Introduction
Lung cancer is the second most common cancer worldwide and the leading cause of cancer death [
1]. Approximately 85% of all lung cancers are non-small cell lung cancer (NSCLC) [
2].In advanced non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) mutations are presented in approximately 40% of Asian populations and approximately 10% to 15% in non-Asian populations [
3,
4].
EGFR exon 19 deletion and 21 L858R mutation are the most common
EGFR alterations, which account for about 85% to 90% of
EGFR mutations, considered as common
EGFR mutations [
5]. Meanwhile, approximately 10% of NSCLC patients with
EGFR mutations harbored as uncommon mutations. Major uncommon
EGFR mutation included G719X, S768I, and L861Q.
On the one hand, major large prospective clinical studies exploring the efficacy of
EGFR tyrosine kinase inhibitors (EGFR-TKIs) in the first-line treatment of advanced NSCLC were restricted to common
EGFR mutations, including FLAURA study (osimertinib versus gefitinib or erlotinib) [
6], and ARCHER 1050 study (dacomitinib versus gefitinib) [
7]. Common
EGFR mutations showed efficacy to different generations of EGFR-TKIs, including the first- to third- generation EGFR-TKIs, while evidence of applying EGFR-TKIs in uncommon mutations were limited [
3,
8,
9]. On the other hand, there were studies reported the activity of second-generation EGFR-TKI afatinib in treating uncommon
EGFR mutations, which encourage the exploration of other second-generation EGFR-TKIs in treating advanced NSCLC harboring uncommon
EGFR mutations [
10].
Dacomitinib, a highly selective, irreversible second-generation EGFR-TKI, inhibits all human
EGFR signaling. ARCHER 1050 study indicated that compared to gefitinib, dacomitinib showed a significant improvement in progression-free survival (PFS) in treating patients with
EGFR-mutation-positive NSCLC (14.7 for dacomitinib vs. 9.2 months for gefitinib, hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.47 to 0.74;
P < 0.0001), leading to the approval of dacomitinib as the new standard first-line treatment for patients with
EGFR exon 19 deletion and L858R mutation positive NSCLC by China National Medical Products Administration in 2019 [
7]. Although some phase I/II clinical trial explored the application of dacomitinib in uncommon mutations [
11,
12], there is limited evidence for dacomitinib treating advanced NSCLC patients with uncommon
EGFR mutations in a real-world setting. Therefore, in this study, we conducted a real-world, ambispective cohort study exploring the efficacy and safety of dacomitinib in treating NSCLC patients with uncommon
EGFR mutations.
Materials and method
Study design and eligibility criteria
Treatment-naïve patients with advanced NSCLC treated in the Department of Thoracic Oncology, Hunan Cancer Hospital between December 2019 and June 2022 were screened for EGFR mutation type. Eligible patients were pathological confirmed unresectable stage III or stage IV NSCLC with uncommon EGFR mutation (mutation other than exon 19 deletion and Leu858Arg point mutation in exon 21 [L858R]); with at least one measurable target lesion; receiving dacomitinib as first-line therapy; Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0–2; and adequate organ and bone marrow function. Exclusion criteria were as follows: concomitant cancer or serious disease; previous exposure to any other EGFR-TKIs, radiation therapy or chemotherapy; follow-up data not available; or uncontrolled symptomatic brain metastasis.
The tests of EGFR mutations were conducted in genetic testing laboratory of Hunan Cancer Hospital and were identified using one of the following local test methods: peptide nucleic acid–mediated polymerase chain reaction clamping, direct sequencing, and/or next-generation sequencing.
This study protocol was confirmed by the Ethics Committee of Hunan Cancer Hospital and conducted in accordance with the Declaration of Helsinki. Each patient participating in the study signed informed consent form.
Treatment plan
All patients were treated with dacomitinib. Initial doses of dacomitinib were 30 mg (for elderly patients or patients with inferior ECOG PS status assessed by clinicians) or 45 mg per day, administered orally once a day until disease progression or intolerant side effects developed. When grade 3–4 adverse events (AEs) occurred, treatment would be suspended until patients recovered to no more than grade 1 AE and the dose of dacomitinib should be adjusted to the lower level (45 mg adjusted to 30 mg and 30 mg adjusted to 15 mg) afterward. For patients with grade 2 AEs, dose adjustment was not necessary unless grade 2 AEs recurred.
Response assessment and evaluation of adverse reactions
Computed tomography (CT) scans or magnetic resonance imaging (MRI) were applied to evaluate treatment response before and during dacomitinib treatment. Target lesions were assessed every two cycles (6 weeks). Imaging results were recorded and response was evaluated per modified Response Evaluation Criteria in Solid Tumors (mRECIST, version 1.1) [
13]. Telephone follow-up was conducted every 3 months. Adverse events were recorded and assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Outcomes
The primary endpoint was progression-free survival (PFS), defined as the time interval from treatment to disease progression or death. Secondary endpoints included objective response rate (ORR, defined as the percentage of patients who achieved complete remission [CR] and partial remission [PR]), disease control rate (DCR, defined as the percentage of patients who achieved CR, PR, and stable disease [SD]), overall survival (OS, defined as the time interval from treatment to death of any cause) and safety.
Statistical analysis
SPSS software (version 26, IBM) was used for all the statistical analysis. GraphPad Prism software (version 9, GraphPad Software, San Diego, CA, United States) was used for visualization. Categorical variables were presented as numbers and percentage and compared using the Chi-squared test and Fisher’s exact test. Continuous variables were presented as median and range and compared using Mann–Whitney U-test. Survival data were analyzed using the Kaplan–Meier method and compared using log-rank test. P-value < 0.05 indicates a statistically significant difference.
Discussion
In this study, we reported the efficacy and safety results of 16 patients with advanced NSCLC harboring major uncommon EGFR mutations receiving the second-generation EGFR-TKI dacomitinib as first-line therapy. Overall, the ORR was 68.8%, DCR was 93.8% and median PFS was 14.0 months. The high response rate and survival results indicated that dacomitinib could be one of the treatment choices for patients with uncommon EGFR mutation.
EGFR-TKIs are recognized as standard first-line treatment option for the treatment of patients with common EGFR-mutated advanced NSCLC. Common EGFR mutations, including
EGFR exon 19 deletion and L858R,were considered as sensitive to EGFR-TKIs, while uncommon
EGFR mutations are considered less sensitive with low response and survival rates [
14‐
19]. For first-generation EGFR-TKIs, including gefitinib and erlotinib, previous studies reported in treating patients with major uncommon an ORR of 25.7% to 48.8%, with median PFS of 5.0 to 6.0 months [
14,
20,
21]. For major uncommon
EGFR mutations, including L861Q, G719X, and S768I, a study reported that gefitinib or erlotinib generated an ORRs of 33.3 to 43.1% and median PFS of 2.2 to 7.7 months [
17]. On the other hand, compared to first-generation of EGFR-TKI, clinical studies and real-world data showed that second- and third- generation of EGFR-TKIs might be more effective for NSCLC patients with uncommon
EGFR mutations. Afatinib was approved as first-line treatment for patients with
EGFR L861Q, G719X, and S768I mutation in 2018 by Food and Drug Administration of the United States. Wu et al. reported that the median PFS was significantly longer for patients harboring major uncommon
EGFR mutations treated with afatinib compared to patients treated with gefitinib and erlotinib (median PFS for gefitinib group versus erlotinib group versus afatinib group: 3.0 months versus 0.9 months versus 10.5 months;
p = 0.013) [
8]. Additionally, the combined post-analysis of the three LUX-lung trials showed that for patients harboring major uncommon mutations treated with afatinib, including G719X, L861Q, and S768I, the ORRs were 77.8%, 56.3%, and 100%, respectively, with median PFS of 13.8 months, 8.2 months and 14.7 months, respectively [
22]. The differences of efficacy between first and second generations of EGFR-TKIs mainly contributed to different molecular mechanisms. The first-generation EGFR-TKIs block
EGFR activity in an ATP-competitive and -reversible manner, while second-generation EGFR-TKIs could generate covalent binding to
EGFR at Cys797 residue, which led to the irreversible inhibition of the
EGFR [
23]. Moreover, second-generation EGFR-TKIs could irreversible inhibit human epidermal growth factor receptor (
HER) 2 and
HER3, which could explain the better efficacy of afatinib in treating patients harboring uncommon
EGFR mutations compared to first-generation EGFR-TKIs.
Similar to afatinib, dacomitinib is an inversible, second-generation TKI. In a single-arm, ambispective study in China, a total of 32 patients with NSCLC harboring major uncommon
EGFR mutations treated with dacomitinib, among whom 18 receiving dacomitinib as first-line treatment [
24]. Results showed that in first-line settings, patients had ORR of 72.2% (13/18) and DCR of 100%(18/18).Median PFS not reached in this study. For patients with major uncommon mutations showed different ORR (G719X versus L861X versus S768I: 56.5% vs 44.4% vs 62.5%) and median PFS (10.3 months for G719X versus not reached for L861X versus 6.5 months for S768I). Results of this study of dacomitinib were comparable with the results of our real-world study, in which the ORR of whole group was 68.8%, median PFS 14.0 months, ORR of patients with G719X was 66.7% and 50.0% of patients with L861Q mutation.
Furthermore, third-generation EGFR-TKI has also shown the efficacy in advanced NSCLC patients with uncommon mutations. In the KCSG-LU15-09 trial by Cho et al., among 32 patients with uncommon
EGFR mutations G719X, L861Q and S768I, the ORRs of osimertinib was 53%, 78%, 38%, and median PFS of 8.2 months, 15.2 months, and 12.3 months, respectively [
25]. UNICORN study, a multicenter, retrospective study, further explored the efficacy of osimertinib in treating uncommon EGFR mutations (exon 20 insertions excluded) [
26]. A total of 60 patients were included. For patients with G719X, ORR was 47%, mPFS 8.8 months, and mDoR 9.1 months. For patients with L861Q, ORR was 80%, mPFS 16 months, and mDoR 16 months. There were some differences in efficacy between results of osimertinib, afatinib and dacomitinib. However, so far, most data of osimertinib were from real-world studies and revealed variable activity. There was no randomized controlled trial directly comparing the efficacy of osimertinib and the second-generation EGFR-TKIs in NSCLC patients harboring uncommon
EGFR mutations. Prospective data is lacking and more clinical evidence is warranted.
Brain metastasis occurred in about 40–50% of advanced NSCLC during the disease course [
27]. However, limited data have been reported on the efficacy of EGFR-TKIs for NSCLC patients harboring uncommon
EGFR-mutant with brain metastases. Osimertinib has potential central nervous system activity for treatment response in NSCLC patients. A case report reported that one NSCLC patient with leptomeningeal metastases harboring uncommon
EGFR mutations G719S and L861Q taking double-dose osimertinib treatment and achieved over 1-year stable disease [
28]. Ma et al. reported that afatinib and osimertinib were effective in four of seven patients with uncommon EGFR mutations found in cerebrospinal fluid ctDNA [
29]. KCSG-LU15-09 study reported that patients with uncommon EGFR mutations taking osimertinib 80 mg orally once per day could achieve an intracranial ORR of 40.0% (2/5) [
25].Several studies have demonstrated the potential efficacy of dacomitinib in
EGFR-positive NSCLC with CNS metastases, with ORR ranging from 87.5% to 92.9% and DCR of 100% [
30‐
33]. A recent study by Li et al. showed that intracranial disease control was observed in 92.9% of advanced NSCLC patients with brain metastasis treated with dacomitinib (13/14) [
34]. In our study, all six (100%) patients with evaluable brain metastasis demonstrated disease control of brain metastases. Results of our study further supported the efficacy of dacomitinib in NSCLC patients with brain metastases harboring uncommon mutations, with intracranial ORR of 85.7% and intracranial DCR of 100%.
Apart from efficacy, adverse events were another major concern in EGFR-TKI treatment. Compared with first-generation EGFR-TKIs, dacomitinib was associated with increased toxicity of diarrhea, rash, stomatitis, and paronychia. In this study, the adverse effects of dacomitinib were manageable, and there was no patient who discontinued treatment due to side effects. Overall adverse effects of dacomitinib in the treatment of uncommon EGFR mutations were within acceptable and tolerable ranges.
This study has some limitations. On the one hand, this study is a real-world ambispective analysis, clinical activity of dacomitinib remains to be explored in larger sample size, head-to head clinical study. In addition, as compound EGFR mutation showed different clinical profile [
3,
35], efficacy of dacomitinib in treating patients harboring compound EGFR mutation should be further explored as there were relatively small number of these patients enrolled in this study. Also, selection bias is inevitable compared with prospective clinical trials.
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