Lung cancer stands as a primary contributor to global cancer-related fatalities (1), with nearly 20% of deaths in China attributed to this disease, surpassing the world average of approximately 18.4% (2, 3). Non-small cell lung cancer (NSCLC) represents the predominant subtype (4), and with increased life expectancy, the incidence among elderly patients with NSCLC is steadily climbing (5). For this demographic, selecting between radiotherapy, chemotherapy, or surgery is intricate, considering factors like the cytotoxic effects of chemotherapy drugs, surgical risks, and the presence of underlying health conditions (6). As a result, elderly patients with NSCLC face a dilemma: a general reluctance toward comprehensive treatment, yet an enduring unmet clinical need.

Immunotherapy, a potent approach that boosts the body’s immune system to combat cancer, has become a pivotal force in the battle against the disease (7). NSCLC stands out as one of the cancers highly responsive to immune checkpoint inhibitors (ICIs), proven to significantly alleviate symptoms and prolong the survival of certain advanced patients with NSCLC (8, 9). Additionally, immunotherapy demonstrates enhanced tolerance and fewer side effects, making it a favorable option for elderly patients with compromised physical conditions (3).

Tumor angiogenesis has been identified as a crucial therapeutic target for malignant tumors. By modulating signaling pathways linked to angiogenesis, effective inhibition of tumor growth can be achieved (10, 11). Multiple studies have shown that combining anti-angiogenic drugs with chemotherapy, targeted therapy, and immunotherapy enhances efficacy in patients with NSCLC (12), providing a moderate extension of their survival (13, 14).

Currently, identifying an effective treatment plan for elderly patients with NSCLC is an urgent clinical imperative, and the potential of combining anti-angiogenic drugs with immunotherapy emerges as a novel therapeutic strategy. As a novel recombinant human vascular endothelial inhibitor, Endo, when paired with a PD-1 inhibitor, markedly suppresses tumor growth in NSCLC mice by improving the tumor microenvironment and activating autophagy (15). Furthermore, the combination of anti-PD-1 with anti-angiogenic drugs shows promise in enhancing the survival rates of advanced NSCLC patients (16). Health authorities have greenlit the gradual integration of this combination therapy into clinical practice. Thus, this study systematically reviews the efficacy and safety of combining Endo with immunotherapy (anti-PD-1) (17) in patients with NSCLC aged 80 and above.

Currently, elderly NSCLC patients encounter a dilemma. Platinum-based chemotherapy is frequently employed for advanced NSCLC, but its use often brings about adverse effects such as nausea, vomiting, nephrotoxicity, myelosuppression, and neurotoxicity (19–21). These side effects, coupled with the frail physical condition, low tolerance, and reluctance to undergo treatment, frequently lead elderly patients to discontinue the therapy. Previous studies have affirmed the efficacy and relatively well-controlled safety profile of anti-PD-1 (22) (8, 9) and anti-angiogenic drugs (13–17) in advanced patients with NSCLC. Therefore, this retrospective analysis aims to explore the effectiveness and safety of combining anti-PD-1 with Endo in patients with NSCLC aged 80 and above.

A total of 181 elderly patients with NSCLC aged over 80 were initially enrolled in this study, underscoring the significance and sizable representation of this patient demographic. Unfortunately, during the follow-up period, a considerable number of patients discontinued treatment due to their physical condition and intolerance to the associated toxicities and side effects. This underscores the pressing need in clinical settings for an effective and well-tolerated treatment strategy tailored to meet the unique requirements of this population. Given the known toxic side effects of chemotherapy, alternative non-chemotherapeutic treatment options have been explored. The combination of antiangiogenic drugs with anti-PD-1 represents a novel therapeutic approach widely adopted in clinical practice. This study retrospectively analyzed the efficacy and clinical significance of patients treated with the combination of Endo and anti-PD-1. Ultimately, only 14 cases met the inclusion criteria, with all enrolled patients having an ECOG physical strength status score of 2. Males and squamous carcinomas were prevalent, half of the patients had a history of smoking, and those in stage III and above constituted the majority, comprising 79% of the total patient cohort. The majority of elderly patients with NSCLC presented with intermediate to advanced stages, and half had a history of smoking, possibly linked to less distinctive or more common symptoms (e.g., cough, sputum, hemoptysis). As of the follow-up date on January 25, 2024, survival analysis revealed a mPFS of 102 days and a mOS of 311 days.

Immunotherapy has demonstrated effectiveness in patients with NSCLC (23), with some individuals experiencing sustained responses to immunotherapy-related drugs, leading to the formation of a long-term survivor group (24). To analyze the impact of different durations of maintenance therapy on the survival of elderly patients with NSCLC aged over 80, the enrolled patients were categorized into a long-term group (5 cases) and a short-term group (9 cases) based on their physical condition, treatment readiness, and the duration of subsequent maintenance therapy. The findings revealed that the mPFS and mOS for the long-term group were 441 and 686 days, respectively, while those for the short-term group were 74 and 141 days, respectively. Although the long-term group exhibited longer mPFS and mOS compared to the short-term group, statistical significance was observed only in terms of mOS (P<0.05). This underscores the potential benefits of a more extended treatment course for elderly patients with NSCLC, particularly in terms of overall survival. Given that elderly patients in real-world studies often present with later-stage disease due to delayed detection and that this study included relatively few stage I and II patients, we conducted a subgroup analysis of stage III and IV patients. The analysis revealed that both the mPFS and mOS were longer in the long-cycle group compared to the short-cycle group, with a significant difference in mPFS (441 days for the long-cycle group versus 60 days for the short-cycle group). We hypothesize that may be attributed to the ongoing survival of some patients in the combination maintenance group as of the follow-up period, and the overall survival data for these patients may not have matured sufficiently. This study will continue to be monitored, and updates will be provided subsequently.

Furthermore, owing to varying treatment requirements (25, 26) and the emergence of intolerable side effects in some patients, certain participants in the study opted for a single drug (Endo or anti-PD-1) during follow-up maintenance therapy, while others chose to continue the combination therapy. Simultaneously, three enrolled patients did not undergo subsequent maintenance therapy, and two of them only received one subsequent maintenance therapy. These five patients were excluded, and the remaining participants were divided into the monotherapy maintenance group (3 cases) and the combination maintenance group (6 cases) to further investigate whether the efficacy of the combination of anti-angiogenic drugs and anti-PD-1 surpassed that of single-agent maintenance. The survival analyses of the two groups revealed that the mPFS of the monotherapy maintenance group was 204 days, which was shorter than the mPFS of the combination maintenance group (441 days). Conversely, the mOS of the monotherapy maintenance group was 686 days, exceeding the mOS of the combination maintenance group (311 days). Although the monotherapy maintenance group and the combination maintenance group demonstrated contrasting results in terms of mPFS and mOS, none of these findings reached statistical significance (P>0.05). In the subsequent survival analysis of maintenance therapy for stage III and IV NSCLC patients, a similar pattern emerged: the mPFS was 204 days in the monotherapy maintenance group compared to 74 days in the combination maintenance group. Similarly, the mOS was 686 days in the monotherapy group and 594 days in the combination group. However, the P-values indicated no statistically significant differences between the groups.

Considering the unique characteristics of the elderly NSCLC patient population, we conducted an analysis of the clinicopathological data for 14 enrolled patients. The overall safety profile of Endo combined with anti-PD-1 was found to be favorable. A total of 77 adverse events were documented, with 73 (94.8%) classified as grade 1–2 adverse events and 4 (5.2%) as grade 3–4 adverse events. Notably, there were no grade 5 adverse events. Among these events, anemia (16.9%) emerged as the most common. These findings align with existing studies (27, 28), indicating the absence of new treatment-related adverse events and affirming the overall manageability of the treatment’s safety.

This study, being a single-center retrospective analysis, addresses a substantial demand for treatment among the elderly NSCLC patient population. However, there remains a scarcity of prospective studies considering both patient willingness to undergo treatment and the impact of therapeutic drugs. Additionally, the overall sample size became modest after applying the inclusion criteria, and in subsequent subgroup analyses, while some statistically significant results were obtained, the small sample size and the incomplete maturity of the data at present may pose certain limitations that warrant further exploration. We plan to incrementally update the data in subsequent follow-ups. The primary objective of this study is to investigate whether the combination of Endo and anti-PD-1 represents a novel treatment strategy for elderly patients with NSCLC aged over 80. The current findings suggest advantages of this regimen for the treatment of elderly patients with NSCLC. To further evaluate the clinical value of this treatment approach, we intend to pursue multicenter, prospective studies in the future.

The combination of Endo and anti-PD-1 could be an effective treatment choice for patients with NSCLC aged 80 and above.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Chaohu Hospital Affiliated with Anhui Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

TX: Writing – original draft. QG: Writing – original draft. HZ: Writing – review & editing. JG: Writing – review & editing. GY: Writing – review & editing.