First-line immunotherapy in advanced non-squamous non-small cell lung cancer patients with rare mutations: a retrospective cohort study

Introduction

Lung cancer is the most common malignancy and the leading cause of cancer-related death worldwide (1). There are approximately 2.2 million new cases of lung cancer and 1.79 million lung cancer-related deaths annually (1). Non-small cell lung cancer (NSCLC) accounts for 80–85% of these cases, and the majority of NSCLC patients are diagnosed at an advanced stage (2). With the development of immune checkpoint inhibitors (ICIs), treatment comprised of these drugs either alone or in combination with chemotherapy has emerged as a highly effective treatment strategy for mutation-negative advanced NSCLC patients, becoming the gold standard first-line treatment (3-5).

The emergence of targeted therapies acting on mutated driver genes has substantially changed the treatment landscape of NSCLC (6,7). Previous clinical trials have shown that targeted therapies significantly improve the clinical outcomes of NSCLC patients harboring driver-gene mutations, particularly the epidermal growth factor receptor (EGFR), activin receptor-like kinase (ALK), and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) mutations (8,9). However, recent studies have shown that ICIs may not work as well in these patients (8-10).

Beyond the well-known driver-gene mutations in EGFR, ALK, ROS1 and Kirsten rat sarcoma viral oncogene homolog (KRAS), about 8–17.1% of NSCLC patients have rare mutations, which mainly include the human epidermal growth factor receptor 2 (HER2), V-Raf murine sarcoma viral oncogene homolog B (BRAF), mesenchymal epithelial transition (MET), rearranged during transfection (RET), and neurotrophic tyrosine receptor kinase (NTRK) genes (11,12). The distribution of mutation subtypes in NSCLC varies across ethnicities. For example, the incidence of HER2 mutations in Asian patients with NSCLC ranges from 1.4% to 6.7% (2.4–5.94% in Chinese cohorts), compared to 1% to 3% in Western populations (13). NSCLC with rare mutations exhibits poorer survival, higher metastatic potential, and aggressive histology compared to common mutation subtypes (14). Despite approved targeted therapies for NSCLC with rare mutations, treatment efficacy remains limited by acquired resistance and disease progression (11,12). Notably, emerging evidence suggests that the efficacy of ICIs monotherapy in the second-line or subsequent treatment of patients with rare mutations is comparable to that observed in first-line therapies, which suggests that immunotherapy could overcome the poor prognosis associated with these uncommon subtypes (15-17). Moreover, while the majority of immunotherapy research in the rare-mutation population has focused on KRAS-mutant NSCLC, clinical data evaluating first-line ICIs efficacy in patients with other rare mutations is lacking (18,19).

This retrospective study was performed to assess the therapeutic efficacy of first-line ICIs in the treatment of advanced NSCLC patients harboring the HER2, BRAF, MET, RET, and NTRK rare mutations. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-716/rc).

Methods

Study design

A retrospective analysis was performed of all patients with lung cancer treated at the Department of Thoracic Medicine, Peking University Cancer Hospital from January 2016 to April 2024. A total of 2,107 adult patients with pathologically confirmed advanced non-squamous NSCLC underwent genetic testing. Patients with EGFR, ALK, ROS1 and KRAS mutations were excluded from the analysis. Patients diagnosed with HER2, BRAF, MET, RET, and NTRK rare mutations or those with mutation-negative status were enrolled in this study. The screening flowchart for the study is shown in Figure 1. Patients with rare mutations (HER2, BRAF, MET, RET, and NTRK) were divided into the immunotherapy and targeted therapy groups based on their first-line treatment regimen. Additionally, mutation-negative patients receiving first-line immunotherapy were included as the control group. Patient medical records were reviewed to extract data on the following characteristics: age, gender, smoking status, mutation status, programmed death-ligand 1 (PD-L1) status, Eastern Cooperative Oncology Group performance status (ECOG-PS), histology, and immunotherapy or targeted therapy.

Figure 1 Patient selection flowchart. ALK, activin receptor-like kinase; BRAF, V-Raf murine sarcoma viral oncogene homolog; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; KRAS, Kirsten rat sarcoma viral oncogene homolog; MET, mesenchymal epithelial transition; NSCLC, non-small cell lung cancer; NTRK, neurotrophic tyrosine receptor kinase; RET, rearranged during transfection; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase.

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The patients were informed about the objective of the study and provided informed consent. This study was approved by the Ethics Committee of Peking University Cancer Hospital (ethics approval number: 2023YJZ82).

Deoxyribonucleic acid (DNA) extraction and DNA panel sequencing

Tumor DNA was extracted from formalin-fixed paraffin-embedded (FFPE) lung cancer specimens using a Direct FFPE DNA Kit (Qiagen #A31133) in accordance with the manufacturer’s instructions.

PD-L1 expression

Advanced NSCLC FFPE specimens were subjected to PD-L1 immunohistochemistry. The 3-mm-thick, hematoxylin and eosin-stained segments that included tumor cells were examined. To measure PD-L1 expression, a specimen had to include at least 100 viable tumor cells. PD-L1 22C3 pharmDx (Dako) was used to detect PD-L1 expression. Tumor cells showing membranous staining for PD-L1 were considered positive. These routine pre-treatment tests were performed in the hospital laboratory.

Efficacy evaluation

In this study, efficacy was evaluated after every two cycles of treatment and was categorized as a complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors version 1.1. The objective response rate (ORR) was defined as the sum of the proportion of the CR plus PR patients. The disease control rate (DCR) was defined as the sum of the proportion of the CR, PR, and SD patients. Progression-free survival (PFS) was calculated as the time from the patient’s first-line therapy to tumor progression. Overall survival (OS) was defined as the time from the date the patient received the first-line therapy to death from any cause. The data of the last follow-up visit of the patients who did not progress, who did not die, or who were not lost to follow-up were recorded. The data cut-off for evaluation was June 24, 2024.

Statistical analysis

PFS and OS were analyzed using the Kaplan-Meier test and compared using the log-rank test. For baseline comparability, clinical characteristics were compared between different cohorts using appropriate statistical tests. Fisher’s exact test was used for categorical variables, and continuous variables were compared using the t-test or Mann-Whitney U test, depending on the distribution. All statistical analyses were conducted using SPSS (version 27.0) or R (version 4.1.1). Statistical significance was defined as a two-sided P value <0.05.

Results

Characteristics of patients with rare mutations

A total of 66 patients with rare mutations who received first-line immunotherapy or targeted therapy at Peking University Cancer Hospital from January 2016 to April 2024 were included in this study. One hundred and forty-two consecutive gene mutation-negative patients in the same cohort who received first-line immunotherapy were also included in this study as a control group. Among the 66 patients with rare mutations, the most common mutations were HER2 (n=30, 45.45%), followed by BRAF (n=14, 21.21%), MET (n=13, 19.70%), RET fusion (n=8, 12.12%), and NTRK rearrangement (n=1, 1.52%). In the immunotherapy group (n=39), HER2 was the most common mutation (n=24, 61.64%), followed by BRAF (n=8, 20.52%), RET (n=4, 10.26%), MET (n=2, 5.13%), and NTRK (n=1, 2.56%). In the targeted therapy group (n=27), the most common mutation was MET (n=11, 40.74%), followed by HER2 (n=6, 22.22%), BRAF (n=6, 22.22%), and RET (n=4, 14.82%) (Figure S1A-S1C).

Patients with or without rare mutations who received first-line immunotherapy

Among the patients with rare mutations (n=39) or negative mutation (n=142) who received first-line immunotherapy, there were no significant differences in terms of age, sex, staging, and smoking history (Table 1). Regarding high PD-L1 expression (≥50%), the patients in the rare-mutation cohort had significantly higher expression levels than those in the mutation-negative cohort (15.38% vs. 9.15%, P=0.042). Additionally, the most common first-line immunotherapy in both cohorts was ICI plus chemotherapy (97.44% vs. 92.96%). Twenty-one (53.85%) and 69 (47.18%) patients received second-line therapy in both cohorts. Notably, the majority of patients chose targeted therapy (n=9, 23.08%) as the second-line therapy in the rare-mutation cohort.

Among patients who received first-line immunotherapy, there was no significant difference in efficacy between the rare-mutation cohort and mutation-negative cohort in terms of the ORR (35.90% vs. 44.37%, P=0.34) and DCR (94.87% vs. 90.85%, P=0.42). No significant differences were observed in the median PFS (14.53 vs. 12.43 months, P=0.93) and median OS (34.40 vs. 32.37 months, P=0.51) between the patients in these two cohorts (Table S1 and Figure 2) (efficacy across molecular subgroups appears in Table S2).

Figure 2 PFS (A) and OS (B) in the rare-mutation cohort and the mutation-negative cohort who received first-line immunotherapy. CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

First-line immunotherapy or targeted therapy in patients with rare mutations

To evaluate the long-term efficacy of first-line immunotherapy in patients with rare mutations, 27 patients with rare mutations who received first-line targeted therapy were also included in the study as a control group. The baseline clinical characteristics between the two groups were well-matched, with no significant differences in age, gender, staging, and smoking history between the first-line immunotherapy and targeted therapy groups (Table 2).

We compared the efficacy of first-line immunotherapy and targeted therapy in the patients with rare mutations. The immunotherapy cohort had a significantly higher DCR (94.87% vs. 70.37%, P=0.006) and a longer median OS (34.40 vs. 16.37 months, P=0.008). Additionally, there was a favorable trend in the ORR (35.90% vs. 29.63%, P=0.46) and median PFS (14.53 vs. 7.03 months, P=0.10) (Table S3 and Figure 3).

Figure 3 PFS (A) and OS (B) of patients with rare mutations who received first-line immunotherapy or targeted therapy. CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

Discussion

This study evaluated the efficacy of first-line immunotherapy in non-squamous NSCLC patients with rare mutations. The results revealed that among the patients who received first-line immunotherapy, those with rare mutations had comparable PFS and OS to those without mutations. Additionally, patients with rare mutations who received first-line immunotherapy had longer median OS than those who received first-line targeted therapy. Despite the study’s small sample size, the findings suggest that first-line immunotherapy may be effective in patients with rare mutations.

The efficacy of immunotherapy in rare mutations remains unclear, especially in first-line treatment and combined chemotherapy with immunotherapy, with most research focusing on single-agent therapies (20,21). A retrospective study of 91 patients with HER2 mutations found that the efficacy and prognosis of first-line immunotherapy combined with chemotherapy were similar between HER2-mutant patients [median PFS: 6.0 months, confidence interval (CI): 3.9–7.8] and mutation-negative patients (median PFS: 5.2 months, 95% CI: 4.4–6.5) (22). Other mutation types in NSCLC also show similar survival benefits. A study has shown that BRAF-mutant patients had better prognoses than mutation-negative patients, whether treated with first-line ICI therapy alone (7.6 vs. 4.6 months) or ICI combination therapy (17.5 vs. 5.2 months) (22). Similarly, two independent studies reported comparable survival outcomes between MET-mutant and MET-wild-type NSCLC patients who received first-line immunotherapy (22,23). However, Dudnik et al. found limited benefit of immunotherapy in BRAF V600-mutant NSCLC patients (n=29), with an ORR of 25% and a median PFS of 3.7 months (95% CI: 1.6–6.6) (24). Our study showed that immunotherapy has potential clinical benefits in NSCLC patients harboring rare mutations, even in BRAF mutant NSCLC patients (ORR: 50%, median PFS: 21.37 months). In our study, the first-line immunotherapy-chemotherapy combination regimen administered to >95% of patients reflects real-world clinical practice patterns.

Currently, there is ongoing debate about which is the best first-line treatment option for patients with rare mutations between immunotherapy and targeted therapy. Several targeted therapies have received regulatory approval for the treatment of NSCLC patients with rare mutations, including dabrafenib plus trametinib for patients with BRAF V600E mutations, and trastuzumab deruxtecan for patients with HER2 alterations (25-28). Some studies have found that first-line immunotherapy provides similar benefits compared to targeted therapy, especially in patients with HER-2 and BRAF mutations (16,29). A study involving 26 HER2-mutant NSCLC patients found that those treated with first-line immunotherapy had better outcomes than those who received immunotherapy after targeted therapy (ORR: 60% vs. 33.3%, P=0.545; median PFS: 8.4 vs. 5.5 months, P=0.469) (15). Wiesweg et al. found that OS was comparable between patients with BRAF V600E mutation receiving first-line dabrafenib plus trametinib and those treated with chemoimmunotherapy (median OS: 28.0 vs. 27.8 months, P=0.68) (29). However, different results have been observed in RET fusion-positive NSCLC. The phase III LIBRETTO-431 trial showed superior efficacy of first-line selpercatinib (median PFS: 24.8 vs. 11.2 months for ICI-chemotherapy; P<0.001) (30). Our study showed that patients with rare mutations have longer OS when receiving immunotherapy as first-line treatment compared to targeted therapy (34.40 vs. 16.37 months, P=0.008). However, due to the small sample size, subgroup analysis could not be performed for each mutation type. As a result, prospective studies with large sample sizes and detailed molecular analyses need to be conducted to better understand and improve the therapeutic efficacy of immunotherapy for these patients.

Our study shows that patients with rare mutations can benefit from immunotherapy, but further research is warranted to explore the detailed mechanisms and related immune markers. High PD-L1 levels are strongly associated with improved outcomes following treatment with ICIs (31-33), and PD-L1 remains the primary marker for predicting efficacy in NSCLC patients receiving immunotherapy (34-36). In our study, the patients in the rare-mutation cohort had significantly higher PD-L1 expression levels (≥50%) compared to those in the mutation-negative cohort (15.38% vs. 9.15%, P=0.042), which may partly explain the long survival of immunotherapy in patients with rare mutations. Further research is needed on the molecular interactions and the tumor immune microenvironment of these gene mutations.

This study had several limitations. First, its single-center retrospective design might have selection bias and might limit its generalizability. Second, while our rare-mutation cohort size (n=66) exceeded the majority of previous rare-mutation studies (typically <50 cases), it was insufficient for robust subgroup analyses. Future multicenter prospective studies with adequate sample sizes need to be conducted to validate these findings.

Conclusions

The efficacy of first-line immunotherapy in advanced non-squamous NSCLC patients is not affected by the presence of rare mutations. The patients with rare mutations who received first-line immunotherapy had better survival than those who received first-line targeted therapy.

Acknowledgments

We would like to thank the patients and their families for participating in the study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-716/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-716/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-716/prf

Funding: This work was supported by Clinical Research Fund for Distinguished Young Scholars of Peking University Cancer Hospital (No. QNJJ2022024 to Y.W.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-716/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The patients were informed about the objective of the study and provided informed consent. This study was approved by the Ethics Committee of Peking University Cancer Hospital (ethics approval number: 2023YJZ82).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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