Clinical Outcomes of Osimertinib Combined with Platinum-Based Chemotherapy in EGFR-Mutant Non-Small Cell Lung Cancer: A Retrospective Study

Introduction

Lung cancer remains one of the most common and deadliest malignant tumors worldwide, posing a serious threat to public health. According to data released by the International Agency for Research on Cancer (IARC) in 2022, over 2.2 million new cases of lung cancer and more than 1.8 million deaths were reported globally, ranking first among all cancers.¹ In China, lung cancer also tops the charts in incidence and mortality, significantly impacting quality of life and life expectancy.² Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of all lung cancers, is the predominant pathological type. Due to the insidious nature of early-stage NSCLC, about 70% of patients are diagnosed at an advanced stage, losing the opportunity for surgical cure. Thus, systemic therapy becomes the core strategy for improving prognosis.³ Traditionally, platinum-based doublet chemotherapy has been widely used for advanced NSCLC patients, especially during periods when molecular profiling was unavailable or targeted therapies were not accessible.^4,5 Although chemotherapy has achieved certain benefits in tumor reduction and symptom relief, its overall effectiveness is limited, with unsatisfactory median progression-free survival (PFS) and overall survival (OS), and adverse effects often compromise patient compliance and quality of life. With advances in molecular biology, EGFR mutations have been identified as one of the most critical oncogenic drivers in NSCLC, especially prevalent among Asian populations.⁶ The most common EGFR mutations include exon 19 deletions (Del19) and the exon 21 L858R point mutation, both of which are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs).⁷ First- and second-generation TKIs (eg, gefitinib, afatinib) have demonstrated significant efficacy in prolonging PFS in patients with EGFR-mutant NSCLC, gradually replacing chemotherapy as the first-line standard of care.⁸ Osimertinib, a third-generation EGFR-TKI, exhibits high selectivity and irreversible binding capability. In addition to effectively inhibiting EGFR-sensitive mutations, it can overcome T790M resistance mutations and shows favorable blood–brain barrier penetration, demonstrating remarkable efficacy in patients with brain metastases.⁹ Multiple studies have confirmed that osimertinib significantly outperforms first-generation TKIs in both PFS and OS with fewer adverse effects, and it has become the recommended first-line treatment for EGFR-mutated NSCLC.^10,11 However, despite the impressive efficacy of osimertinib monotherapy, a proportion of patients still present with suboptimal initial response or develop early resistance, indicating limitations of monotherapy in certain clinical scenarios. Consequently, EGFR-TKI–based combination strategies have received increasing attention. Recently, the Phase III FLAURA2 trial demonstrated that first-line osimertinib plus platinum-pemetrexed chemotherapy significantly prolonged progression-free and overall survival compared with osimertinib monotherapy in untreated EGFR-mutant advanced NSCLC, with a median overall survival of 47.5 months vs 37.6 months, respectively (HR 0.77; P=0.02).¹² The combination regimen also showed manageable toxicity consistent with the known safety profiles of osimertinib and chemotherapy. In addition, data from the ORIENT-31 study provided further support for incorporating multi-modality strategies in EGFR-mutant NSCLC, demonstrating that combining anti-angiogenic therapy and chemotherapy could meaningfully improve survival outcomes after TKI resistance.¹³ These findings highlight the potential value of integrating osimertinib with chemotherapy in achieving deeper and more durable disease control. Based on this rationale, the present study retrospectively analyzed clinical outcomes of EGFR-mutant NSCLC patients treated with platinum-based chemotherapy alone or in combination with osimertinib, aiming to evaluate the comprehensive clinical value of the combined regimen and to provide evidence for further optimizing individualized treatment strategies.

Materials and Methods

Study Design and Subjects

This was a single-center, retrospective controlled study. Clinical data were collected from 112 patients diagnosed with EGFR-mutant non-small cell lung cancer (NSCLC) in the Department of Respiratory and Critical Care Medicine of our hospital between June 2018 and October 2020. All patients were pathologically confirmed to have NSCLC, and EGFR mutation status was determined using next-generation sequencing (NGS), confirming the presence of sensitizing mutations (exon 19 deletion or exon 21 L858R point mutation). This study was approved by the Ethics Committee of Zhuji Hospital of Traditional Chinese Medicine (Approval No.: YWLC22017) and complied with the ethical principles of the Declaration of Helsinki. All patients signed informed consent forms prior to treatment, authorizing the use of their clinical data for scientific research. Given the retrospective design of this study, potential selection bias cannot be completely avoided. To reduce this bias, we applied strict inclusion and exclusion criteria and consecutively enrolled all eligible patients during the study period. Since this was an observational non-randomized study, baseline characteristics between groups were compared to control possible confounding factors. In addition, because this was a retrospective exploratory study, no formal sample size calculation or power analysis was performed, and the sample size was determined by the number of eligible cases available.

Inclusion and Exclusion Criteria

Inclusion criteria: (1) Aged 18–75 years, regardless of gender; (2) Pathologically confirmed NSCLC, clinical stage IIIb–IV,¹⁴ with no indication for surgery; (3) EGFR mutation type was 19-Del or L858R, without concurrent T790M mutation; (4) Receiving systemic treatment for the first time, with no prior EGFR-TKI or other anti-tumor therapy; (5) At least one measurable lesion according to RECIST 1.1 criteria; (6) Karnofsky Performance Score (KPS)¹⁵ ≥ 70, with an expected survival of ≥ 3 months; (7) Complete clinical data and good compliance with follow-up.

Exclusion criteria: (1) Presence of other malignancies or severe internal diseases, such as active tuberculosis or severe heart, liver, or kidney dysfunction; (2) Diagnosed with significant psychiatric or cognitive disorders; (3) Prior treatment with EGFR-TKI, anti-angiogenic agents (eg, bevacizumab), or immunotherapy; (4) Allergic or intolerant to study medications; (5) Pregnant or breastfeeding women.

Grouping and Treatment Regimens

According to the actual treatment plans, the 112 eligible patients were divided into two groups. Control group (n=56): Received a standard platinum-based chemotherapy regimen, ie, pemetrexed + cisplatin. Specifically, pemetrexed 500 mg/m² was administered via intravenous infusion on day 1, and cisplatin 75 mg/m² was administered intravenously on day 1. Each cycle lasted 21 days, and treatment continued for 4–6 cycles. Experimental group (n=56): In addition to the control regimen, patients received oral osimertinib at a dose of 80 mg once daily, with or without food, continuously until disease progression or intolerable adverse effects. Supportive treatment such as folic acid and vitamin B12 was provided before chemotherapy. In the event of severe adverse reactions, dose reduction or chemotherapy delay was allowed as appropriate. All patients underwent regular reexamination and adverse event monitoring.

Observation Indicators and Evaluation Methods

Short-Term Efficacy Evaluation

Based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1),¹⁶ imaging results at 12 weeks post-treatment were categorized into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Objective response rate (ORR) = CR + PR; Disease control rate (DCR) = CR + PR + SD.

Angiogenesis Factor Detection

Fasting venous blood samples (10 mL) were collected in the early morning one week before treatment (before treatment) and at the end of the third cycle (post-treatment). Serum was separated and analyzed for vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) levels using enzyme-linked immunosorbent assay (ELISA).

Tumor Marker Measurement

Serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA21-1) were determined using electrochemiluminescence assays at the same time points as above.

Survival Outcome Follow-Up

Follow-up was conducted through outpatient visits, phone calls, or WeChat to record progression-free survival (PFS) and overall survival (OS). PFS was defined as the time from treatment initiation to the first imaging-confirmed progression or death. OS was defined as the time from treatment initiation to death; lost-to-follow-up cases were censored at the last follow-up.

Safety Assessment

Adverse events during treatment were recorded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0,¹⁷ including gastrointestinal reactions (nausea, vomiting, diarrhea), liver and kidney function damage, skin reactions (rash, dryness), and hematologic toxicities (neutropenia, thrombocytopenia), and the frequency and severity were evaluated.

Statistical Analysis

Baseline comparability between the two groups was examined to minimize the impact of confounding variables on treatment outcomes. GraphPad Prism 8 was used for figure plotting, and SPSS 22.0 software was used for data analysis. Categorical data were expressed as percentages (%), and chi-square (χ²) tests were used for analysis. Measurement data were expressed as (); independent sample t-tests were used for between-group comparisons, and paired t-tests were used for within-group comparisons. Kaplan-Meier method was used to plot survival curves for PFS and OS, and Log rank tests were used to compare survival differences. A P-value < 0.05 was considered statistically significant.

Results

Comparison of Baseline Characteristics

There were no significant differences between the two groups in terms of gender, age, body mass index (BMI), disease duration, smoking status, pathological type, TNM stage, Karnofsky Performance Status (KPS) score, and EGFR mutation type (P > 0.05), indicating comparability. See Table 1.

Table 1 Comparison of Baseline Characteristics (, n[%])

Comparison of Short-Term Efficacy

There was no statistically significant difference in ORR between the two groups (P > 0.05). However, the DCR in the Experimental group was significantly higher than that in the control group (83.93% vs 67.86%, P < 0.05), indicating that osimertinib combined with platinum-based chemotherapy provided superior disease stabilization. These findings highlight the enhanced short-term clinical benefit of the combination regimen compared with chemotherapy alone. See Table 2.

Table 2 Comparison of Short-Term Efficacy [n (%)]

Comparison of Angiogenesis Factor Levels

After treatment, VEGF and Ang-2 levels decreased in both groups, with mean VEGF reduction of 34.2% in the Experimental group compared to 18.7% in the control group (P < 0.05), and Ang-2 reduction of 31.8% vs 15.5%, respectively (P < 0.05). These results suggest that the combination therapy more effectively suppresses tumor angiogenesis, which may contribute to improved disease control. See Figure 1.

Figure 1 Comparison of Angiogenesis Factor Levels (). Notes: Compared with before treatment in the same group, #P < 0.05; compared with control group at the same time point, *P < 0.05.

Comparison of Tumor Marker Levels

After treatment, both CEA and CYFRA21-1 levels decreased in the two groups, with the Experimental group showing a greater decline (CEA: 43.7% vs 25.1%; CYFRA21-1: 39.5% vs 20.3%; both P < 0.05), indicating that osimertinib plus chemotherapy more effectively reduced tumor burden. These findings support the superior anti-tumor activity of the combination regimen over chemotherapy alone. See Figure 2.

Figure 2 Comparison of Tumor Marker Levels (, μg/mL). Notes: Compared with before treatment in the same group, #P < 0.05; compared with control group at the same time point, *P < 0.05.

Comparison of Follow-Up Survival Outcomes

The median PFS in the Experimental group was 15.7 months, higher than 10.6 months in the control group (x² = 18.337, P < 0.001), representing a 48.1% prolongation of PFS. The median OS in the Experimental group was 24.6 months, compared with 17.5 months in the control group (x² = 24.679, P < 0.001), reflecting a 40.6% improvement. Kaplan-Meier curves (Figures 3 and 4) illustrate significantly longer survival with combination therapy. These results underscore the potential clinical value and novelty of osimertinib-based combination treatment in EGFR-mutant NSCLC.

Figure 3 Comparison of PFS Survival Curves Between Groups.

Figure 4 Comparison of OS Survival Curves Between Groups.

Comparison of Adverse Reactions

No grade III or higher adverse reactions occurred in either group. All adverse events were manageable and resolved with standard supportive care. There were no statistically significant differences between groups in nausea/vomiting, gastrointestinal reactions, hepatic or renal function impairment, skin reactions, or hematologic toxicities (P > 0.05), indicating that the addition of osimertinib does not increase treatment-related toxicity. This further supports the safety and feasibility of the combination therapy. See Table 3.

Table 3 Comparison of Adverse Reactions [n (%)]

Discussion

With the advancement of molecular targeted therapies, treatment strategies for EGFR-mutant NSCLC have been continuously optimized, and osimertinib, as a third-generation EGFR-TKI, has gradually become an important first-line treatment option. However, clinical challenges such as drug resistance and disease progression persist during treatment. Therefore, exploring more effective combination therapies to prolong survival and delay resistance has become one of the current research hotspots. In this study, osimertinib combined with platinum-based chemotherapy was used as the core intervention to systematically analyze its short-term efficacy, biomarker changes, angiogenesis levels, long-term survival effects, and safety in EGFR-mutant NSCLC patients, aiming to provide data support and mechanistic evidence for optimizing therapeutic strategies.

The results of this study showed that compared with chemotherapy alone, osimertinib combination therapy significantly improved DCR, suggesting that this regimen possesses a stronger overall tumor control capacity in inhibiting disease progression and delaying deterioration. Although traditional platinum-based doublet chemotherapy remains one of the foundational treatments for advanced NSCLC, its antitumor mechanism mainly relies on non-specific DNA damage, with limited efficacy and lack of molecular-level targeted selectivity.^18,19 Particularly for EGFR mutation-positive patients, chemotherapy does not precisely act on the driver mutation pathway,²⁰ making its overall efficacy generally inferior to targeted therapy. Osimertinib, as a new-generation EGFR-TKI, irreversibly binds to mutant EGFR proteins and exerts high inhibitory activity against exon 19 deletions and L858R point mutations, while also overcoming resistance related to the T790M mutation.²¹ Additionally, it demonstrates superior blood-brain barrier permeability compared with first- and second-generation TKIs, showing significant efficacy in patients with central nervous system metastases,²² which broadens the applicability of combination therapy. In this study, the median PFS of the Experimental group reached 15.7 months, significantly higher than the control group’s 10.6 months. Although slightly lower than the 18.9 months reported in the FLAURA study²³ for osimertinib monotherapy in EGFR-mutant NSCLC compared to first-generation TKIs, it still reflects that osimertinib combined with chemotherapy can effectively prolong disease control time in real-world settings. Moreover, the median OS of the Experimental group reached 24.6 months, significantly higher than 17.5 months in the chemotherapy group, further confirming the potential of this combination strategy in improving long-term outcomes. The synergistic effect of the combination may stem from multi-pathway inhibition: on one hand, osimertinib directly disrupts the EGFR signaling axis, suppressing tumor cell proliferation at its source;²⁴ on the other hand, chemotherapy induces stress-related apoptosis in tumor cells or disrupts pro-angiogenic mechanisms within the tumor microenvironment, thereby enhancing antitumor effects.²⁵ This dual mechanism may explain the improved DCR, PFS, and OS observed in the combination group, highlighting both molecular-level and clinical translational relevance. This therapeutic model is particularly suitable for patients with high tumor burden, slow response to monotherapy, or insufficient initial efficacy. The study by Zhou et al²⁶ also supports this view, proposing that combining TKIs with standard chemotherapy significantly improves disease control rates and survival outcomes, especially in certain high-risk populations.

Tumor angiogenesis is not only a fundamental process for maintaining nutrient supply and metabolic demand in tumor tissues but also plays a critical role in local invasion and distant metastasis of tumor cells.²⁷ Studies²⁸ have shown that multiple pro-angiogenic factors in the tumor microenvironment co-regulate the angiogenic process through complex signaling networks, among which VEGF is the most representative initiator, directly promoting endothelial cell proliferation, chemotaxis, and lumen formation. Ang-2, on the other hand, destabilizes blood vessels by disrupting the pericyte-endothelial interaction, thereby sensitizing endothelial cells to signals such as VEGF and synergistically promoting tumor neovascularization.²⁹ Studies³⁰ have demonstrated that the EGFR pathway, as a commonly activated signaling axis in NSCLC, not only drives sustained proliferation and anti-apoptosis of tumor cells, but also upregulates HIF-1α expression through downstream cascades such as PI3K/AKT and RAS/RAF/MEK/ERK, thereby enhancing VEGF synthesis and secretion and indirectly accelerating tumor angiogenesis. As a third-generation EGFR-TKI, osimertinib can specifically inhibit the phosphorylation of mutant EGFR, blocking the signaling pathway at the source,³¹ and theoretically downregulate the expression of angiogenesis-related factors, thus exerting a negative regulatory effect on tumor neovascularization. The results of this study demonstrated that serum VEGF and Ang-2 levels were significantly decreased after treatment in the osimertinib-combination group compared to the control group, with a greater magnitude of reduction, indicating that osimertinib may not only exert anti-tumor effects through targeted inhibition but also possess potential anti-angiogenic pharmacological properties. This effect may stem from the downstream downregulation of angiogenic factors following EGFR pathway inhibition, or from a remodeling effect of osimertinib on the tumor microenvironment, indirectly suppressing angiogenic signals. From a translational perspective, the role of angiogenesis in targeted resistance and tumor metastasis is receiving increasing attention, and the dual antitumor mechanism of osimertinib—both controlling tumor growth and potentially suppressing angiogenesis—provides new theoretical support for its role in combination therapy. These findings suggest that osimertinib plus chemotherapy could be considered in clinical practice for patients with high tumor burden or early TKI resistance, and may guide future combination strategies with anti-angiogenic agents or immunotherapy. Especially in patients with early TKI resistance or strong vascular dependency of tumors, osimertinib combined with other anti-angiogenic agents (such as bevacizumab) or chemotherapy may offer greater clinical promise.

CEA and CYFRA21-1 are important tumor markers widely used in clinical practice for NSCLC monitoring. Although they are not specific molecules, their dynamic changes can reflect tumor biological behavior and treatment response trends.³² This study showed that in both the control group and the combination treatment group, the levels of CEA and CYFRA21-1 decreased after treatment, suggesting that systemic antitumor therapy indeed led to a reduction in tumor burden. However, compared with chemotherapy alone, the combination therapy group using osimertinib exhibited a more significant decrease in these markers, indicating a stronger inhibitory effect on tumor activity. The mechanism may lie in the fact that while chemotherapy induces tumor cell apoptosis through direct DNA damage, its action is non-selective; whereas osimertinib, as a highly targeted EGFR-TKI, can effectively block the continuous signaling of tumor cells by inhibiting the pathway activated by driver mutations,³³ thus significantly suppressing tumor metabolic activity and biomarker secretion. Finally, treatment safety is a key component in evaluating the clinical feasibility of novel therapeutic regimens, especially for diseases like NSCLC that require long-term maintenance therapy. In the observation and analysis of adverse events in this study, it was found that although targeted agents were introduced in the osimertinib combination therapy group, the overall incidence of adverse events was not significantly different from that in the chemotherapy-alone group. Common side effects such as nausea, vomiting, gastrointestinal discomfort, rash, and liver and kidney dysfunction were similarly distributed between the two groups, and no treatment interruptions due to severe toxic events were observed. This suggests that the regimen has a good safety margin in real-world application. These results provide a solid evidence base for its further promotion in EGFR-mutant NSCLC patients and lay a safety framework for future exploration of combination strategies with immunotherapy or anti-angiogenic agents.

This study still has certain limitations: firstly, as a retrospective single-center study, the sample size is relatively small, and some baseline characteristics are imbalanced, which may introduce potential selection bias and affect the generalizability of the conclusions; secondly, subgroup analyses based on brain metastases, T790M mutation status, and other driver genes were not conducted, making it difficult to comprehensively assess inter-group differences; moreover, the validation of angiogenesis mechanisms remains at the serum level, lacking histological evidence and mechanistic experimental support. Future research may be expanded in the following directions: (1) Conduct multi-center, prospective randomized controlled trials with larger sample sizes to control for potential selection bias; (2) Use multi-omics and mechanistic studies to explore how osimertinib modulates angiogenesis and tumor microenvironment; (3) Evaluate its combination effects with immunotherapy or anti-angiogenic agents to optimize individualized treatment strategies and improve long-term clinical outcomes.

Conclusion

The findings of this study indicate that combining osimertinib with standard platinum-based chemotherapy in EGFR-mutant NSCLC patients significantly improves disease control rate, prolongs progression-free and overall survival, reduces levels of angiogenesis-related factors (VEGF and Ang-2) and tumor markers (CEA and CYFRA21-1), and maintains an acceptable safety profile. This regimen represents a promising therapeutic strategy, offering enhanced comprehensive antitumor efficacy compared with chemotherapy alone. Further multi-center, prospective studies are warranted to confirm its long-term benefits and explore the underlying mechanisms.