Combination regimens as potential treatment of non-small-cell lung cancer patients with HER2 mutation in the real world: a multicenter study

Abstract

Background:

Non-small-cell lung cancer (NSCLC) with human epidermal growth factor receptor 2 (HER2) mutations poses significant treatment challenges. While chemotherapy combined with immunotherapy or anti-angiogenic therapy has been explored, no standardized regimen exists for these patients. This study aims to evaluate the efficacy of different treatment regimens for HER2-mutated NSCLC.

Objectives:

Our study aimed to investigate the survival among NSCLC patients with HER2 mutation who received various treatment regimens in real-world settings, providing insights and guidance for clinical practice.

Designs:

Survival analyses were conducted on patients who underwent different treatment regimens, including chemotherapy, immunotherapy, tyrosine kinase inhibitors (TKIs), and combination therapies, to evaluate their effectiveness.

Methods:

This retrospective study included 118 patients diagnosed with HER2 mutations through next-generation sequencing at Zhejiang Cancer Hospital and Jinling Hospital affiliated with Nanjing University Medical School from September 2017 to December 2024. Data on treatment regimens and clinical outcomes, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), were collected. Kaplan–Meier analysis estimated PFS and OS, and Cox regression identified factors influencing PFS.

Results:

Among the 118 patients, ORR and DCR were 22.9% and 58.5%, respectively. Median PFS and OS were 7.3 and 44.9 months, respectively. Combination therapies significantly improved PFS compared to single chemotherapy or immunotherapy or TKIs group (7.8 vs 5.3 months, p = 0.001). Patients with brain metastases also showed better PFS with combination therapies (7.8 vs 2.8 months, p = 0.001). The chemotherapy, immunotherapy, and anti-angiogenic therapy combination (C + I + A) yielded the best outcomes, with a PFS of 16.3 months. Cox regression revealed treatment regimen as the only factor significantly influencing PFS.

Conclusion:

Combination regimens, especially C + I + A, significantly improve PFS and offer superior therapeutic benefits for patients with HER2-mutated NSCLC compared to single chemotherapy or immunotherapy or TKIs treatments.

Keywords

brain metastases C + I + A regimen combination therapies HER2 mutation NSCLC

Introduction

Lung cancer is the leading cause of cancer-related death worldwide, contributing to high morbidity and mortality rates among patients.¹ Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases, making it the most common subtype.² With the advancement of next-generation sequencing (NGS) technology, several therapeutic targets have been identified, including EGFR, ALK, ROS1, and others, laying the foundation for targeted therapies.^3–5 Related tyrosine kinase inhibitors (TKIs) have since been approved for clinical use.⁶

As one of the oncogenic drivers, mutations in the human epidermal growth factor receptor 2 (HER2) account for approximately 2%–3% of cases in NSCLC.⁷ The treatment regimens for HER2 mutations are distinct from those targeting other mutations. The efficacy of a range of pan-Her TKIs has been limited, with the majority of patients experiencing PFS of less than 6 months.⁸ New drugs targeting HER2 mutations continue to be developed. Pyrotinib has demonstrated promising efficacy in patients with HER2 mutations, achieving a PFS of 6.9 months.⁹ Poziotinib has also shown a PFS of 5.5 months in patients with HER2 mutations.¹⁰ However, compared to other targeted mutations, the efficacy of various TKIs for HER2 mutations has been limited, and there is currently no HER2-specific TKI approved as a priority treatment for these patients. In addition, current treatment guidelines still recommend first-line therapy based on the absence of other driver mutations.¹¹ During the exploration of new therapies, antibody–drug conjugates (ADCs) have garnered significant attention and high expectations. However, trastuzumab emtansine demonstrated a relatively modest PFS of only 5 months.¹² Later, the newer ADC drug, trastuzumab deruxtecan, demonstrated significant therapeutic potential. Its unprecedented PFS of 8.7 months led to its approval by the U.S. Food and Drug Administration.¹³ Although trastuzumab deruxtecan showed promising efficacy, its high cost and limited accessibility may restrict its widespread use in clinical practice. Recently, our team published the results of SHR-A1811 (an ADC) in phase I and II trials. SHR-A1811 demonstrated a PFS of 8.4 months, with a median duration of response of 13.7 months, potentially offering greater therapeutic benefits for patients, particularly within the Chinese population.¹⁴ However, as the drug is not yet on the market, it is essential to identify relatively effective treatment regimens as temporary therapeutic options.

According to the previous studies, a PFS of 8.8 months suggests that combining pembrolizumab with pemetrexed and a platinum-based drug could be an effective first-line treatment option for patients with HER2 mutations.¹⁵ In addition, chemotherapy combined with anti-angiogenic therapy has demonstrated therapeutic efficacy in a retrospective study.¹⁶ However, there is still a lack of real-world data offering systematic analysis and clear treatment options for patients. Building on previous research, the current study aims to explore optimal treatment regimens and provide therapeutic recommendations for patients with HER2 mutations in the first-line setting.

Methods

Patient eligibility

The current study included NSCLC patients from Zhejiang Cancer Hospital and Jinling Hospital, affiliated with Nanjing University Medical School, between September 2017 and December 2024. The inclusion criteria were listed as follows. All patients were diagnosed with adenocarcinoma based on pathological confirmation and had HER2 mutations confirmed through NGS. Tissue biopsy was used for mutation detection, with both HER2 exon 20 insertions and other HER2 mutations included in the analysis. Eligible patients were those with stage IV or stage IIIB/C NSCLC who had not undergone surgery or radiotherapy. Data from patients who received first-line therapy were analyzed. Inclusion criteria required patients to have sufficient bone marrow function, normal liver and kidney function, and adequate tolerance for treatment. Complete blood count criteria (without blood transfusion or hematopoietic growth factor support within 14 days prior to screening): Absolute neutrophil count ⩾ 1.5 × 10⁹/L; platelet count ⩾ 100 × 10⁹/L; and hemoglobin ⩾ 90 g/L. Blood biochemistry criteria should also be defined as follows: total bilirubin ⩽ 2 × upper limit of normal (ULN; ⩽3 × ULN for patients with Gilbert’s syndrome); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ⩽ 2.5 × ULN; for patients with liver metastases, ALT and AST ⩽ 5 × ULN. Serum creatinine (Cr) ⩽ 1.5 × ULN or estimated glomerular filtration rate (eGFR) ⩾ 60 mL/min using the Cockcroft-Gault formula: Albumin ⩾ 30 g/L. The primary tumor and metastatic sites were assessed using CT or MRI, and PET-CT was used to evaluate whole-body lesions. Bone metastases were detected by PET-CT or bone scans.

As for the exclusion criteria, patients with HER2 amplification were excluded from the study. Those who had received prior systemic therapy were excluded. Patients with severe comorbidities, such as cardiovascular diseases, infectious diseases, abnormal coagulation, or immune deficiencies, were excluded.

As the lead institution for the research, the Institutional Review Board (IRB) of Zhejiang Cancer Hospital (IRB-2022-396) approved the study. The research adhered to the Declaration of Helsinki, and individual consent was waived. The reporting of this study conforms to the statement of ESMO Guidance for Reporting Oncology real-world evidence.¹⁷

Next-generation sequence

Sample collection and DNA extraction

Cut 6–10 sections of 5–10 μm thickness from Formalin-Fixed, Paraffin-Embedded (FFPE) samples and transfer them into 1.5 mL centrifuge EP tubes for DNA extraction.

DNA extraction and quantification

DNA is extracted according to the QIAamp DNA FFPE Tissue Kit (Qiagen, Hilden, North Rhine-Westphalia, Germany) instructions, and the extracted DNA is quantified using the PicoGreen fluorescence assay (Invitrogen, Carlsbad, California, the United States).

Library preparation

The extracted genomic DNA (50–200 ng) is fragmented into approximately 200 base pair fragments using sonication (Novartis, Basel, Basel-Stadt, Switzerland). The genomic DNA is then used for library construction following the steps outlined in the KAPA LTP Library Preparation Kit.

Sequencing

Sequencing is performed on the Illumina NextSeq 500 platform. The sequencing procedure follows the protocol provided by the official Illumina cBot guidelines.

Sequence analysis

Low-quality sequencing reads are filtered. Sequencing reads are aligned to the human reference genome using the BWA aligner. Variant analysis is performed for SNV, InDel, structural variation (SV), and copy number variation (CNV) types using the following tools:

MuTect (http://www.broadinstitute.org/cancer/cga/mutect) for SNP variant analysis.

GATK (https://www.broadinstitute.org/gatk/) for InDel variant analysis.

contra.py (http://contra-cnv.sourceforge.net/) for CNV analysis. Custom-developed software based on abnormal paired-end sequences for SV analysis.

Treatment methods

All patients with HER2 mutations were included in the study and treated according to established regimens. The treatment protocols, including drug selection and dosages, were consistent with the National Comprehensive Cancer Network guidelines and expert consensus. For monotherapy, treatment regimens included chemotherapy, immunotherapy, and TKIs. Chemotherapy regimens consisted of pemetrexed with platinum, docetaxel, and nab-paclitaxel plus carboplatin. Monotherapy immunotherapy options included durvalumab, atezolizumab, and nivolumab. TKIs used in the study included afatinib, pyrotinib, and anlotinib. For combination therapies, regimens analyzed included chemotherapy combined with immunotherapy, chemotherapy combined with anti-angiogenic therapy, and chemotherapy combined with immunotherapy and anti-angiogenic therapy. In the combination therapy group, chemotherapy regimens included pemetrexed with platinum, nab-paclitaxel or paclitaxel plus platinum, and docetaxel. The immunotherapy drugs used were durvalumab, tislelizumab, sintilimab, camrelizumab, pembrolizumab, and toripalimab. Anti-angiogenic therapies included apatinib, bevacizumab, and endostar. Each treatment cycle was defined as 21 days.

Responses

Response evaluation was conducted in accordance with the Response Evaluation Criteria in Solid Tumors. The primary endpoints for response assessment included the Objective Response Rate (ORR) and Disease Control Rate (DCR). ORR was defined as the sum of complete response (CR) and partial response (PR), while DCR included CR, PR, and stable disease (SD). Disease progression, defined as an increase in tumor size of more than 20% or the appearance of new metastases, was categorized as progressive disease (PD). Response evaluations were performed every two or three cycles, with the size of the primary tumor and metastatic sites recorded at each assessment.

Statistical analysis

Survival analyses were conducted in two key aspects: progression-free survival (PFS) and overall survival (OS). PFS was defined as the time from the initiation of systemic treatment to disease progression or death. OS was defined as the time from the initiation of systemic treatment to death or the last follow-up, with the last follow-up date being November 30, 2024. Kaplan–Meier analysis was used to estimate survival curves for both PFS and OS, and the log-rank test was applied to assess differences between groups. Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) software (version 25; IBM, Armonk, NY, USA) and GraphPad Prism software (version 9; GraphPad Software, San Diego, CA, USA). GraphPad Prism was also used to plot survival curves. The Cox proportional hazards model was employed to analyze factors influencing PFS in the real world. The hazard ratio (HR) and 95% confidence interval (CI) were used as the primary indices, and forest plots were generated using R software. And the p-value < 0.05 was considered statistically significant.

Results

Patient characteristics

The study included 118 NSCLC patients with HER2 mutations who were treated between September 2017 and December 2024. Detailed patient information is provided in Table 1. Of the patients, 54.2% (n = 64) were male, and 45.8% (n = 54) were female. The median age of all patients was 57.5 years (ranging from 32 to 81 years), with 30 patients (25.4%) being older than 65 years. The majority of patients were diagnosed with stage IV NSCLC, accounting for 89% (n = 105). Regarding smoking history, 43 patients (36.4%) had a history of smoking. The Performance Status (PS) for all patients ranged from 0 to 1, with 59.3% (n = 70) having a PS of 1.

Table 1.

Baseline characteristics for all patients with HER2 mutations.

Characteristics	Non-small-cell lung cancer patients (n = 118)
Characteristics	No.	%
Sex
Male	64	54.2
Female	54	45.8
Age
Median	57.5
Range	32–81
⩽65	88	74.6
>65	30	25.4
Stage
III	13	11.0
IV	105	89.0
Smoking history
Former	43	36.4
Never	75	63.6
ECOG PS
0	48	40.7
1	70	59.3
Liver metastases
No	108	91.5
Yes	10	8.5
Bone metastases
No	68	57.6
Yes	50	42.4
Brain metastases
No	91	77.1
Yes	27	22.9
HER2 mutation
HER2 exon 20 insertion	89	75.4
Others	29	24.6
Therapy mode
C or I or TKI	51	43.2
Chemotherapy	24	20.3
Immunotherapy	3	2.6
TKI	24	20.3
Combination therapies	67	56.8
C + I	32	27.1
C + A	22	18.6
C + I + A	13	11.1

C, chemotherapy; C + A, chemotherapy combined with anti-angiogenic therapy; C + I, chemotherapy combined with immunotherapy; C + I + A, chemotherapy combined with immunotherapy and anti-angiogenic therapy; ECOG PS, Eastern Cooperative Oncology Group Performance status; HER2, human epidermal growth factor receptor 2; I, immunotherapy; TKI, tyrosine kinase inhibitor.

Metastasis patterns included liver metastases in 10 patients (8.5%), bone metastases in 50 patients (42.4%), and brain metastases in 27 patients (22.9%). Regarding mutation types, 73.7% (n = 87) of patients had the HER2 exon 20 variations, which was the most common mutation type. The different HER2 mutation subtypes for NSCLC are listed in Table 2.

Table 2.

Subtypes of HER2 mutations in all NSCLC patients.

Mutation subtypes	NSCLC patients (n = 118)
Mutation subtypes	No.	%
HER2 Exon 20 variations
p.Y772_A775dup	42	35.6
p. G776delinsVC	8	6.8
p.G778_P780dup	6	5.1
p.V777_G778insCG	1	0.8
p. G776delinsLC	1	0.8
p. A771insAYVM	3	2.5
UN*	26	22.0
Activating point mutations
p. V777L	3	2.5
p. V755P	1	0.8
p. L755S	1	0.8
p. D483N	1	0.8
p. L655V	1	0.8
p. V659E	1	0.8
p. Y1221C	1	0.8
p. S1134I	1	0.8
Variants of uncertain significance
Exon 19	1	0.8
Exon 21	1	0.8
Uncertain types	19	16.1

HER2, human epidermal growth factor receptor 2; NSCLC, non-small-cell lung cancer; UN*, it means unknown, although a HER2 exon 20 variation is confirmed, the precise mutation site has not been identified.

In terms of treatment regimens, 51 patients (43.2%) received single therapy, including chemotherapy (n = 24), immunotherapy (n = 3), and TKIs (n = 24). The remaining 67 patients (56.8%) received combination therapies, with 32 patients (27.1%) receiving chemotherapy combined with immunotherapy (C + I), 22 patients (18.6%) receiving chemotherapy combined with anti-angiogenic therapy (C + A), and 13 patients (11.0%) receiving chemotherapy combined with both immunotherapy and anti-angiogenic therapy (C + I + A).

Clinical efficacy

The ORR for all patients was 22.9%, and the DCR was 58.5%. There was no significant difference in ORR between single C or I or TKI group and combination therapies (17.6% vs 26.9%, p = 0.238). However, the difference in DCR between the two groups was significant (43.1% vs 70.2%, p = 0.003). Among patients who received single C or I or TKI therapy, 9 patients achieved PR, and 13 patients had SD. In addition, 12 patients experienced PD, and 17 patients could not be evaluated. In the combination therapy group, 18 patients achieved PR, and 29 patients had SD. Only 5 patients experienced PD, while 15 patients could not be evaluated for efficacy. The detailed efficacy data are provided in Table 3.

Table 3.

Response rates for the intent-to-treat NSCLC population.

Response rates	C or I or TKI (n = 51)		Combination therapies (n = 67)		p Value
Response rates	No.	%	No.	%	p Value
Overall response	9	17.6	18	26.9	0.238
Complete response	0	0	0	0
Partial response	9	17.6	18	26.9
Stable disease	13	25.5	29	43.3
Progressive disease	12	23.5	5	7.5
Not evaluated	17	33.4	15	22.3
ORR (%)	17.6		26.9		0.238
DCR (%)	43.1		70.2		0.003

C, chemotherapy; DCR, disease control rate; I, immunotherapy; NSCLC, non-small-cell lung cancer; ORR, objective response rate; TKI, tyrosine kinase inhibitor.

Survival

The PFS for the entire cohort of patients was 7.3 months, and the OS was 44.9 months (Figure 1(a) and (b)). In the combination therapy group, the PFS was 7.8 months, compared to 5.3 months for the single C or I or TKI therapy group. The difference in PFS between the two groups was significant (p = 0.001; Figure 1(c)). However, there was no significant difference in OS between the single C or I or TKI therapy and combination therapy groups (36.6 vs 46.6 months, p = 0.358; Figure 1(d)).

Figure 1.

Kaplan–Meier estimates of PFS and OS. (a) PFS in all patients with Her-2 mutation (n = 118, mPFS = 7.3 months). (b) OS in all patients with Her-2 mutation (n = 118, mOS = 44.9 months). (c) PFS differences in patients with single C or I or TKI group and combination therapies in first-line therapy (5.3 vs 7.8 months, p = 0.001). (d) OS differences in patients with single C or I or TKI group and combination therapies in first-line therapy (36.6 vs 46.6 months, p = 0.358).

Within the combination therapy groups, there was a significant difference in PFS among the subgroups receiving chemotherapy + immunotherapy (C + I), chemotherapy + anti-angiogenic therapy (C + A), and chemotherapy + immunotherapy + anti-angiogenic therapy (C + I + A; 7.7 vs 7.4 vs 16.3 months, p = 0.005; Figure 2(a)). However, OS did not differ significantly among the subgroups (41.3 vs 44.9 months vs not reached, p = 0.445; Figure 2(b)). Notably, the C + I + A regimen significantly prolonged PFS in patients with HER2 mutations, with a PFS of 16.3 months in the first-line setting. The treatment duration for the C + I + A regimen is shown in Figure 3.

Figure 2.

Kaplan–Meier estimates of PFS and OS. (a) PFS differences in patients received C + I, C + A and C + I + A in first-line therapy (7.7 vs 7.4 vs 16.3 months, p = 0.005). (b) OS differences in patients received C + I, C + A, and C + I + A in first-line therapy (41.3 vs 44.9 vs not reached, p = 0.445).

Figure 3.

Swimmer’s plot showing PFS for all non-small-cell lung cancer patients with Her-2 mutation receiving chemotherapy combined with immunotherapy and anti-angiogenic therapy, and details of their therapy information on drugs.

Brain metastases

In patients with brain metastases, the results demonstrated the superiority of the combination therapies. The PFS for patients receiving a single C or I or TKI therapy was only 2.8 months, while the combination therapy groups had a PFS of 7.8 months (p = 0.001; Figure 4(a)). However, there was no significant difference in OS between the two groups (31.1 vs 44.9 months, p = 0.354; Figure 4(b)).

Figure 4.

Kaplan–Meier estimates of PFS and OS for patients with brain metastases. (a) PFS differences in patients with single C or I or TKI group and combination therapies for patients with brain metastases (2.8 vs 7.8 months, p = 0.001). (b) OS differences in patients with single C or I or TKI group and combination therapies for patients with brain metastases (31.1 vs 44.9 months, p = 0.354). (c) PFS differences in patients received single C or I or TKI group, C + I, C + A, and C + I + A (2.8 vs 7.6 vs 9.1 vs 26.3 months, p = 0.004). (d) OS differences in patients received single C or I or TKI group, C + I, C + A, and C + I + A (31.1 vs 41.3 vs 44.9 vs not reached, p = 0.579).

Within the combination therapy groups, the C + I + A regimen appeared to be the most effective choice for patients with brain metastases. The PFS differed significantly among the single C or I or TKI therapy, C + I, C + A, and C + I + A subgroups (2.8 vs 7.6 vs 9.1 vs 26.3 months, p = 0.004; Figure 4(c)). However, there was no significant difference in OS among these subgroups (31.1 vs 41.3 vs 44.9 months vs not reached, p = 0.579; Figure 4(d)). Notably, three patients treated with the C + I + A regimen are still alive.

COX analyses

Cox regression analysis was used to explore factors influencing PFS. For all patients, multivariate analysis assessed variables such as sex, age, smoking history, PS, liver metastases, bone metastases, brain metastases, and treatment modality. The analysis revealed that treatment modality was the only significant factor influencing PFS (p = 0.003, HR = 0.520, 95% CI, 0.340–0.795; Figure 5(a)). For patients receiving combination therapies, multivariate analysis also evaluated sex, age, smoking history, PS, liver metastases, bone metastases, brain metastases, and therapy regimen. The results showed that the type of concrete combination therapy regimen was the only factor significantly influencing PFS (p = 0.001, HR = 0.451, 95% CI, 0.281–0.725; Figure 5(b)).

Figure 5.

Forest plots of potential factors affecting PFS for (a) all patients with Her-2 mutation and (b) patients received combination therapies in the real world, and results of multivariable analysis using a Cox proportional hazards model.

Discussion

The current study, which involved a larger sample size, analyzed the survival outcomes of lung cancer patients with HER2 mutations receiving first-line treatment in a real-world setting. The results highlighted the superiority of combination therapy regimens over single-agent treatments, particularly the regimen combining chemotherapy, immunotherapy, and anti-angiogenic therapy. This study is the first to assess the efficacy of different treatment options specifically for HER2 mutation patients with brain metastases, offering valuable insights. The promising efficacy of combination therapies for patients with brain metastases may provide important guidance for clinicians in their treatment decisions.

HER2 mutation is a distinct genetic alteration that differs significantly from HER2 overexpression and HER2 amplification in NSCLC patients. Most previous studies have focused on analyzing the efficacy of TKIs for patients with HER2 mutations. However, both pan-Her inhibitors and selective HER2 TKIs have not demonstrated promising efficacy in these patients.¹⁸ Poziotinib, while effective, is associated with a high risk of toxicity, which may significantly limit its clinical use.^10,19 Emerging ADCs offer new hope for patients with HER2 mutations, but their limited availability and high cost may restrict access for many patients. According to previous studies, monotherapy chemotherapy has shown limited efficacy, with PFS in first-line treatment for HER2 mutation patients ranging from 4.6 to 7.5 months.^11,20–23 Mono-immunotherapy has shown an extremely low response rate in patients with HER2 mutations, with PFS ranging from 1.9 to 2.5 months.^24–26 In our study, the single chemotherapy or immunotherapy or TKI therapy group also showed limitations, with a PFS of 5.3 months. By contrast, the combination regimen achieved a PFS of 7.8 months. Regarding combination therapies, some studies have suggested that chemotherapy combined with anti-angiogenic therapy may be more effective than chemotherapy combined with immunotherapy.²⁷ The underlying mechanism suggests that the PI3K/AKT signaling pathway may influence the tumor microenvironment, contributing to immunosuppression in patients with HER2 mutations.¹⁶ In our study, no significant differences were observed between the therapies. However, we explored a novel treatment approach for patients with HER2 mutations, introducing the concept of the “Combination of Four Drugs.” The C + I + A regimen achieved a PFS of 16.3 months for HER2 mutation patients in the first-line setting. In addition, this regimen demonstrated promising efficacy in patients with brain metastases. Our team has previously analyzed a similar treatment pattern in patients with KRAS mutations.²⁸ The results also suggest the potential benefits of the four-drug combination for patients. According to previous reports, anti-angiogenic therapy can help alleviate the tumor microenvironment suppression, thereby improving treatment outcomes.²⁹ Some studies suggest that the immunomodulatory effects of anti-angiogenic therapy can help reprogram the tumor microenvironment, promoting an immune-permissive response.^30,31 Preclinical studies have shown that disorganized tumor vasculature may hinder CD8+ T-cell trafficking into the tumor microenvironment, thereby impairing T-cell effector function.³² Vascular endothelial growth factor could also induce the TOX-mediated exhaustion of CD8+ T cells.³² Moreover, adaptive immune cells may contribute to the development of vascular abnormalities, creating a complex interplay between the two. Building on the foundational role of chemotherapy, immunotherapy combined with anti-angiogenic therapy could play a crucial role in improving treatment efficacy for patients. There is also a therapeutic approach suggesting that immunotherapy combined with anti-angiogenic therapy may be a viable option for patients who cannot tolerate chemotherapy.³³ A phase II prospective study demonstrated significantly promising efficacy of atezolizumab plus chemotherapy, with or without bevacizumab, in patients who had previously received targeted therapies.³⁴ There is also evidence suggesting that bevacizumab, in combination with atezolizumab and chemotherapy, may be a recommended option for first-line treatment in patients.³⁵ However, to improve survival and prognosis, careful patient selection is essential. Some studies suggest that patients with bone or liver metastases and poor PS should be excluded from combination regimens, particularly those who have already received more than three lines of therapy.³⁶ In our current study, one patient who received the C + I + A regimen had a duration of response exceeding 30 months. While the trend toward promising efficacy of C + I + A was observed, the sample size for patients receiving this regimen was still limited. We anticipate that further studies will be needed to confirm our findings in the future.

There are several limitations in the current study. First, the small sample size of certain subgroups, particularly the C + I + A subgroup, warrants further investigation in future research. And some patients were unable to undergo an accurate efficacy evaluation due to loss to follow-up. Second, the mechanisms underlying the improved efficacy of combination regimens should be explored in more detail. Third, the retrospective nature of the study introduces inherent biases, which cannot be avoided. In the future, prospective studies are needed to provide more treatment options for both patients and clinicians in clinical practice.

Conclusion

For patients with HER2 mutations, combination therapies demonstrated better survival outcomes compared to monotherapy. Among combination therapies, the chemotherapy combined with immunotherapy and anti-angiogenic therapy resulted in the longest survival, offering a promising new treatment option for HER2 mutant patients in clinical practice.

Footnotes

Acknowledgements

The authors would like to appreciate all patients and their families for their cooperation. In addition, we are thankful to all the research staff and co-investigators involved in this investigation.

Declarations

ORCID iDs

Yue Hao

Chengyu Chen

Dong Wang

References

Yan

. Advances and challenges in the treatment of lung cancer. Biomed Pharmacother 2023; 169: 115891.

Abdelaziz

Gaber

Abd-Elwakil

, et al. Inhalable particulate drug delivery systems for lung cancer therapy: nanoparticles, microparticles, nanocomposites and nanoaggregates. J Control Release 2018; 269: 374–392.

Zhou

. Combination therapy for EGFR-mutated lung cancer. N Engl J Med 2023; 389(21): 2005–2007.

Golding

Luu

Jones

, et al. The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC). Mol Cancer 2018; 17(1): 52.

Nagasaka

Brazel

S-II

. Taletrectinib for the treatment of ROS-1 positive non-small cell lung cancer: a drug evaluation of phase I and II data. Expert Opin Investig Drugs 2024; 33(2): 79–84.

Laskin

Liu

Tolba

, et al. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol 2020; 31(12): 1693–1703.

Wang

Jiang

Qin

, et al. HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib. Ann Oncol 2019; 30(3): 447–455.

Peters

Curioni-Fontecedro

Nechushtan

, et al. Activity of afatinib in heavily pretreated patients with ERBB2 mutation-positive advanced NSCLC: findings from a global named patient use program. J Thorac Oncol 2018; 13(12): 1897–1905.

Zhou

Wang

, et al. Pyrotinib in HER2-mutant advanced lung adenocarcinoma after platinum-based chemotherapy: a multicenter, open-label, single-arm, phase II study. J Clin Oncol 2020; 38(24): 2753–2761.

10.

Cornelissen

Garassino

, et al. Poziotinib in non-small-cell lung cancer harboring HER2 exon 20 insertion mutations after prior therapies: ZENITH20-2 trial. J Clin Oncol 2022; 40(7): 710–718.

11.

Eng

Hsu

Chaft

, et al. Outcomes of chemotherapies and HER2 directed therapies in advanced HER2-mutant lung cancers. Lung Cancer 2016; 99: 53–56.

12.

Shen

Buonocore

, et al. Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. J Clin Oncol 2018; 36(24): 2532–2537.

13.

Smit

Goto

, et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med 2022; 386(3): 241–251.

14.

Song

Hong

, et al. SHR-A1811 (antibody-drug conjugate) in advanced HER2-mutant non-small cell lung cancer: a multicenter, open-label, phase 1/2 study. Signal Transduct Target Ther 2024; 9(1): 182.

15.

Gandhi

Rodríguez-Abreu

Gadgeel

, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018; 378(22): 2078–2092.

16.

Yang

Liu

, et al. First-line immunotherapy or angiogenesis inhibitor plus chemotherapy for HER2-altered NSCLC: a retrospective real-world POLISH study. Ther Adv Med Oncol 2022; 14: 17588359221082339.

17.

Castelo-Branco

Pellat

Martins-Branco

, et al. ESMO guidance for reporting oncology real-world evidence (GROW). Ann Oncol 2023; 34(12): 1097–1112.

18.

Kris

Camidge

Giaccone

, et al. Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors. Ann Oncol 2015; 26(7): 1421–1427.

19.

Elamin

Robichaux

Carter

, et al. Poziotinib for patients with HER2 exon 20 mutant non-small-cell lung cancer: results from a phase II trial. J Clin Oncol 2022; 40(7): 702–709.

20.

Mazières

Barlesi

Filleron

, et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Ann Oncol 2016; 27(2): 281–286.

21.

Song

Shi

, et al. HER2 mutations in Chinese patients with non-small cell lung cancer. Oncotarget 2016; 7(47): 78152–78158.

22.

Wang

Zhang

, et al. Outcomes of pemetrexed-based chemotherapies in HER2-mutant lung cancers. BMC Cancer 2018; 18(1): 326.

23.

Yang

Wang

Zhao

, et al. Exon 20 YVMA insertion is associated with high incidence of brain metastasis and inferior outcome of chemotherapy in advanced non-small cell lung cancer patients with HER2 kinase domain mutations. Transl Lung Cancer Res 2021; 10(2): 753–765.

24.

Chen

Pan

Cheng

, et al. Immune microenvironment features and efficacy of PD-1/PD-L1 blockade in non-small cell lung cancer patients with EGFR or HER2 exon 20 insertions. Thorac Cancer 2021; 12(2): 218–226.

25.

Mazieres

Drilon

Lusque

, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019; 30(8): 1321–1328.

26.

Guisier

Dubos-Arvis

Viñas

, et al. Efficacy and safety of anti-PD-1 immunotherapy in patients with advanced NSCLC with BRAF, HER2, or MET mutations or RET translocation: GFPC 01-2018. J Thorac Oncol 2020; 15(4): 628–636.

27.

Xia

Yang

, et al. Immunotherapy or antiangiogenic therapy plus chemotherapy as first-line treatment of patients with PD-L1(-) advanced non-squamous non-small cell lung cancer in a Chinese cohort. Cancer Med 2023; 12(13): 14282–14292.

28.

Wang

, et al. Exploration of efficacy of different therapy regimens for advanced NSCLC patients with KRAS mutation in the first-line treatment. Clin Transl Oncol 2024; 26(10): 2479–2487.

29.

Horvath

Thienpont

Zhao

, et al. Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC)—novel approaches and future outlook. Mol Cancer 2020; 19(1): 141.

30.

Chen

Hurwitz

. Combinations of bevacizumab with cancer immunotherapy. Cancer J 2018; 24(4): 193–204.

31.

Tan

Kobayashi

Saw

SPL

, et al. Immunotherapy with chemotherapy and anti-angiogenic therapy for EGFR mutated NSCLC: challenging the dogma. Expert Rev Anticancer Ther 2023; 23(2): 117–120.

32.

Lee

Yang

Chon

, et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med 2020; 52(9): 1475–1485.

33.

Gao

Song

Sun

, et al. Efficacy and safety of combined immunotherapy and antiangiogenesis with or without chemotherapy for advanced non-small-cell lung cancer: a systematic review and pooled analysis from 23 prospective studies. Front Pharmacol 2022; 13: 920165.

34.

Amari

Tomasini

Dantony

, et al. Safety and patient-reported outcomes of atezolizumab plus chemotherapy with or without bevacizumab in stage IIIB/IV non-squamous non-small cell lung cancer with EGFR mutation, ALK rearrangement or ROS1 fusion progressing after targeted therapies (GFPC 06-2018 study). Lung Cancer 2024; 193: 107843.

35.

Perdrizet

Leighl

. The role of angiogenesis inhibitors in the era of immune checkpoint inhibitors and targeted therapy in metastatic non-small cell lung cancer. Curr Treat Options Oncol 2019; 20(3): 21.

36.

Yao

Wang

Sheng

, et al. Efficacy and safety of combined immunotherapy and antiangiogenic therapy for advanced non-small cell lung cancer: a two-center retrospective study. Int Immunopharmacol 2020; 89(Pt A): 107033.