A real‐world study of dacomitinib in later‐line settings for advanced non‐small cell lung cancer patients harboring EGFR mutations

Abstract Objective Dacomitinib has been approved for the first‐line treatment of non‐small cell lung cancer (NSCLC) carrying classical epidermal growth factor receptor (EGFR) mutations; however, real‐world data on its later‐line application are lacking. Materials and methods Patients’ data were retrospectively collected from the Chinese National Cancer Center and the PLA hospital between August 2019 and August 2021. Kaplan‐Meier method and Log‐rank test were utilized to assess progression‐free survival (PFS) and overall survival (OS). Univariate and multivariate Cox regression analysis was conducted to determine prognostic indicators. Results In total, 56 NSCLC patients harboring EGFR mutations treated with later‐line single dacomitinib or combinatory dacomitinib were enrolled. A total of 53 patients (94.6%) had treatment‐related adverse events; eight patients (14.3%) had grade 3 or 4 events. Among 49 evaluable patients, 26.5% (13 patients) had a confirmed partial response and 73.5% (36 patients) had disease control; the median duration of follow‐up was 9.6 months (95% confidence interval [CI], 8.4–10.8 months), the median progression‐free survival was 5.4 months (95% CI, 3.5–7.3 months), and the half‐year, 1‐year, and 2‐year OS rate were 79.2%, 70.6%, and 64.1%, respectively. Univariate analysis suggested that smoking, line of dacomitinib, and interval between last EGFR‐tyrosine kinase inhibitor (TKI) and dacomitinib were associated with PFS and OS; chemotherapy between last EGFR‐TKI and dacomitinib, and EGFR‐TKI generation followed by dacomitinib were respectively associated with PFS and OS; multivariate analysis indicated chemotherapy between last EGFR‐TKI and dacomitinib negatively affect PFS, and smoking and third‐generation EGFR‐TKI followed by dacomitinib negatively affect OS. Conclusions This real‐world study has shown that dacomitinib is active and well‐tolerated in NSCLC patients harboring different EGFR mutations in later‐line settings, even for those with brain metastases. Patients who benefited more from the first TKI were more likely to benefit from dacomitinib, and earlier application of dacomitinib after front‐line TKI resistance may be considered.


| INTRODUCTION
Dacomitinib is a second-generation (2G), irreversible, highly selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that inhibits signaling from both heterodimers and homodimers of all members of the human EGFR family. The glorious ARCHER 1050 trial laid the foundation for its use as one of the standard first-line options in patients with EGFR-mutant non-small cell lung cancer (NSCLC). 1 In 2018, Food and Drug Administration approved dacomitinib in the above setting due to its significantly improved median progression-free survival (mPFS) over gefitinib (14.7 vs. 9.2 months, p < 0.0001) in the ARCHER 1050 study.
Notably, due to study design, re-biopsy difficulty, and blood gene testing availability at that time, these clinical trials did not include mutation status after front-line TKI treatment, especially for T790M (the key resistance mechanism to 1G/2G TKIs, being detected in more than 50% patients), as a basis for grouping and subgroup analysis. Although dacomitinib efficacy against T790M mutation was observed in a variety of human tumor xenograft models, 5 effective inhibition of T790M is only possible at clinically unattainable concentrations. On the other hand, in patients who are negative for T790M and other targetable targets (e.g., MET [MET proto-oncogene, receptor tyrosine kinase] mutations) after progression on a front-line 1G/2G TKI, dacomitinib is theoretically more therapeutically advantageous due to its general inhibition of the entire EGFR family.
In this study, we retrospectively analyzed 56 Chinese NSCLC patients harboring EGFR mutations progressed on previous therapies in two medical centers, explored the treatment patterns, and evaluated the real-world efficacy and safety of later-line dacomitinib utilizing nextgeneration sequencing (NGS).

| Patient eligibility and data collection
Patients were retrospectively collected from the Chinese PLA General Hospital and National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College. Eligible patients had a histologically confirmed diagnosis of unresectable stage III or stage IV NSCLC harboring NGS-confirmed EGFR mutations. All patients had received standard front-line treatment (TKI and/or chemotherapy) and progressed before dacomitinib administration. Tumor tissue or cellfree DNA (cfDNA) from plasma, pleural effusion, or cerebrospinal fluid samples before dacomitinib treatment were tested using targeted NGS, which was performed by qualified third-party genetic testing companies that had been accredited by the College of American Pathologists (CAP). The NGS was performed as routine care in our study population, and the results were already available before the patients initiated dacomitinib administration. This research was conducted under the Declaration of Helsinki and approved by Research Ethics Board. Because this was a retrospective cohort study, informed consent was waived.
Conclusions: This real-world study has shown that dacomitinib is active and well-tolerated in NSCLC patients harboring different EGFR mutations in laterline settings, even for those with brain metastases. Patients who benefited more from the first TKI were more likely to benefit from dacomitinib, and earlier application of dacomitinib after front-line TKI resistance may be considered.

K E Y W O R D S
application, dacomitinib, later-line, non-small cell lung cancer, real-world 2.2 | Treatment and efficacy/ toxicity evaluation All patients were treated with later-line single dacomitinib or combinatory dacomitinib. The starting dose was determined by the physician based on the patient condition. In general, the starting dose was 45 mg for patients with the Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 and the weight ≥60 kg; 30 mg for patients with the PS of 1 and the weight <60 kg; 30 mg for patients with the PS of 1 and the weight ≥60 kg, with an increase to 45 mg if the patient could tolerate well; and 15 mg for patients with PS ≥2. Tumor responses assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) include complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). The ORR was defined as the sum of CR + PR ratio, and the DCR was defined as the sum of CR + PR + SD ratio. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

| Statistical analysis
Categorical variables are reported as numbers and percentages. Survival curves were created using the Kaplan-Meier method and compared using the Log-rank test. Univariate and multivariate Cox proportional hazards models were used to evaluate the relationships between the various characteristics and OS/PFS, with the results reported as hazard ratios (HRs) and 95% confidence intervals (CIs). The multivariate analysis included significant characteristics from the univariate analyses and characteristics that were considered clinically significant and was performed using the backward likelihood ratio (Backward LR) test. Scatter plots were used to assess correlations and Pearson coefficients were used to assess the strength of correlations. The data cut-off date was August 15, 2021, when the survival status of the patients was determined. PFS was defined as the time from dacomitinib administration to disease progression or death from any cause, whereas OS was defined as the time from dacomitinib administration to death from any cause. Statistical analyses were performed and pictures were created using GraphPad Prism 8 software (GraphPad Software). Differences were considered statistically significant at two-sided p values of less than 0.05.

| Baseline characteristics
In this retrospective study, 56 EGFR-mutant NSCLC patients with/without brain metastases were treated with later-line dacomitinib between August 2019 and August 2021. Table 1 demonstrated the demographic, clinicopathologic, and molecular characteristics of this cohort. Nearly 47% of patients were women (26 of 56) and more than 62% were non-smokers (35 of 56). Ages varied between 31 and 83 years. Almost all (55 of 56) pa tients had adenocarcinoma as the main histologic type of their tumor. Of the 56 patients, 5 had stage III and 45 had stage IV, and 6 patients had undergone resection of early-stage lung cancer or radical chemoradiotherapy previously and they had recurred as stage IV NSCLC. As to the mutation type, most patients (53.6%) harbored 21L858R, and nearly 30% carried 19del; rare mutations accounted for nearly 20%. Twenty-three patients (41.1%) had one or more nodules in the brain. Patients had received a median of 3 (range, 2-13) previous lines of therapies before dacomitinib for advanced disease; most patients (33.9%) received dacomitinib as third-line therapy. The most frequently used TKIs before dacomitinib were osimertinib, gefitinib, and icotinib, respectively. For TKI-pretreated patients (n = 54), most patients (50 patients, 92.6%) were negative for T790M before dacomitinib administration. The ECOG PS of the 56 patients ranged from 0 to 4; 5 (8.9%) patients had a score of 0, 44 (78.6%) had a score of 1, and 7 (12.5%) patient had a score of ≥2.
A total of 53 patients (94.6%) had treatment-related adverse events (TRAEs) and 8 patients (14.3%) had grade 3 or 4 TRAEs, but no grade 5 TRAEs occurred ( Table 2).  Interestingly, when we analyzed the effect of chemotherapy on the efficacy of dacomitinib between the application of the last TKI and dacomitinib, we found that patients who did not receive chemotherapy during the period had a better PFS (p = 0.027) than those who did, although not a better OS (p = 0.141) ( Table 3). In addition, when we compared the efficacy of chemotherapy with dacomitinib after the last TKI treatment, a trend of better PFS (mPFS, 6.5 vs. 5.0 months; p = 0.265) and OS (mOS, not reached vs. 13.7 months; p = 0.130) of dacomitinib was revealed, although differences were not significant (Table 3). We also found a significant shortening of both mPFS (p = 0.036) and mOS (p = 0.045) when the duration of the interval between the last TKI and dacomitinib exceeded 4 months. Moreover, a better OS (not reached vs. 13.7 months, HR = 0.333, 95% CI 0.106-0.978; p = 0.048) but not PFS ( Figure S2D)

| Survival analysis
Similar to the results from Kaplan-Meier method, univariate regression analysis also revealed that smoking, line of dacomitinib, and interval between last TKI and dacomitinib were associated with PFS and OS; chemotherapy between last TKI and dacomitinib, and TKI generation followed by dacomitinib were respectively associated with PFS and OS. Multivariate analysis indicated that PFS was only independently predicted by chemotherapy between last EGFR-TKI and dacomitinib (HR  Table 3) and OS was independently predicted by smoking (HR 0.270; 95% CI 0.093-0.785; p = 0.016) and TKI generation followed by dacomitinib (HR 0.238; 95% CI 0.073-0.776; p = 0.017).

| Correlation analyses
A scatter plot analysis of the PFS of dacomitinib between treatment duration of first TKI and interval between last TKI and dacomitinib is shown in Figure 3(A,B). The PFS of dacomitinib was positively correlated with treatment duration of first TKI (r = 0.332, p = 0.014) and negatively correlated with interval between last TKI and dacomitinib (r = −0.293, p = 0.032).
Correlations with the treatment duration of last TKI, the interval between first TKI and dacomitinib, and interval regimen number were also examined and none were found to be associated with the efficacy of dacomitinib administration (data not shown).

| DISCUSSION
This is one of the largest real-world studies that evaluated the efficacy of dacomitinib for patients with advanced NSCLC harboring EGFR mutations in later-line settings. At the time of analysis, the median duration of follow-up was 9.6 months (range, 8.4-10.8), the mPFS was 5.4 months (95% CI, 3.5-7.3 months), and the half-year, 1-year, and 2-year OS rate were 79.2%, 70.6%, and 64.1%, respectively. The ORR and DCR were 26.5% and 73.5% in the whole cohort, respectively. Multivariate analysis indicated chemotherapy between last EGFR-TKI and dacomitinib negatively affect PFS, and smoking and thirdgeneration EGFR-TKI followed by dacomitinib negatively affect OS. Correlation analysis revealed PFS of dacomitinib was positively correlated with treatment duration of first TKI and negatively correlated with interval between last TKI and dacomitinib. Our results show that dacomitinib is active in advanced NSCLC patients harboring EGFR mutations in later-line settings.
Currently, chemotherapy (with or without antivascular drugs or immunotherapy) is recommended for patients who have been resistant to previous TKI(s) and harbor no secondary targetable genes [6][7][8] ; however, post-TKI chemotherapy has only mediocre efficacy. Therefore, patients harboring sensitizing EGFR mutations and progressed on previous TKI therapy have an unsatisfied medical need.
For patients after 1G/2G TKI resistance, in the 1G/2G TKI→dacomitinib cohort of our study, an ORR of 36.4% was obtained, with an mPFS of up to 7.8 months, while mOS has not been achieved; however, the results of the classic AURA3 study showed that for patients treated with conventional chemotherapy regimens after the failure of first-line EGFR-TKI therapy, the mPFS and mOS was only 4.4 and 22.5 months respectively, with an ORR of 31.0%. 9 This suggests that the application of dacomitinib after 1G/2G TKI progression may be no worse than or even better than chemotherapy. In the phase III study BR.26, 2 the efficacy of dacomitinib versus placebo was assessed in patients progressing on conventional chemotherapy and at least one previous first-generation TKI (erlotinib or gefitinib). In re-grouped patients harboring EGFR mutations, dacomitinib obtained an ORR of 11.4%, and slightly improved the mPFS from 0.95 to 3.52 months, but did not prolong the mOS (7.52 vs. 7.23 months). We speculate that the reasons for the markedly improved ORR and prolonged PFS in our study include the following: (1). Clear genetic testing guidance. All patients in our study underwent genetic testing before dacomitinib, and the vast majority (52/56) of them were T790M-negative patients. As shown in our study, three of the four T790Mpositive patients showed de novo resistance to dacomitinib, and only 1 patient got SD as best response; (2). The majority of patients in the 1G/2G TKI→dacomitinib cohort (16/25) did not receive chemotherapy before dacomitinib. As found in our study, the absence of chemotherapy between front-line TKI and dacomitinib resulted in a longer PFS. For patients after 3G TKI (mostly osimertinib) resistance, in the 3G TKI→dacomitinib cohort of our study, an ORR of 16.0% was achieved, with an mPFS of 3.8 months and mOS of 13.7 months. 10 This was very close to the study data reported by White et al.,11 in which the patients with advanced EGFR-mutant lung cancer received platinum doublet chemotherapy regimens after progression on osimertinib got a median time on treatment of 3.9 months (95% CI 1.9-7.8 months) and OS of 12.8 months (95% CI 6.9-19.5 months), indicating a comparable efficacy of later-line dacomitinib and chemotherapy.
When we compared the efficacy of chemotherapy with dacomitinib head-to-head after the last TKI treatment in our whole cohort, a trend of better ORR (29.4% vs. 12.5%, p = 0.192), PFS (mPFS, 6.5 vs. 5.0 months; p = 0.103) and OS (mOS, not reached vs. 13.7 months; p = 0.130) of dacomitinib was revealed, although differences were not significant. Our study provides additional evidence for the use of dacomitinib in patients after progression on previous TKI, especially in the circumstances where additional anti-vascular agents or immunotherapy did not bring additional PFS and OS benefit compared to single chemotherapy. 11 An interesting phenomenon we found was that 1G/2G TKI→dacomitinib group had a trend for better ORR (36.4% vs. 16%, p = 0.211), PFS (7.8 vs. 3.8 months, p = 0.232) and OS (not reached vs. 13.7 months, p = 0.048) than 3G TKI→dacomitinib cohort. This is also supported by the identification of 3G EGFR-TKI followed by dacomitinib as a poor independent predictor of OS in multivariate analysis. We speculate that there are two reasons for this result. Firstly, most patients in the 3G TKI→dacomitinib group had received 1G/2G TKI treatment before 3G TKI treatment. In addition, there is evidence that, compared with patients who are resistant after 1G/2G TKI, patients who are resistant after 3G TKI osimertinib have more off-target resistance mechanisms outside EGFR that dacomitinib cannot overcome. 12 Currently, classical EGFR mutations (19DEL and 21L858R) are highly sensitive to different-generation EGFR-TKIs; however, uncommon mutations are less sensitive, with reported less satisfying response rates and survival in many studies. [13][14][15][16][17][18] A combined post hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 demonstrated that 2G EGFR-TKI afatinib was active (mostly in first-line setting) in NSCLC patients that harbored certain types of uncommon EGFR mutations, especially  20 has shown that dacomitinib has potent efficacy for central nervous system (CNS) metastasis in EGFR-positive NSCLC. In our study, there were no significant differences in PFS and OS between patients with and without brain metastases, reflecting the effectiveness of dacomitinib in patients carrying brain metastases in later-line settings. On the other hand, a total of 15 of all 22 patients with brain metastases were symptomatic, of which 9 patients (60.0%) had symptom relief. In addition, only 3 (13.6%) of these 22 patients with brain metastases progressed again due to brain progression.
According to the ARCHER 1050 study, 21 the OS benefit was maintained in those patients who had a stepwise dose reduction of dacomitinib (from 45 to 30 or 15 mg per day). In our study, there was no significant difference in ORR (18.2% vs. 28.0% vs. 30.8%), mPFS (3.8 vs. 5.6 vs. 6.1 months, p = 0.762), and 1-year OS rate (76.2% vs. 67.2 vs. 73.8%, p = 0.965) in 15, 30, and 45 mg group, respectively. However, due to the limited size of the study, no definite conclusions could be drawn.
First, the study was undersized, resulting in potentially compromised results from the multivariate analysis. Therefore, we included not only significant characteristics from the univariate analyses but also characteristics that were considered clinically significant. Second, the landscape of lung cancer treatment is now changing rapidly, with fewer patients using the 1G TKIs as the 3G TKI osimertinib enters the first-line recommendation. However, considering factors such as the huge base of lung cancer patients worldwide, the health economics advantage of the 1G TKIs, the disadvantage of osimertinib for Asian populations, etc., studies on the "1+3+2" model or the "1+2" model are still of clinical significance. Last but not least, this was a single-arm small study, which might have led to patient selection bias. Thus, our data should be interpreted cautiously. Furthermore, resistance mechanisms of dacomitinib were not investigated.
In conclusion, this real-world study has shown that dacomitinib is active and well-tolerated in NSCLC patients harboring different EGFR mutations in later-line settings, even for those with brain metastases. Patients who benefited more from the first TKI were more likely to benefit from dacomitinib. Earlier application of dacomitinib after front-line TKI resistance may be considered, but more clinical studies need to be conducted to confirm this conclusion.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.