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Abstract

Objective

To assess the clinical efficacy and side effects of EGFR-TKI with or without chemotherapy in the treatment of EGFR mutation-positive advanced lung adenocarcinoma.

Methods

A total of 103 IIIB or IV EGFR mutation-positive lung adenocarcinoma patients admitted to the oncology department of Fujian Provincial Hospital from January 2017 to October 2020 were selected. According to genetic mutation status, patients were divided into the following groups: 19del alone, 19del combined with TP53 or other co-mutations, L858R mutation alone, and L858R mutation combined with TP53 or other co-mutations. Targeted drugs or targeted drugs combined with chemotherapy were respectively administered in the four groups. In patients with simple 19 deletion, only targeted drugs with no combined therapy were applied, resulting in seven total groups. The difference between short-term treatment and long-term treatment effects and the occurrence of adverse reactions was calculated and compared.

Results

There was no statistical significance of difference in the incidence of adverse reactions in seven groups (p > 0.05). The short-term disease control rate of the combination group was higher than the targeted drug group with the difference yielding statistical significance (p < 0.001). The short-term objective response rate of the combination group was higher than the targeted drug group, also yielding statistical significance (p < 0.001). By October 2020, the median progression-free survival (PFS) was 16 months in the EGFR-TKI-targeted combined with chemotherapy group and 10 months in the single-drug EGFR-TKI group, and the PFS time was longer in the combination group than in the single targeted drug group, the difference being statistically significant (p = 0.001).

Conclusions

In the treatment of advanced lung adenocarcinoma patients with EGFR-gene sensitive mutations, compared with single EGFR-TKI-targeted therapy, EGFR-TKI-targeted drug combined chemotherapy can control the disease progression more effectively, and does not increase adverse reactions.

Keywords

Advanced lung adenocarcinoma chemotherapy EGFR gene mutation EGFR tyrosinase inhibitors

Introduction

Lung cancer demonstrates the highest morbidity and mortality globally, with 2.2 million new cases and 1.79 million deaths worldwide in 2020.¹ In China, lung cancer ranks first in both morbidity and mortality among malignant tumors.² Non-small cell lung cancer (NSCLC) is the most common subtype (makes up 87% of total cases of lung cancer). Lung adenocarcinoma is the most common subtype of NSCLC presented in the clinic, accounting for about 40%.³ According to the analysis of lung adenocarcinoma, clear family genetic history, living conditions, and incidence of smoking are the causes of lung adenocarcinoma.⁴ Radical surgical resection is the most effective treatment, but only 25%–30% of patients have surgery. Even after radical surgical treatment, 30%–70% of patients will relapse, or even develop distant metastasis. Most NSCLC patients have local progression or metastasis when presenting symptoms and cannot be surgically removed.⁵ In the past, patients with definite diagnosis were mainly treated with regular chemotherapy to prolong life, but the overall survival was still less than 2 years and the prognosis was poor.⁶ With the use of molecularly targeted therapies and the advancement of molecular detection technology, the treatment of NSCLC has developed very rapidly in the past 10 years.⁷ For advanced lung adenocarcinoma treatment, chemoradiotherapy, molecular targeting, and immunotherapy are primarily used.⁸ EGFR is the main driver gene in Asian patients, mostly in non-smoking, female, adenocarcinoma patients.⁹ The discovery of EGFR tyrosine kinase inhibitor (EGFR-TKI) has revolutionized the traditional treatment of advanced NSCLC.¹⁰

The effect achieved by chemotherapy alone is not significant in clinical treatment, while EGFR-TKI targeted therapy can effectively control tumor progression in the initial EGFR-sensitive advanced lung adenocarcinoma treatment.^11,12 In this paper, gene mutation status of EGFR and a combination therapy will be analyzed to explore the difference in progression-free survival (PFS) caused by gene mutation or therapy strategy, providing evidence for the treatment of patients with advanced lung adenocarcinoma.

Materials and methods

1.1 This is a prospective study.

We used the online tool “Power and Sample Size.com” (http://powerandsamplesize.com) for sample size calculation (α = 0.05, = 0.02). The calculated sample size for each treatment method is 20. In this study, 103 EGFR mutation positive stage IIIB or IV lung adenocarcinoma patients were enrolled in the department of oncology of Fujian Provincial Hospital from January 2017 to October 2020. Inclusion criteria: ① Initial treatment of lung adenocarcinoma confirmed by pathology or cytology. ② Classic mutation of EGFR gene. ③ The minimum of life expectancy is 3 months. ④ Patients with clinical stage III ∼ IV were considered as advanced lung cancer after comprehensive evaluation of imaging, medical history and examination at the same time, and were excluded from other malignant tumors.

1.2 According to gene mutation status, 103 EGFR-sensitive mutation patients were separated into four different groups: 19del alone, 19del combined with TP53 or other co-mutations, L858R alone, and L858R mutation combined with TP53 or other co-mutations.¹³ Other mutations include PIK3CA, KRAS, BRAF, MET, and ERBB2. The four groups were respectively treated with targeted drugs or targeted drugs combined with chemotherapy. In 19del alone group, only targeted drugs were used, no chemotherapy was applied. The difference of recent treatment effect and the occurrence of adverse reactions in seven groups were compared. Chemotherapy regimen: Pemetrexed Disodium 500 mg/m2D1 Cisplatin 25 mg/m2D1-3 or Carboplatin AUC5 were given intravenously. Every chemotherapy cycle lasted 3 weeks. Four to six cycles were given depending on the patient’s recovery and tolerance. Targeted drug therapy: oral Gefitinib tablets (Iressa, National drug approval J20180014, Astra Zeneca Pharmaceutical Co., LTD) 250 mg/day, once a day, patients took it orally until the end of follow-up. Patients stopped taking the medication when they could not tolerate the side effects or the disease progressed.

Ethics: This study complied with Declarations of Helsinki. Fujian Provincial Hospital Ethics Committee (Approval NUMBER/ID: K2021-11-010) provided ethical approval for this study. Consent forms of participation were signed by all patients.

1.3 Efficacy evaluation before treatment, patients in the three groups received head MRI, chest and abdomen CT (including adrenal gland), bone X-ray or MRI, or whole body PET-CT and other examinations to determine the size and metastasis of the target tumor, and compared the imaging data and related examinations 12 weeks after treatment.

(1) Short-term efficacy: According to WHO criteria for evaluation of solid tumor efficacy (RECIST1.1),¹⁴ patients were separated into progressive disease (PD), stable disease (SD), partial response (PR) and complete response (CR) groups. Complete response: indicated that all lymph nodes had shrunk to less than 10 mm and all visible lesions were cleared and maintained for at least a month; PR: the sum of the maximum diameters of all target tumors was reduced by more than 30% from baseline and remained stable for at least a month; PD: signifies that there is more than 20% growth in the sum of all target tumor maximum diameters from the minimum, and there is at least 5 mm increases in the absolute value of the maximum diameters, or that one or more new lesions emerge; SD stands for the status between PR and PD. ORR= (CR + PR)/total number of cases ×100%.

(2) Long-term efficacy: From enrollment to follow-up, tumor PFS and 1-year survival were calculated.

(3) Adverse effects: We performed statistical analysis on the occurrence of adverse events. The adverse reactions in TKI with chemotherapy group include acute central nervous system adverse reactions, vomiting, nausea, rash, diarrhea, liver function damage, and bone marrow suppression. And adverse reactions in TKI-monotherapy group include rash, diarrhea, nausea, vomiting. Common Terminology Criteria for Adverse Events (CTCAE4.0) of the National Cancer Center of Adverse Events and the tumor radiotherapy group (RTOG) classification standard was used.¹⁵

1.4 Follow-up was conducted by outpatient review, We-chat or telephone interview, and followed up every 3 months within 1 year after treatment, and then every 6 months. The follow-up was terminated in October 2020.

1.5 Statistical analysis: SPSS26.0 was used for data processing. The detection rate of hot spot gene mutation in different patients and the efficacy of different treatment methods were compared using x^2 test and Fisher’s exact probability method. Kaplan-Meier method was used to perform survival analysis. p < 0.05 was considered statistically significant.

Results

Baseline characteristics

Among 103 cases, 57 were male and 46 were female. Fifty cases were under 65 years old, 53 cases were equal to or over 65 years old; 37 patients had smoking history, 66 did not have smoking history; 27 cases were classified as Stage III B/III C, 76 cases were classified as stage IV; in 48 cases ECOG scores were 1–2 and in 55 cases ECOG scores were 3–4. In Table1, group1 represents 19del alone, group2 represents 19del combined with TP53 or other mutations, group3 represents L858 R mutation alone, group4 represents L858R combined with TP53 or other mutations. Table 1 illustrates the baseline data of patients, in which gender, age, smoking history, and tumor stage had no statistical significance in the four mutation groups (p > 0.05). The difference of ECOG score in four mutation groups was statistically significant (p < 0.05).

Table 1.

Baseline characteristics.

	Group1	Group2	Group3	Group4	X ²	p value
Gender
Male	20	10	7	20	0.763	0.858
Female	16	10	7	13	0.763	0.858
Age
<65 years	18	7	7	18	1.987	0.575
≥65 years	18	13	7	15	1.987	0.575
Smoking
Yes	10	6	4	17	5.516	0.161
No	26	14	10	16	5.516	0.161
Stage
IIIB/IIIC	8	7	6	6	4.20	0.241
IV	28	13	8	27	4.20	0.241
ECOG
Score 0–1	21	19	13	32	20.934	<0.001
≥2	15	1	2	1	20.934	<0.001

Group1: 19del alone.

Group2: 19del combined with TP53 or other mutations.

Group3: L858R mutation alone.

Group4: L858R combined with TP53 or other mutations.

Comparison of recent therapeutic effects among each group

In Table 2, green box represents TKI treatment alone, yellow box represents TKI + chemotherapy. Group1 represents 19del alone, group2 represents 19del combined with TP53 or other mutations, group3: L858R mutation alone, group4: L858 R mutation combined with TP53 or other mutations. In this study, the differences between different treatment methods in the seven groups of patients with four types of gene mutations were statistically significant (p < 0.001), and the differences in the proportion of patients with partial remission and stable disease were statistically significant (p < 0.001), The difference of DCR%, ORR% in the seven groups was statistically significant (p < 0.001), and the difference of PFS in the seven groups was statistically significant (p = 0.001).

Table 2.

Comparison of recent therapeutic effects among each group.

Efficacy and adverse reactions in each group

In Table 3, green box represents TKI treatment alone, yellow box represents TKI + chemotherapy. Group1 represents 19del alone, group2 represents 19del combined with TP53 or other mutations, group3: L858 R mutation alone, group4: L858R mutation combined with TP53 or other mutations. There were statistically significant differences in efficacy among the seven groups (p < 0.001), but no statistically significant differences regarding side effects (p > 0.05).

Table 3.

Efficacy and adverse reactions in each group.

Survival analysis

Figure 1, Figure 2 illustrated the PFS of the two groups.19del group had 36 cases, and all of these cases were treated with Gefitinib alone, with a median PFS of 10 months. There were 20 cases of 19del combined with TP53 or other co-mutations, and the median PFS was 14.5 months. There were 8 cases of TKI treatment alone, and the median PFS was 10 months. Twelve patients were treated with TKI plus chemotherapy, and the median PFS was 17 months. There were 14 cases with L858R mutation alone, and the median PFS was 16 months. Gefitinib alone was used in 2 cases, with a median PFS of 9 months. Twelve patients were treated with TKI plus chemotherapy, and the median PFS was 16 months. There were 33 patients with L858R mutation combined with TP53 or other co-mutations, and the median PFS was 15 months. Gefitinib alone was used in 3 cases, with a median PFS of 8.8 months. TKI plus chemo had 30 cases. The median PFS was 15 months. By the cut-off time of follow-up, the median PFS was 10 months in the TKI treatment group and 16 months in the TKI plus chemotherapy group. The median PFS in TKI plus chemotherapy group was significantly longer as compared to that in TKI alone group, the difference was statistically significant (p < 0.001).

Figure 1.

Kaplan-Meier analysis of progression-free survival classified by the gene mutation status.

Figure 2.

Kaplan-Meier analysis of progression-free survival classified by treatment methods.

Discussion

One of the difficulties in discussing modern precision oncology is that most EGFR-mutated NSCLC patients are prone to EGFR-TKI-targeted drugs related acquired resistance.^12,16 In China, lung cancer has the highest morbidity and mortality, and it has high heterogeneity in genetic composition.¹⁷ The study by Yang et al. showed that different immune cells were facilitating factors to the high heterogeneity of lung cancer.¹⁸ With the development of clinical targeted therapy, except for a small number of patients with primary drug resistance, the vast majority of patients will inevitably develop drug resistance in the course of targeted drug therapy. For NSCLC, especially in patients with epidermal growth factor receptor-positive lung adenocarcinoma, targeted therapy has become the first line of choice.¹⁹ EGFR is a transmembrane tyrosine kinase receptor involved in cell apoptosis, proliferation, invasion, and metastasis. It belongs to the epidermal growth factor receptor (HER/ERBB) family, thus it is widely expressed in human epithelial tissues.²⁰ Its molecular structure mainly includes extracellular ligand binding domain, transmembrane domain, and intracellular tyrosine kinase domain. EGFR mutation autophosphorylation of cytoplasmic tyrosine kinases. Continuous activation of downstream signaling pathways ultimately lead to the development of a variety of tumors.^21,22 In NSCLC, EGFR mutations mainly occur in adenocarcinoma, female, and non-smoking patients, with a positive mutation rate of more than 50%.²³ The most common mutation subtypes were exon 19 deletion mutation and exon 21 L858 R point mutation, which accounted for 91.8% of all mutation types and were EGFR-sensitive mutations.²⁴ Patients with the classical mutation (19DEL and L858R) showed longer PFS than patients with the rare mutation (such as G719X, L861Q, S768I, L747S, L833V, 20ins and 19ins), and patients with the classical mutation had a better response to EGFR-tyrosine kinase inhibitors.^25-27 In clinical practice, patients engaged in intervention reflect different reactions to TKIs, even though the same mutation sites exist.²⁸ EGFR receptor tyrosine kinase inhibitor (EGFR) is a highly selective and potent small-molecule EGFR inhibitor that competitively binds to the functional domain of tyrosine kinase with ATP, inhibits autophosphorylation, blocks proliferation, and decreases invasion and metastasis of tumor cells involved in EGFR, and thus plays an anti-tumor role.²⁹ EGFR-TKI is effective in 70–80% advanced EGFR-sensitive mutant NSCLC patients, and PFS can reach 9–13 months.³⁰ However, due to tumor drug resistant gene changes, activation of downstream signaling pathways, epithelial-mesenchymal and other drug resistance pathways resulting in secondary resistance to EGFR-TKI remains a problem.³¹ Patients (10–20%) with positive EGFR-TKI mutation develop primary resistance to EGFR-TKI due to tumor heterogeneity.³² Both the 19del mutation and the 21L858 R mutation can lead to the dominant EGFR kinase activation state and affect its downstream activity of promoting cell survival and apoptosis.³³ However, due to different activation mechanisms and states of the two mutations, their affinity and sensitivity to EGFR-TKIs are also different.³⁴ In recent years, to improve the effectiveness of targeted drugs for advanced NSCLC patients, some scholars proposed EGFR-TKI targeted combination therapy. Researchers treated NSCLC with Erlotinib combined with GC, and the results showed that PFS of GC-Erlotinib was significantly longer as compared to PFS of GC-placebo (median 29.4 v 23.4 weeks), with good tolerance and no increase in blood toxicity.³⁵ EGFR-TKI-targeted combination therapy is superior to EGFR-TKI-targeted therapy alone, and the main reason may be related to the synergy between chemotherapy and EGFR-TKI-targeted drugs. In the treatment of stage IV EGFR-TKI mutant NSCLC, studies evidenced that the ORR and PFS of EGFR-TKI combined with chemotherapy was superior to that of EGFR-TKI targeted therapy alone. The incidence of grade I-II nausea and vomiting and grade I, II radiation pneumonia in the two EGFR-TKI-targeted combination therapy groups was higher as compared to that in the single EGFR-TKI-targeted group, but the occurrence of other adverse reactions, such as bone marrow suppression, liver function injury, and rash, diarrhea, showed no statistical significance compared with the single EGFR-TKI-targeted group.³⁶ The other two combined treatment groups had slight differences in short-term and long-term efficacy and adverse reactions, but there was no statistical significance. Researchers studied advanced lung adenocarcinoma patients with EGFR gene sensitive mutation. The control group selected Gefitinib, and the experimental group combined GP chemotherapy based on the control group. The results showed differences in disease control rate, total response rate, and OS between the two groups (p < 0.05).^37,38 The effectiveness of EGFR-TKI combined with chemotherapy in lung adenocarcinoma was analyzed to explore the best plan to improve patients’ quality of life and treatment effects. Patients (34.9%) with EGFR mutation also reflected mutations in other genes, for instance, TP53, MET amplification or jump mutation in exon 14 of MET gene, HER2 amplification, and mutation, KRAS, etc.³⁹ Such co-mutations interact with EGFR and are related to the occurrence of drug resistance to EGFR-TKIs.⁴⁰

According to previous experience and literature reviews, such patients have a short response time to EGFR-TKIs treatment. Subsequently, drug resistance in a short period may likely occur.⁴¹ Therefore, we used different treatment strategies to observe PFS in patients with single mutation and co-mutation incidence. This study showed that the ECOG score differed statistically across the mutation groups. The variance of the treatment methods administered in the seven groups of patients with four types of gene mutations were statistically significant, and the differences in the proportion of patients with partial remission and stable disease was statistically significant in the seven groups of patients with four types of gene mutations.

In the combination group, the disease control rate was much higher than the simple targeting group, and the objective effective rate was much higher in the combination group, as compared to that in the simple targeting group, reflecting statistical significance (p < 0.05). Progression-free survival in the combination group was much longer than the targeted group (p < 0.05) by the end of follow-up, and there was no statistical difference in side effects. The results evidenced that combination therapy was more effective in controlling tumor progression. Therefore, the combined treatment has a more significant therapeutic effect on advanced lung adenocarcinoma, and the treatment regimen of the seven groups did not increase significant toxicity and side effects.

There are limitations in this study. First, the sample size was relatively small and the duration of this study was short, so instead of using OS as primary endpoint, we used PFS as an alternative. Second, the clinical treatments were based on clinical guidelines as well as patients’ willingness, so the treatment allocations were not randomized. In future studies, we would like to make further improvements on these limitations, and we also hope to explore the prediction value of different types of mutations.

Conclusion

To summarize, in the treatment of advanced lung adenocarcinoma with EGFR-sensitive mutation, EGFR-TKI-targeted therapy combined with chemotherapy does not significantly increase the adverse reactions of patients compared with single EGFR-TKI-targeted therapy, and can more effectively control the progression of the disease and alleviate the tumour, which has the potential to be popularized in clinical practice.

Footnotes

Acknowledgements

We are grateful to each patient for assistance in this study.

Authors’ Contributions

The study was designed by Tongjian Cui, Jianping Zheng and Ping Li collected data and performed experiments and analyses. Jianping Zheng drafted the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethics approval

The study has been approved by the Institutional Review Board of Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital Ethics Committee (Approval NUMBER/ID: K2021-11-010), and all experiments were performed in accordance with the guidelines.

Informed consent

Written informed consent was obtained from all subjects before the study.

Trial registration

This trial is registered on the ISRCTN registry with trial registration number ISRCTN14796973.

ORCID iD

Jianping Zheng

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Observation on the clinical efficacy and side effects of EGFR-TKI ± chemotherapy in the treatment of EGFR mutation-positive advanced lung adenocarcinoma

Abstract

Objective

Methods

Results

Conclusions

Keywords

Introduction

Materials and methods

Results

Baseline characteristics

Comparison of recent therapeutic effects among each group

Efficacy and adverse reactions in each group

Survival analysis

Discussion

Conclusion

Footnotes

Acknowledgements

Authors’ Contributions

Declaration of conflicting interests

Funding

Ethics approval

Informed consent

Trial registration

ORCID iD

References