months) in the C+U group. The PFS was mature in 11 (61.1%) patients, and the tumors of seven patients were still under control (Figure 2B). In contrast, among the 48 evaluable patients (6 patients could not be evaluated due to lack of target lesions) in the C group, the ORR was 33.3% (16/48), and the DCR was 77.1% (37/48) (Figure S1). At the data cut-off date, the mPFS was 6.1 months (95% CI, 4.3–7.9 months), and the median follow-up duration was 10.5 months (95% CI, 8.1–12.9 months) in the C group. However, there were no significant differences in ORR (P=0.636) (Figure 3), DCR (P=0.765) (Figure 3), PFS (P=0.889) (Figure 4), and OS (P=0.703) (Figure 4) between the C and C+U groups.

Figure 3 Stratified analyses of objective response rate and disease control rate of the whole cohort (n=72). The objective response rate (P=0.636) as well as disease control rate (P=0.089) of the C group was not significantly different compared with the C+U group. However, the C+U group showed a worse treatment response than the C group in all application line subgroups (A), although the differences were not statistically significant. Patients in the C+U group receiving third-line dacomitinib had a significantly lower disease control rate than those in the C group (P=0.040) (B). *, this indicates a statistically significant difference between the two groups. Comparisons between the two groups were made using the chi-square test. C+U, common mutations combined with uncommon mutations.

Figure 4 Stratified analyses of progression-free survival and overall survival of the whole cohort (n=72). In the survival analysis, the progression-free survival (P=0.889) (A) as well as OS (P=0.703) (B) of the C group was not significantly different compared with the C+U group. However, the progression-free survival of the C+U group was worse than that of the C group when receiving 1^st (P=0.047) (C) or ≥3^rd (P=0.018) (G) line dacomitinib treatment, and the OS of the C+U group was worse than that of group C when receiving ≥3^rd line treatment (P=0.003) (H). C+U, common mutations combined with uncommon mutations; OS, overall survival.

All patients had grade 1–2 adverse effects (AEs), but no grade 4–5 treatment-emergent AEs occurred. No significant differences were found in grade 1–3 AEs between the C and C+U groups (Table 2). In the C+U group, only one patient required a dosage reduction from 45 to 15 mg due to intolerable grade 3 rash, and one patient had a dosage increase from 30 to 45 mg due to good tolerance. In the C group, 2 patients required a dosage reduction from 45 to 15 mg due to intolerable grade 3 diarrhea or rash, and 3 patients had a dosage increase from 30 to 45 mg due to good tolerance.

Survival analysis

Stratified analyses

Given the significant differences of baseline characteristics in the application line of dacomitinib between the C and C+U groups, we conducted stratified analyses on ORR, DCR, PFS, and OS based on different application lines. The total ORR (33.3% vs. 40.0%, P=0.636) and the DCR (77.1% vs. 73.3%, P=0.089) of the C group were not significantly different compared with those of the C+U group (Figure 3). However, stratified results showed that the ORR gradually decreased as the application line moved back. The C+U group showed a worse treatment response than the C group in all application line subgroups (Figure 3A), although the difference was not statistically significant. Patients in the C+U group receiving third-line dacomitinib had a significantly lower DCR than those in the C group (P=0.040) (Figure 3B). In the survival analysis, both the PFS (P=0.889) (Figure 4A) and OS (P=0.703) (Figure 4B) of the C group were not significantly different compared with those of the C+U group. However, stratified analyses demonstrated that the PFS of the C+U group was worse than that of the C group when receiving first-line (P=0.047) (Figure 4) or ≥ third-line (P=0.018) (Figure 4) dacomitinib treatment, and the OS of the C+U group was worse than that of the C group when receiving ≥ third-line treatment (P=0.003) (Figure 4).

Univariate and multivariate analyses

To determine the effect of the compound mutation status on prognosis, we conducted univariate and multivariate analyses (Table 3) for the whole cohort (C group plus C+U group). In the univariate analysis, age (P=0.037), smoking status (P=0.033), total tumor burden (P=0.011), and administration of dacomitinib (P<0.001) were all statistically significant prognostic factors for PFS, while only the application line of dacomitinib (P<0.001) was a statistically significant prognostic factor for OS. In the multivariate analysis, smoking status (HR =2.541, 95% CI: 1.069–6.040; P=0.035), brain metastases (HR =0.467, 95% CI: 0.232–0.946; P=0.035), and application line of dacomitinib (HR =5.049, 95% CI: 1.694–15.050; P=0.004) were independent predictors of PFS, whereas only smoking status (HR =5.971, 95% CI: 1.118–31.888; P=0.037) and compound mutation status (HR =5.405, 95% CI: 1.096–26.316; P=0.038) were independent predictors of OS (Table 3).

Discussion

According to previous studies, the incidence of complex EGFR mutations can be as high as 26%, which may be attributed to the progressive improvements in detection technology (4,9,10). Based on the combination mode and the incidence of different types of uncommon mutations, complex EGFR mutations can be roughly divided into the following four main types: (I) a combination of uncommon and common mutations (such as E709K + L858R) (C+U group in our study), (II) double major uncommon mutations (such as G719X + S768I), (III) major uncommon mutations combined with non-major uncommon mutations (such as G719X + R108K), and (IV) double common mutations (such as 19del + L858R) (1,3,15-18). In our study, we focused on the first type of complex EGFR mutations. To the best of our knowledge, there are only a few reports on the efficacy of dacomitinib on treating complex EGFR mutations, and the influence of complex mutations on prognosis remains elusive. Our study revealed that patients with NSCLC harboring uncommon mutations combined with common mutations (C+U group) were less responsive to treatment with dacomitinib than those harboring common mutations (C group).

Currently, EGFR-TKIs have the best therapeutic outcomes for common mutations, with the outcomes for uncommon mutations being generally inferior to common mutations (19,20), except for some sensitive major uncommon mutations (including G719X, L861Q, and S768I) (21). Compound mutations imply the presence of heterogeneous clones (both primary and secondary) within the tumor and heterogeneity in the therapeutic response. It is taken for granted that the primary clone determines the outcome of treatment, but according to previous studies (22,23), the treatment response does not depend exclusively on the primary clone but mainly on the concomitant mutations (secondary clone). When a common or major uncommon mutation is combined with a sensitive uncommon mutation (such as L858R + G719C, G719C + S768I), the therapeutic effect is not necessarily affected (19). However, when it is combined with a resistant uncommon mutation (such as L858R + Q787R, L858R + H870R, and G719C + E709K), the therapeutic effect is generally diminished (22).

Keam et al. (19) found no significant difference in ORR (74.8% vs. 68.8%) and mPFS (11.9 vs. 8.1 months) between the common mutations group (n=16) and the group of combined uncommon and common mutations (n=16) who received either gefitinib or erlotinib. However, Hata et al. (24) revealed that patients who mainly received gefitinib harboring 19del and L858R had a better ORR (86%, 6/7) than those that carried uncommon mutations combined with common mutations (40%, 2/5). No statistical significance was detected (P=0.222), although the mPFS was longer in the former group (16.5 vs. 3.8 months) (P=0.046). By comparing NSCLC patients harboring common EGFR mutations (n=97), Tan et al. (3) revealed that treatment outcomes of patients harboring uncommon mutations combined with common mutations (n=52, similar to the first complex mutations type defined in our study), complex uncommon mutations (n=22, as the combination of the second and third complex mutations types defined in our study), and uncommon mutations treated with first-line gefitinib/erlotinib/icotinib or afatinib were significantly different (ORR: 76.3%, 61.5%, 54.5%, and 50.0%, P=0.023; mPFS: 13.3, 14.7, 8.1, and 6.0 months, P=0.004). We speculate that these conflicting results may arise from the study size and treatment context (e.g., number of lines treated) in the different studies.

In our study, contrary to the results of Tan et al. (3), patients in the C group harboring 19del or L858R had a better ORR (71.4%, 10/14) than those in the C+U group (62.5%, 5/8), although not statistically significant (P=0.665). In addition, the mPFS was also longer in the C group (not reached vs. 7.5 months; P=0.047). This suggests that the treatment disadvantages caused by uncommon mutations in the C+U group cannot be reversed by second-generation TKI dacomitinib. Besides, an in vitro study by Nishino et al. showed that, several uncommon EGFR mutations (including L718Q, L718V, L792H, and L792F) combined with L858R could lead to various responses when dacomitinib were administrated on Ba/F3 cells, and most combinations had worse responses than the single L858R did (25). Nevertheless, previous studies suggested that the second-generation TKI, afatinib, showed superior efficacy over gefitinib/erlotinib/icotinib in patients harboring uncommon mutations combined with common mutations (ORR: 100% vs. 54.5%, P=0.017; mPFS: not reached vs. 13.6 months, P=0.032) (1,3,17). Another point we should mention is that, in addition to second-generation TKI, limited evidence showed that the third-generation TKI osimertinib also had promising efficacy for EGFR uncommon mutations (2). However, the efficacy of osimertinib for compound EGFR mutations warrants more data to confirm.

Recently, several studies have shown that dacomitinib is potentially effective in EGFR-positive NSCLC with central nervous system metastasis, with the ORR ranging from 87.5–92.9% and DCR of 100% (26-29). Peng et al. demonstrated that a patient with brain metastases harboring G719A achieved an objective response, indicating a potential therapeutic effect in NSCLC patients harboring uncommon mutations with brain metastases (26). It is worth mentioning that, in our study, we did not observe any significant differences in the ORR (40% vs. 42.9%, P=0.893), DCR (90% vs. 71.4%, P=0.234), or mPFS (10.2 vs. 6.8 months, P=0.721) in NSCLC patients with brain metastases between the C and C+U groups. This shows that dacomitinib still has a good intracranial control ability in a population harboring a combination of common and uncommon mutations. To our knowledge, this is the first study to report the benefits of dacomitinib in this subset of patients.

An interesting finding in our study is that in the C+U group, the proportion of L858R is significantly higher than that of 19del. In fact, the previous study conducted by Hong et al. suggested that, compared with patients with 19del, those with L858R were more likely to incorporate other concomitant mutations and had worse survival (30). Wu et al. (1) reported that L858R was the predominant subtype contained in the complex EGFR mutation, which could possibly explain the phenomenon in our study. Besides, the TP53 mutation rate was 18.5% as we calculated in the C group, which was indeed relatively lower than that reported by other scholars (~ more than 30%) (31), we thought that this may contributed to the heterogeneity of the gene testing panels and the relatively small number of the study population.

The wide application of highly sensitive NGS technology and the liquid-based mutation detection analysis in clinical practice can identify a broader spectrum of uncommon EGFR mutations. Determining the precise treatment based on these mutations is the next challenge we must embrace.

A limitation of this study is the small sample size of the C+U group, which may make the comparison with the C group not strongly convincing. Second, as this is not a multi-center study, selection bias cannot be avoided. Therefore, our data should be interpreted with caution. Furthermore, the resistance mechanisms of dacomitinib have not been investigated thus far.

In conclusion, through limited cases, this real-world study revealed a worse response and prognosis of patients with NSCLC harboring complex EGFR mutations than those harboring common EGFR mutations when treated with dacomitinib. Nevertheless, according to the limited available evidence and our study results, second-generation EGFR-TKI dacomitinib is optional for this subset of patients, especially for those with brain metastases.

Acknowledgments

We would also like to thank Editage (www.editage.cn) for English language editing.

Funding: This work was supported by the National Natural Science Foundation of China (Grant No. 82072590) and the Beijing Health Promotion Association (Grant No. 2021-053-ZZ).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-21-1841/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-21-1841/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-21-1841/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 (as revised in 2013). The study was approved by the Research Ethics Boards of the Chinese PLA General Hospital and the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital (No. 18-070 and 1648). The Research Ethics Boards waived the need for informed consent as this was a 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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