Efficacy Differences of First-line EGFR-TKIs Alone vs. in Combination with Chemotherapy in Advanced Lung Adenocarcinoma Patients with Sensitive EGFR Mutation and Concomitant Non-EGFR Genetic Alteration(s)

Abstract

Objective: To explore whether EGFR-TKI combined with chemotherapy would benefit patients with advanced lung adenocarcinoma with both sensitive EGFR mutation and concomitant non-EGFR genetic alterations.

Materials and Methods: Cases of advanced lung adenocarcinoma with EGFR mutation combined with concomitant non-EGFR genetic alterations were retrospectively collected. And the patients were required to receive first-line EGFR-TKI and chemotherapy combination or EGFR-TKI monotherapy. Demographic, clinical and pathological data were collected, and the electronic imaging data were retrieved to evaluate the efficacy and time of disease progression. Survival data were obtained through face-to-face or telephone follow-up. The differences between the two groups in objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were investigated.

Results: 107 patients were included, including 63 in the combination therapy group and 44 in the monotherapy group. The ORR were 78% and 50% (P =0.003), and DCR were 97% and 77% (P =0.002), respectively. At a median follow-up of 13.7 months, a PFS event occurred in 38.1% and 81.8% of patients in the two groups, with median PFS of 18.8 and 5.3 months, respectively (P <0.0001). Median OS was unreached in the combination group, and 27.8 months in the monotherapy group (P =0.31). According to the Cox multivariate regression analysis, combination therapy was an independent prognostic factor of PFS.

Conclusion: In patients with EGFR-mutant advanced lung adenocarcinoma with concomitant non-EGFR genetic alterations, combination of TKI and chemotherapy was significantly superior to EGFR-TKI monotherapy, which should be the preferred treatment option.

Key Points

• Clinical use of NGS makes discovery of concomitant genetic alterations associated with EGFR This kind of patients should be treated as a separate subtype.
• Chemo-targeted combination is superior than TKI alone in this type of patients, which is a possible reason of why this combination treatment benefits the EGFR-mutant patients

1. Background

Lung cancer is the leading cause of cancer-related death worldwide [1], and non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all cases [2]. NSCLC with sensitive epidermal growth factor receptor (EGFR) mutations may be susceptible to treatment with EGFR tyrosine kinase inhibitors (EGFR-TKI), a breakthrough in lung cancer treatment this century that has opened a new chapter in the targeted therapy of solid tumors. At present, NSCLC with EGFR mutations has become the most important subtype of NSCLC. The EGFR mutation rate is as high as 51.4% in Asian patients with lung adenocarcinoma [3], making it particularly important to optimize the treatment protocol for NSCLC with EGFR mutations. Ongoing in-depth research has raised new questions about treatment of NSCLC with EGFR mutations, the most important of which is the effect of combination therapy with EGFR-TKI and other drugs, especially chemotherapy drugs.

The clinical trial NEJ009 has shown promising results of chemotherapy combined with a first-generation EGFR-TKI: Among patients with sensitive EGFR mutations receiving pemetrexed/carboplatin combined with gefitinib, progression-free survival (PFS) is 20.9 months, and overall survival (OS) is 50.9 months [4], suggesting that combination therapy may be a potential new treatment protocol. However, the mechanism and the target population of combination therapy are unknown. One hypothesis is that for NSCLC patients with both EGFR mutation and concomitant non-EGFR genetic alteration(s), combination therapy inhibits the EGFR pathway and also counteracted the bypass activation associated with the concomitant alteration(s), thereby achieving better efficacy. To date, no evidence-based study is available to support this hypothesis. This study was designed to test this hypothesis.

2. Materials And Methods

2.1 Patients

We searched the electronic medical records of the Affiliated Cancer Hospital and the First Affiliated Hospital of Zhengzhou University to include patients treated between January 2018 and May 2020 who met the following criteria: histologically confirmed lung adenocarcinoma; clinical or pathological stage IV (tumor–node–metastasis [TNM] stage, edition 8); performance status (PS) score 0-2; and next-generation sequencing with biopsy specimens at initial diagnosis. Due to the retrospective nature of this analysis, we were unable to ensure any consistent testing platform or panel. The panels all included at least epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), proto-oncogene tyrosine-protein kinase 1 (ROS1), Kirsten rat sarcoma virus gene (KRAS), the c-Met tyrosine kinase gene (MET), rapidly accelerated fibrosarcoma (RAF), human epidermal growth factor receptor 2 (HER2), rearranged during transfection (RET), and tumor protein 53 (TP53); sensitive EGFR mutations (exons 18-21); and at least one non-EGFR mutation. The patients had to have first-line treatment with a first- to third-generation EGFR-TKI alone or in combination with chemotherapy, at least one evaluable lesion (per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1), and complete imaging data.

Based on first-line treatment mode, the patients were divided into the monotherapy (targeted therapy) group and the combination therapy (targeted therapy combined with chemotherapy) group. Information such as demographics, PS score, stage (IVA, IVB), central nervous system (CNS) metastases, EGFR mutation sites, type of concomitant non-EGFR alteration(s), and first-line treatment protocol was collected. 

2.2 Efficacy evaluation and follow-up

 Imaging evaluation were performed every 6 weeks after the initial dosing, including enhanced chest and upper abdominal CT and enhanced CT of any tumor site present at baseline, as well as enhanced brain magnetic resonance imaging (MRI) in patients with CNS metastases. Electronic imaging data were retrieved, and the efficacy was evaluated based on RECIST 1.1 to determine best response and the time of disease progression. The patients were followed up by face-to-face visit or telephone to collect their survival status. Endpoints included progression-free survival (PFS), overall survival (OS), objective remission rate (ORR), and disease control rate (DCR). PFS was defined as the time from initial dosing to disease progression (per RECIST 1.1) or death. OS was defined as the time from initial dosing to death. 

2.3 Statistical analysis

The chi-squared test or Fisher's exact test was performed to compare ORR and DCR between the two groups. The Kaplan-Meier method was used for survival analysis and to plot PFS and OS curves. The log-rank test was used to analyze the differences in PFS and OS between the two groups. Cox multivariate regression analysis was performed to determine if treatment protocol was an independent prognostic factor. Factors included in the Cox regression analysis were sex, age, PS score, stage, CNS metastases, EGFR mutation sites, non-EGFR mutation(s), and TKI. We used GraphPad Prism 8.0 to perform survival analysis. And all other statistical analyses were performed by SPSS v25.0.

3. Results

A total of 107 eligible patients were included in this study, including 63 in the combination therapy group and 44 in the monotherapy group. Sixty-seven patients were women and 40 were men. The mean age was 58.3 ± 12.1 years. PS score was 0-1 in all the patients except two patients in the monotherapy group (PS = 2). EGFR mutations were all exon 19 deletion or exon 21 L858R point mutation, except for one rare mutation in each group (S768I and G719C).

As for concomitant alterations, 83 of 107 patients had a single mutation, including TP53 mutation (n = 53), MET amplification (n = 13), KRAS mutation (n = 3), and other mutations (n = 14; including BRAF mutation, HER2 amplification, CDK4 amplification, PTEN mutation, DDR2 mutation, TSC1 mutation, and PIK3CA mutation). Twenty-four patients had two or more concomitant alterations, of whom 19 patients had TP53 mutation combined with other alteration(s) (including ATM mutation, SMAD4 mutation, MET amplification, MYC amplification, APC mutation, PIK3CA mutation, CTNNB1 mutation, NTRK1 rearrangement, RB1 mutation, AXL mutations, ALK mutations, and CDK4 mutations). See Table 1 for the balanced baseline characteristics between the two groups.

4. Discussion

As soon as EGFR-TKIs became available, a series of clinical trials, such as INTACT 1 [5], INTACT 2 [6], TALENT [7], and TRIBUTE [8], were conducted to investigate the effect of chemotherapy alone or in combination with TKIs in non-selected patients with advanced NSCLC. However, the results from these studies were all negative. The reasons may include potential antagonism between platinum drugs and EGFR-TKIs [9] or that cell cycle–specific chemotherapy drugs are difficult to play a role because EGFR-TKIs arrest the tumor cell cycle at G1 phase [10].

Based on these hypotheses and the results from basic research, the combination strategy was largely eschewed for some time. However, in 2013, FASTACT-2, a large phase III randomized controlled trial [11], used a combination therapy protocol known as intercalated therapy to avoid concomitant use of chemotherapy and TKI, thereby preventing cell cycle arrest from impairing the efficacy of chemotherapy. Specifically, a group of Asian patients with advanced NSCLC received 28-day cycles of chemotherapy with gemcitabine (days 1, 8) and carboplatin (day 1), as well as erlotinib on days 15-28. After up to six cycles of chemotherapy, oral erlotinib was given every day until disease progression. The results showed that PFS and OS were significantly longer in the chemotherapy-combined-with-erlotinib group than in the erlotinib-alone group. A similar study, ISCAN [12], reached similar conclusions, although the time point for intercalated chemotherapy was slightly different.

In 2016, JMIT, a phase II randomized controlled trial, was designed based on a different hypothesis, that platinum drugs and EGFR-TKIs are antagonistic [13]. Pemetrexed was given in combination with oral gefitinib (daily, from day 1 of chemotherapy) without using a intercalated strategy. In addition, this was the first trial to enroll patients with advanced NSCLC and sensitive EGFR mutations. The results showed that PFS, the primary endpoint, was significantly longer in the combination group than in the gefitinib-alone group.

In 2018, the initial results of study NEJ009 [14] challenged the presumed mechanism of the clinical benefits observed in FASTACT-2 and JMIT. The trial investigated the efficacy of gefitinib alone or in combination with chemotherapy in patients with advanced non-squamous NSCLC and sensitive EGFR mutations. The chemotherapy regimen was pemetrexed combined with carboplatin, a platinum-based two-drug regimen, and gefitinib was given from day 1 of chemotherapy without a preset interval. The trial achieved the best outcomes with chemo-targeted combination therapy, as this regime extended PFS from 11.9 months to 20.9 months (p < 0.001) and OS from 38.8 months to 50.9 months (p = 0.021) [4], suggesting that intercalated chemotherapy with TKI (based on the theory of TKI-induced cell cycle arrest) or the use of non-platinum-containing chemotherapy in combination with TKI (based on the theory of antagonism between platinum drugs and TKI) was unwarranted. The failure of early clinical trials is likely related to a lack of precise patient selection.

During this period, researchers are also developing a more in-depth understanding of lung cancer with EGFR mutations. High-throughput technology shows that 45% to 55% of patients with EGFR mutations also harbor a concomitant non-EGFR genetic alteration(s), and these patients are far less responsive to EGFR-TKIs than those with pure EGFR mutations [15,16]. This may be related to the resistance that rapidly develop in association with the activation of alternate pathways, and chemotherapy combined with TKI may prevent rapid activation of alternate pathways because the regime works on both EGFR and non-EGFR pathways. Our study indirectly confirms this hypothesis: In the TKI monotherapy group, the ORR was 50%, the median PFS was 5.3 months, which were significant lower or shorter than the historical data of first-line EGFR-TKI therapies. In the combination therapy group, the ORR was 78%, the median PFS was 18.8 months, the HR of disease progression was reduced by 77%, and the HR of death was reduced by 55%. These data indicate that the combination therapy overcomes the shortcomings of TKI monotherapy in patients with both EGFR and concomitant non-EGFR genetic alteration(s), which may be one of the benefit logics of chemo-targeted combination strategy. Answering questions such as whether patients with a pure EGFR mutation will benefit from the combination therapy (and if so, what is the mechanism) and the clinical benefits relative to those observed in patients with both EGFR and non-EGFR alterations will facilitate the precise selection of a treatment protocol.

This study has obvious limitations due to the nature of retrospective analyses and the small sample size. For example, this study showed that approximately 25% of patients harbored two or more non-EGFR mutations in this real-world clinical setting, but according to Cox multivariate regression analysis, the number of non-EGFR mutations was not an independent prognostic factor for PFS. The number of non-EGFR mutations seen in this study may be incorrect, or it may be unbalanced due to the different testing platforms and panels used across studies, which along with the small sample size makes it impossible to draw any definitive conclusion about the relationship between the number of non-EGFR mutations and the efficacy of combination therapy.

5. Conclusion

The efficacy of combination therapy in patients with both EGFR and concomitant non-EGFR genetic alteration(s) may be an important contributor to the superior efficacy of combination therapy over EGFR-TKI monotherapy in patients with EGFR mutations in general. However, given the nature of this retrospective analysis and the small sample size, prospective studies are needed to validate the results. In the future, we will investigate the efficacy of combination therapy versus EGFR-TKI monotherapy in patients with a pure EGFR mutation in order to guide clinical decision-making for patients with EGFR mutations with or without concomitant non-EGFR genetic alteration(s).

Declarations

Ethics approval and consent to participate

This study was approved by the ethics committee of the Affiliated Cancer Hospital and the First Affiliated Hospital of Zhengzhou University. And informed consent was obtained from all participants. No additional administrative permission is required to access the raw data from electronic medical records of the Affiliated Cancer Hospital and the First Affiliated Hospital of Zhengzhou University. We confirm that all methods were performed in accordance with the relevant guidelines and regulations.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request. It’s not publicly available because the data also forms part of an ongoing study.

Competing interests

All authors declared no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within that could inappropriately influence (bias) this article. 

Funding

No funding.

Authors' contributions

Guowei Zhang wrote the main manuscript text. Ruirui Cheng and Yuanyuan Niu conducted data collation and analysis. Xiaojuan Zhang, Jinpo Yang and Chunhua Wei performed patient follow-up.  Huijuan Wang and Xiangtao Yan prepared figures 1-2. Mina Zhang and Zhiyong Ma prepared tables 1-2. All authors reviewed the manuscript.

Acknowledgements

The authors thank all patients and their families for their contributions to this study.

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