Comparison of the efficacy and safety of icotinib monotherapy and combined therapy of icotinib and vinorelbine as first-line treatment for advanced lung adenocarcinoma in patients with sensitive EGFR mutations: A retrospective study

doi:10.21203/rs.3.rs-3101348/v1

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Comparison of the efficacy and safety of icotinib monotherapy and combined therapy of icotinib and vinorelbine as first-line treatment for advanced lung adenocarcinoma in patients with sensitive EGFR mutations: A retrospective study

https://doi.org/10.21203/rs.3.rs-3101348/v1

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This investigation compares the safety and therapeutic efficiency of icotinib monotherapy and icotinib + vinorelbine combination therapy against non-small cell lung cancer (NSCLC) with EGFR gene mutation.

Methods: Data was acquired from105 patients who enrolled in the Fujian Medical University Cancer Hospital between October 2018 and December 2021, including individuals with NSCLC-EGFR mutations who underwent first-line icotinib therapy with or without vinorelbine. Of these 105 cases, 75 patients received icotinib monotherapy (IM), and 35 received icotinib + vinorelbine combination therapy (I+V) and were grouped accordingly. Progression-free survival (PFS) and adverse effects were compared in the two cohorts. Furthermore, the mechanism of drug resistance in the combinational therapy group was also determined.

Results: PFS was notably prolonged in the I+V group (12 months vs. 9.3 months, HR=0.501, 95%CI 0.34-0.75, P<0.01). The mechanism of drug resistance was not affected by I+V therapy. Both the disease control and objective response rates in the I+V group were comparable to the IM group. Moreover, increased gastrointestinal reactions were observed in the I+V group thanin the IM group.

Conclusions: This study provides information about the effects of combined icotinib and vinorelbine therapy as a first-line strategy for advanced NSCLC patients with EGFR mutations. However, further verification via a prospective phase 3 clinical trialis required.

Non-small cell lung cancer

EGFR-TKI

Vinorelbine

Metronomic therapy

Chemotherapy

The association between epidermal growth factor receptor (EGFR) gene mutation and non-small cell lung cancer (NSCLC) tumors was first observed in 2004. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have significantly better therapeutic feedback than chemotherapy in EGFR-TKI mutation patients. TKIs are recommended as a first-line drug to treat patients with advanced lung adenocarcinoma with EGFR mutations [1]. The TKI agents comprise reversible 1st generation compounds (gefitinib, icotinib, and erlotinib), irreversible 2nd generation compounds (afatinib and dacomitinib), and 3rd generation agents that act against secondary resistance mutations (osimertinib). However, despite the treatment with these efficient TKIs, nearly all the patients develop acquired resistance within a few years; therefore, the cure for advanced NSCLC remains undetermined [2,3]. Efforts to control kinase inhibitors resistance include combined anti-vascular factors treatments or chemotherapy [4–6].

Metronomic vinorelbine (mVNR) is an alternative therapeutic strategy against NSCLC. Metronomic chemotherapy (mCHT) involves frequent low dosages of conventional chemotherapeutic agents with no intervals or breaks [7]. Due to mVNR’s (Metronomic vinorelbine) safety profile, EGFR-TKIs combined with vinorelbine may delay resistance.

Icotinib is a selective and reversible 1st generation EGFR-TKI discovered in China. Its use is only approved in China for treating advanced EGFR-mutated NSCLC patients [8]. It is necessary to determine the effects of vinorelbine when used to improve the icotinib efficiency for treating EGFR mutant tumors in patients not receiving systemic therapy. This study presents a retrospective analysis of the effect of icotinib monotherapy and its combined therapy with vinorelbine on patients with advanced NSCLC with EGFR mutations.

2.1 Patient selection

A total of 516 patients who enrolled at the Fujian Medical University Cancer Hospital from October 2018 to December 2021 with Stage IIIB/IV NSCLC and EGFR mutations (Ex19del and Ex21.L858R) as determined by ARMS or next-generation sequencing (NGS) were reviewed. Of these 516 cases, 270 were excluded based on exclusion criteria (enlisted in Fig. 1). 68 patients who underwent icotinib + vinorelbine (I + V) combined treatment and 178 individuals who received icotinib monotherapy (IM) were included in this investigation. After being explained their potential advantages and disadvantages, the patients selected the treatment strategy (I + V or IM).

Of 68 I + V therapy patients, 35 met the following inclusion criteria: (1) Eastern Cooperative Oncology Group performance score of 0–2; (2) histologically or cytologically confirmed advanced NSCLC; (3) received icotinib (125 mg tablet, Betta Pharmaceuticals Co., Ltd, Zhejiang, China) for 6-months or more; and (4) patient available for safety data analysis. The exclusion criteria: patients receiving combination anticancer therapy or those with multiple cancers.

Of 178 IM therapy patients, 70 were selected. For the matched cohort study, patients in the IM group were matched with those in the I + V group at 1:2 ratios based on age, type of EGFR mutation, gender, with brain metastases or without, and clinical stage. This investigation was authenticated by the Ethics Committee of Fujian Cancer Hospital, China, and all the participants were initially informed about the study, and their consent was taken.

2.2 Treatment schedule

The patients were administered 125 mg/TID of icotinib with or without vinorelbine. 20mg of vinorelbine was given orally daily for 14 days, followed by 7 resting days. The treatment continued until disease progression, the incidence of unacceptable adverse reactions, or if requested by either the physician or the patient, and the treatment cycle was repeated every 21 days. The drug resistance mechanisms in tissues were elucidated via NGS; it was indicated that 33 I + V cases developed disease progression.

2.3 Assessments

The response to icotinib therapy was classified as an objective response, described as the sum of several complete remissions (CR) and partial responses (PR). The disease control rate (DCR) = the sum of CR, PR, and stable disease (SD). The primary endpoint in this trial was progression-free survival (PFS), represented by the time from the treatment initiation to the date of disease progression. Treatment-related adverse events were based on clinical monitoring, questionnaires, and laboratory evaluations guide of the National Cancer Institute Common Terminology Criteria for Adverse Events ([NCI CTCAE], version 5.0).

2.4 Statistical analysis

All the statistical analysis was performed SPSS version 20.0 (IBM Corp., Armonk, NY, USA). The quantitative data are presented as the mean ± SD, and the intergroup comparison was performed using an independent sample T-test. The categorical data were compared with the Chi-squared test. The Kaplan-Meier curves evaluated the survival and compared using the log-rank test. Data were deemed significant at < 0.05 p-value.

3.1 Baseline patient characteristics

A total of 105 NSCLC patients with EGFR mutations were included in this investigation. Of these, 35 patients received I + V therapy, while 70 received IM therapy. No significant differences were observed in the baseline characteristics of the two cohorts (Table 1). The follow-up deadline was November 1, 2022, with a median follow-up time of 40 months.

Table 1

Baseline clinical characteristics of patients
Characteristics	Icotinib	Icotinib + vinorelbine	P -value
Age,years
Median	61	62	0.487
Range	36–78	38–83
ECOG PS
0	4(11.4%)	7(10%)	0.905
1	23(65.7%)	49(70%)
2	8(22.9%)	14(20%)
Sex
Male	18(51.4%)	39(55.7%)	0.684
Female	17(48.6%)	31(44.3%)
Smoking status
Non-smoker	13(37.1%)	21(30%)	0.511
Former-smoker	22(62.9%)	49(70%)
EGFR mutation status
Exon 19del	21(60%)	40(57.1%)	0.836
Exon 21L858R	14(40%)	30(42.9%)
Brain metastases
Yes	11(31.4)	12(17.1%)	0.133
No	24(68.6)	58(82.9%)
Concomitant
Yes	16(45.7%)	39(55.7%)	0.408
No	19(54.3%)	31(44.3%)
Data were deemed significant at < 0.05 p-value.

3.2 Efficacy

The I + V therapy group showed prolonged PFS than the IM group (median, 12.0 months vs. 9.3 months; p < 0.01) (Fig. 2). However, the overall response rate (ORR) (68.5% vs. 65.7%) and the DCR (91.4% vs. 85.7%) were similar between the two cohorts (Table 2). The treatment efficacy for each person in the I + V group is shown in Fig. 3.

Table 2

Short-term effect
Response	Case number + Patients (%)		P -value
Response	Icotinib (n = 70)	Icotinib + vinorelbine (n = 35)	P -value
CR	0	0
PR	46(65.7%)	24(68.5%)
SD	14(20%)	8(21.5%)
PD	10(14.2%)	3(8.5%)
Total
ORR	46(65.7%)	24(68.5%)	0.829
DCR	60(85.7%)	32(91.4%)	0.537

3.3 Safety

The incidence of fatigue, loss of appetite, nausea, elevated ALT or AST levels, and elevated total bilirubin were higher in the I + V cohort than in the IM patients (65.7% vs. 27.1%, χ² = 14.46, p < 0.001; 95 57.1% vs. 11.4%, χ² = 34.94, p < 0.001, 39.9% vs. 7.1%, χ² = 16.99, p < 0.001 37.3% vs. 27.1%, χ² = 1.1, p = 0.0369, 14.2% vs. 2.8%, χ² = 4.89, p = 0.03). No grade 5 drug-associated adverse reactions were observed in either group. (Table 3)

Table 3

Incidence of adverse reactions in the I + V group and IM group
Adverse reactions	Combination	group (n = 35)	Overall incidence(%)	Icotinib (n = 70)		Overall incidence(%)	χ²	P ∗
Adverse reactions	Grade 1–2	Grade3-4	Overall incidence(%)	Grade 1–2	Grades 3–4	Overall incidence(%)	χ²	P ∗
Hematological toxicity Leukopenia	12(34.2%)	4(11.4%)	16(45.6%)	13(18.6)	2(2.9%)	15(21.5%)	6.61	0.013
Anemia	10((28.6%)	1(2.9%)	11(31.4%)	8(11.4%)	3(4.3%)	11(15.7%)	3.47	0.077
Thrombocytopenia	5(14.2%)	0	5(14.2%)	3(4.3%)	0	3	3.31	0.113
Non-hematologic toxicity Loss of appetite	21(60%)	2(5.7%)	23(65.7%)	19(27.1%)	0	19(27.1%)	14.46	< 0.001
Fatigue	19(54.3%)	1(2.8%)	20(57.1%)	8(11.4%)	0	8(11.4%)	34.94	< 0.001
Nausea	13(37.1%)	1(2.8%)	14(39.9%)	5(7.1%)	0	5(7.1%)	16.99	< 0.001
Vomiting	5(14.3%)	0	5(14.3%)	2(2.8%)	0	2(2.9%)	4.89	0.04
Rash	12(34.2%)	2(5.7%)	14(39.9%)	22(31.4%)	3(4.2%)	25(35.6%)	0.184	0.675
Diarrhea	11(31.4%)	2(5.7%)	13(37.3%)	21(30.0%)	5(7.1%)	26(37.1%)	0	1.0
Alopecia	3(8.5%)	0	3(8.5%)	1(1.4%)	0	1(1.4%)	3.24	0.107
Oral mucositis	3(8.5%)	1(2.8%)	4(9.3%)	5(7.1%)	0	5(7.1%)	0.547	0.477
pruritus	2(5.7%)	0	2(5.7%)	3(4.3%)	0	3(4.3%)	0.105	1.0
Liver or Kidney function Elevated ALT or AST	10(28.7%)	3(8.6%)	13(37.3%)	15(21.4%)	4(5.7%)	19(27.1%)	1.101	0.0369
Elevated bilirubin	5(14.2%)	0	5(14.2%)	2(2.8%)	0	2(2.8%)	4.898	0.04
Elevated creatinine	0	0	0	0	0	0	0	0
Pulmonary fibrosis	0	0	0	0	0	0	0	0

3.4 Drug resistance mechanisms

Of 35 I + V therapy patients, 28 patients underwent re-biopsy, and 5 did not, while 2 showed no progress. The resistance mechanism is shown in Fig. 4.

This investigation provides evidence that if icotinib is combined with vinorelbine, it is an efficient and safe regimen for patients with EGFR-mutated terminal-stage lung adenocarcinoma. The I + V therapy had a 68.5% response rate and a DCR of 91.4%. The patients who received I + V therapy achieved an average PFS of 12 months. Most patients’ adverse reactions only showed grade-1 or grade-2 type of adverse reactions, while few indicated grade-3 type, which could be easily controlled or reversed. To our knowledge, this investigation is the first that indicates icotinib combined with vinorelbine as an effective first-line treatment option for EGFR-mutated terminal-stage lung adenocarcinoma.

Treatment of advanced NSCLC tumors with EGFR mutations with 1st generation EGFR-TKIs + anti-angiogenesis or cytotoxic anticancer agents has been studied several times. Two studies (JO25567 and NEJ026) revealed that when EGFR-TKIs are combined with bevacizumab, it notably prolonged median PFS in patients, which is not observed in erlotinib monotherapy (16–17 months vs. 9–13 months) for untreated advanced NSCLC with EGFR mutations. When angiogenesis inhibitors were used in combination, the hypertension of Common Terminology Criteria for Adverse Events (CTCAE) grade-3 or higher enhanced to 23% (than 1% with TKI monotherapy) [4,9,10]. In the Chinese population, the combination of the antiangiogenic drug bevacizumab with erlotinib also improved PFS in mutation-positive patients, even in patients with brain metastases [6]. For combined anticancer therapy, carboplatin and pembrolizumab are recommended based on the clinical trials data [11,12]; however, when cytotoxic chemotherapy was added, the CTCAE grade-3 or higher treatment-associated adverse reactions increased from 31.0% for TKI monotherapy to 65.3% [5]. Specifically, grade 3 or higher neutropenia was 31.2% in patients receiving combination therapy than 0.6% in those receiving TKI monotherapy. While these combined patterns extended the duration of PFS in mutation-positive patients, they increased the length of hospital stay.

mCHT was identified in the early 2000s by Kerbel and Hanahan [13,14]. mCHT treatment induces indirect and direct anti-tumor effects by inhibiting angiogenesis, activating the immune system, and directly mediating tumor cell cytotoxicity. Earlier clinical trials have successfully demonstrated the efficacy of mCHT in 1st line, 2nd line and subsequent treatment settings, as well as a maintenance strategy for patients with advanced NSCLC. These studies initially investigated various administration regimens using single-drug treatment with vinorelbine, docetaxel, paclitaxel, or temozolomide then later trials of multiple-drug regimens were performed [15–17]. The most widely studied mCHT drug for treating NSCLC patients is oral vinorelbine (VNR) monotherapy. Natalia Sutiman has reported that combining erlotinib and oral vinorelbine in both conventional schedule vinorelbine (CSV, conventional chemotherapy) and metronomic schedule vinorelbine (MSV, mCHT) schedules is feasible and tolerated by advance stage NSCLC patients who were previously refractory to standard chemotherapy [18]. However, the trial comprised an unselected patient population and was a phase I clinical study. Another report verified that VNR and reversible EGFR-TKIs combination therapy had an intense synergistic effect on both EGFR-wt NSCLC and on H-1975 cells (e.g., CI = 0.501 for 50% of affected cells), enhancing intracellular EGFR-TKIs levels (e.g., + 50.5% vs. gefitinib alone). Therefore, mVNR may directly affect NSCLC cells and can sensitize resistant cells to EGFR-TKIs [19]. 3rd generation agents are the standard-of-care first-line therapy for advanced EGFR-mutant NSCLC patients, such as Osimertinib, Almonertinib, and Furmonertinib [20–22]. However, the 1st and 2nd generation TKI drugs are still being utilized due to economic and accessibility issues. This investigation confirmed that a combined I + V regimen could improve the clinical effect of the treatment. The I + V group markedly improved PFS than the control group. Furthermore, the combination strategy did not alter the mechanism of icotinib resistance.

No severe adverse reactions were observed during this investigation, and no patient required a dose de-escalation. The I + V group indicated increased appetite, fatigue, nausea, ALT or AST levels, and total bilirubin rates than the IM group. The absence of dose adjustment in the I + V group was related to the characteristics of icotinib itself, as some studies report that icotinib is well-tolerated even by elderly NSCLC patients.

This study provides evidence that Icotinib, combined with vinorelbine metronomic treatment, is more feasible and effective against advanced NSCLC with EGFR mutation. However, further verification is required via a prospective phase 3 clinical trial.

There are some limitations inherent in this study. First, an increased study size for the combination group is required. Seconds, this was a single-center retrospective study. Third, overall survival data should be included. We also did not define different subgroups, such as Ex19del or Ex21.L858R.

Together, icotinib + vinorelbine is worth exploring as a first-line drug for advanced NSCLC patients with EGFR mutations. However, this treatment strategy first requires validation from prospective clinical studies.

NSCLC	non-small cell lung cancer
EGFR	epidermal growth factor receptor
TKI	tyrosine kinase inhibitor
EGFR-TKI	epidermal growth factor receptor tyrosine kinase inhibitor
NGS	next-generation sequencing
IM	icotinib monotherapy
I+V	icotinib + vinorelbine
CR	complete remissions
PR	partial responses
DCR	disease control rate
SD	stable disease
PFS	progression-free survival
ORR	overall response rate
VNR	vinorelbine
CSV	conventional schedule vinorelbine
MSV	metronomic schedule vinorelbine
mVNR	metronomic vinorelbine
mCHT	metronomic chemotherapy
CTCAE	Common Terminology Criteria for Adverse Events

Ethics approval and consent to participate

All methods were performed following the relevant guidelines and the principles of the Declaration of Helsinki. This single-institutional study was sanctioned by Fujian Cancer Hospital's Ethics Committee (No. SQ2022-212). All patients provided written informed consent.

Consent for publication

Not applicable

Availability of data and materials

The data supporting the results of this research can be provided by the corresponding author upon reasonable request.

Competing interests

The authors declare no conﬂict of interest.

Funding

This research received no external funding.

Author Contributions

Conceptualization, writing - original draft preparation, Haipeng Xu; Writing - review & editing, Jing Zhang, Huihua Hu, Jian Yu, Dong Lin. All authors have read and agreed to the published version of the manuscript.

Acknowledgements

Not applicable

Authors' information

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You are reading this latest preprint version

Comparison of the efficacy and safety of icotinib monotherapy and combined therapy of icotinib and vinorelbine as first-line treatment for advanced lung adenocarcinoma in patients with sensitive EGFR mutations: A retrospective study

Status:

Version 1

Abstract

Figures

1 INTRODUCTION

2 METHODS

2.1 Patient selection

2.2 Treatment schedule

2.3 Assessments

2.4 Statistical analysis

3 RESULTS

3.1 Baseline patient characteristics

3.2 Efficacy

3.3 Safety

3.4 Drug resistance mechanisms

4 DISCUSSION

5 CONCLUSION

6 LIMITATIONS

Abbreviations

Declarations

Ethics approval and consent to participate

Consent for publication

Availability of data and materials

Competing interests

Funding

Author Contributions

Acknowledgements

References

Additional Declarations

Status:

Version 1