Efficacy and safety of chemotherapy alone or in combination with immune checkpoint inhibitors as the first-line treatment for patients with advanced HER2-mutant non-small cell lung cancer: A multi-center retrospective study

To the Editor: Lung cancer is one of the most common malignancies worldwide and a leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers, with mutations in the human epidermal growth factor receptor 2 (HER2) found in approximately 2–4% of patients with NSCLC.[1,2] Currently, chemotherapy has been the standard treatment for HER2-mutant NSCLC. In recent years, immune checkpoint inhibitors (ICIs) have made significant progress in the treatment of NSCLC. However, the efficacy of ICIs in HER2-mutant NSCLC patients remains uncertain.[2–4] Thus, we conducted a multicenter, real-world retrospective study to evaluate the efficacy and safety of chemotherapy alone or in combination with ICIs in advanced HER2-mutant NSCLC patients. A multi-center, real-world retrospective study was performed on patients with advanced HER2-mutant NSCLC who received first-line systemic treatment at the First Affiliated Hospital of Zhejiang University School of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and Taizhou Hospital of Zhejiang Province between January 1, 2019, and December 1, 2023. The inclusion criteria were: (1) patients aged ≥18 years; (2) patients with the confirmed presence of a HER2 mutation; (3) patients with the diagnosis of advanced NSCLC (stage III or IV); (4) patients who received first-line systemic therapy; and (5) patients with the evidence of measurable lesions based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients who lacked efficacy evaluation data, received first-line HER2-targeted therapy, or did not undergo chemotherapy were excluded. The included patients were categorized into two groups based on their respective first-line treatment regimens: (1) Chemotherapy (chemo) group: Patients received chemotherapy alone; (2) ICI + chemo group: Patients received ICIs in combination with chemotherapy [Supplementary Figure 1, https://links.lww.com/CM9/C708]. Demographical and clinical characteristics at the time of first-line systemic treatment were obtained from patient records. The collected data included age, gender, smoking status, histological type of cancer, cancer staging, Eastern Cooperative Oncology Group performance status (ECOG PS), programmed death-ligand 1 (PD-L1) tumor proportion score (TPS), and the presence of brain, bone, or liver metastases. Besides, treatment regimens, progression dates, best response, last follow-up date, date of death, and types and grades of treatment-related adverse events (TRAEs) were documented from the initiation of first-line therapy until the conclusion of follow-up. All procedures were conducted in accordance with the 2013 revision of the Declaration of Helsinki and the ethical guidelines established by both institutional and national research committees. This study protocol was approved by the First Affiliated Hospital, Zhejiang University School of Medicine (No. IIT20240435B-R1). This retrospective study was authorized by the institutional review board, which granted a waiver for written informed consent. Statistical analyses were performed using SPSS software (International Business Machines Corporation, Armonk, New York, USA). Continuous variables were presented as median and range or mean and standard deviation, while categorical variables were represented by frequencies and percentages. Continuous variables between groups were compared using the t-test, and categorical variables were analyzed using either the chi-square test or Fisher’s exact test, depending on data distribution. The median follow-up duration was calculated using the reverse Kaplan–Meier method. Progression-free survival (PFS) was analyzed using the Kaplan–Meier method, and differences between subgroups were evaluated with the log-rank test. Statistical significance was set at P <0.05 (two-tailed). A total of 40 advanced HER2-mutant NSCLC patients were included. Of these patients, 18 were in the chemo group, while the ICI + chemo group included 22 patients. The baseline characteristics are presented in Supplementary Table 1, https://links.lww.com/CM9/C708, and there were no significant differences in baseline characteristics among the subgroups. Among the 40 patients in the study, 31 (77.5%) experienced disease progression during the follow-up period. The median PFS (mPFS) was 6.8 (95% CI: 5.1–8.4) months, and the median follow-up duration was 21.6 (95% CI: 13.8–29.4) months. By the cutoff date for data collection, 14 patients had achieved an objective response, resulting in an objective response rate (ORR) of 35.0% (14/40). Disease control was achieved in 35 patients, yielding a disease control rate (DCR) of 87.5% (35/40) [Supplementary Table 2, https://links.lww.com/CM9/C708]. In the chemo group, 77.8% (14/18) experienced disease progression during follow-up. The mPFS in this group was 4.5 (95% CI: 1.3–7.7) months. Six patients had objective responses, resulting in an ORR of 33.3% (6/18). Disease control was observed in 15 patients, yielding a DCR of 83.3% (15/18). In the ICI + chemo group, 77.3% (17/22) experienced PFS events, with an mPFS of 8.7 (95% CI: 4.4–13.0) months. An objective response was observed in eight patients, leading to an ORR of 36.4% (8/22). Disease control was achieved in 20 patients, resulting in a DCR of 90.9% (20/22). A difference in PFS was noted between groups (mPFS: 4.5 months vs. 8.7 months, P = 0.048) [Supplementary Figure 2, https://links.lww.com/CM9/C708]. Although the ORR and DCR were somewhat higher in the combination ICIs treatment group compared to the non-ICIs group, these differences were not statistically significant (ORR: 36.4% [8/22] vs. 33.3% [6/18], χ2 = 0.040, P = 0.842; DCR: 90.9% [20/22] vs. 83.3% [15/18], χ2 = 0.058, P = 0.810). Thirty patients experienced TRAEs of any grade [Supplementary Table 3, https://links.lww.com/CM9/C708]. The most common TRAEs included elevated liver enzymes (18/40), neutropenia (16/40), and anemia (11/40). Of these patients, 11 experienced grade 3 or higher TRAEs, with neutropenia being the most frequent high-grade TRAE (8/11), followed by anemia (4/11). No significant difference was observed in the incidence of TRAEs between the chemo and ICI + chemo groups (72.2% [13/18] vs. 77.3% [17/22], χ2 <0.001, P >0.999). Although the ICI + chemo group had a higher occurrence of high-grade TRAEs compared to the chemo group, this difference was not statistically significant (36.4% [8/22] vs. 16.7% [3/18], χ2 = 1.065, P = 0.302). This study provided real-world evidence on the efficacy and safety of HER2-mutant advanced NSCLC. Although some studies have reported no significant difference in PFS between patients receiving ICIs combined with chemotherapy compared to those receiving chemotherapy alone, the data suggest that the former group experienced longer PFS durations.[2,3] Our study further proved that the combination of chemotherapy and ICIs as first-line treatments improved the PFS of advanced HER2-mutant NSCLC patients. However, given that most studies involving ICIs in HER2-mutant NSCLC are retrospective, caution should be exercised when interpreting mPFS results until prospective clinical trial data are available. This study did not include HER2-mutant NSCLC patients who received targeted therapy. However, in recent years, new-generation tyrosine kinase inhibitors and, particularly, antibody-drug conjugates have shown substantial promise for this patient population. In the DESTINY-Lung 02 trial, the ORR for HER2-mutant advanced NSCLC patients treated with 5.4 mg/kg trastuzumab deruxtecan (T-DXd) reached 49.0%. The DCR was as high as 93.1%, and the median duration of response was 16.8 months. At a median follow-up of 11.5 months, the mPFS for 5.4 mg/kg T-DXd was 9.9 months.[5] Preclinical studies have demonstrated that T-DXd can increase PD-L1 expression, boost T-cell activity, and promote the infiltration of CD8+ T cells into tumors. Additionally, it enhances the expression of major histocompatibility complex class I molecules. Therefore, T-DXd in combination with ICIs may be more effective than monotherapy.[6] At the European Society of Medical Oncology Immuno-Oncology Congress, researchers presented interim data from a study evaluating T-DXd in combination with pembrolizumab for HER2-mutant NSCLC patients. In this study, 33 HER2-mutant NSCLC patients received the combination therapy, demonstrating an ORR of 66.7% and an mPFS of 11.3 months. These findings suggest that the T-DXd and pembrolizumab combination exhibits promising antitumor activity in HER2-mutant NSCLC.[7] Compared with the results of our study, the T-DXd–pembrolizumab regimen appears to yield superior efficacy in HER2-mutant NSCLC. The combination of ICIs with targeted therapies could serve as a new first-line treatment option for advanced HER2-mutant NSCLC. This question warrants further investigation. The expression of PD-L1 is a significant biomarker for predicting the efficacy of ICIs in treating NSCLC patients.However, in HER2-mutant NSCLC, the relationship between PD-L1 levels and PFS remains unclear. In this study, three PD-L1-positive patients (PD-L1 TPS ≥1%) received chemotherapy combined with ICIs. Notably, one patient with a PD-L1 TPS of 1% achieved a prolonged PFS of 32.8 months, whereas patients with PD-L1 TPS of 20% and 30% showed shorter PFS (4 months and 10.5 months, respectively). Furthermore, among two PD-L1-negative patients (TPS <1%), PFS was 20.7 months and 6.5 months. These observations suggest that PD-L1 expression levels may not reliably predict the efficacy of ICIs in HER2-mutant NSCLC. However, the limited sample size (only five patients in the ICI + chemo group underwent PD-L1 testing) precludes a robust analysis of PD-L1’s predictive role in this context. Additionally, further exploration is required to evaluate other potential biomarkers, such as human leukocyte antigen typing, tumor-infiltrating lymphocytes, and tumor mutational burden, for predicting ICI efficacy in HER2-mutant NSCLC.[8] Several limitations of our study should be acknowledged. First, its retrospective design and relatively small sample size might introduce the possibility of reporting bias. A comprehensive evaluation of the efficacy and safety of ICIs in HER2-mutant NSCLC patients requires longer follow-up and larger cohorts. Future prospective studies could expand sample sizes through the following strategies. On the one hand, establishing standardized protocols and fostering multicenter collaborations with additional research institutions would enable the collection of comprehensive HER2-mutant case data. On the other hand, given that the current study included cases from only 5 years across centers, extending the patient recruitment timeframe in future investigations may further increase the sample size of HER2-mutant NSCLC patients, thereby improving statistical robustness. In terms of safety, the retrospective design of this study may have led to an underestimation of the incidence of TRAEs, particularly for low-grade events. Incomplete systematic documentation of TRAEs at some participating centers could introduce bias in safety assessments. To address this limitation, we supplemented data through electronic medical record reviews and manual verification of patient laboratory/imaging reports. Nevertheless, future prospective studies should prioritize real-time, detailed documentation of adverse events according to the Common Terminology Criteria for Adverse Events version 5 guidelines during treatment to enhance data accuracy and completeness. Second, all response assessments were made at the discretion of treating physicians at any time point, rather than at predefined intervals as in prospective trials. Third, the study was also limited by some missing patient data. Nevertheless, given the rarity of HER2 mutations and the limited number of multicenter analyses examining the efficacy and safety of first-line chemotherapy with or without ICIs in advanced HER2-mutant NSCLC patients, our study provides valuable real-world insights into treatment outcomes for these patients. In conclusion, our study provided real-world clinical evidence that ICIs in combination with chemotherapy as first-line treatments could enhance outcomes for patients with advanced HER2-mutant NSCLC compared to those who received chemotherapy alone. However, large-scale prospective clinical trials are needed to validate these findings. Funding This work was supported by the Key Research and Development Program of Zhejiang Province (Nos. 2023C03069, 2025C02092, 2025C02094) and Zhejiang Provincial Clinical Research Center for Respiratory Disease (No. 2022E50005). Conflicts of interest None.