Development and validation of a nomogram for evaluating the prognosis of immunotherapy plus antiangiogenic therapy in non-small cell lung cancer

Lung cancer is one of the most common diagnosed cancers and main causes of cancer -related death worldwide, representing approximately one in 10 (11.4%) cancers diagnosed and one in 5 (18.0%) deaths. The survival of patients with lung cancer at 5 years after diagnosis is only 10–20% in most countries during 2010 through 2014. Approximately, 80–85% patients of histological types diagnosed as non-small cell lung cancer (NSCLC) [1].

Compared with classical platinum-based chemotherapy or docetaxel, immune checkpoint inhibitors (ICIs), such as programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1), for treatment of NSCLC demonstrated superior survival [2]. Up to now, Atezolizumab, Nivolumab and Pembrolizumab have been approved by FDA to treat NSCLC. Clinical trials have found that ICI therapy is effective for first-line and second-line treatments of advanced NSCLC, consolidated treatment of locally advanced NSCLC, and neoadjuvant treatment of early NSCLC [3]. Despite the promising efficacy of immunotherapy in NSCLC, the success of ICIs is currently limited to a small number of patients, with the overall response rate for each of these drugs is roughly 15–20% [1]. More efficient strategies are needed.

Since 1971, Judah Folkman proposed that blocking angiogenesis (e.g. antiangiogenesis) would be an effective anticancer therapy, bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor (VEGF), has been approved of antiangiogenic therapy in NSCLC [4]. In trials of patients with recurrent or metastatic NSCLC, bevacizumab with standard pemetrexed/paclitaxel doublet therapy improved both progression-free survival (PFS) and overall survival (OS) compared chemotherapy only [5]. It shows that the combination of anti-angiogenesis therapy and ICI is very promising.

Recent years, adding bevacizumab to immunotherapy has become a common combined immunotherapy strategies in NSCLC treatment [6]. And some studies have shown that antiangiogenic therapy can improve the efficacy of PD-1/PD-L1 antibodies in cancer patients [7]. However, the benefit of the combination strategies in NSCLC treatment is not clear. We aimed to use common hematological indicators to develop a nomogram to quantify risk of progression and predict 5-year survival rate for patients.

In the present study, we described the clinical characteristics, risk factors and constructed a model of the outcome of NSCLC patients treated with anti-PD-1/PD-L1 plus bevacizumab to provide a theoretical basis for better prognosis. In our study, several factors showed significant correlation with OS, which include neutrophils, lymphocytes, pleural metastasis, B cell and Treg cell. These predictive factors used in nomogram can be easily acquired from clinical information and laboratory information system, making it feasible for application in clinical practice.

As adding bevacizumab to immunotherapy has become a common combined immunotherapy strategies in NSCLC treatment, an accurate and simple tool to predict prognosis is an urgent need. In this study, we established and validated a nomogram for NSCLC patients treated with anti-PD-1/PD-L1 plus bevacizumab to rapidly predict the long-term prognosis by combining simple clinicopathological factors and hematological indicators. Due to the poor long-term survival of NSCLC patients, an accurate and economical prediction of prognosis in patients after diagnosis is of increasing clinical significance. We anticipate that this practical predictive tool can potentially guide individualized therapy, as doctors can predict the prognosis of patients and the early intervention can be given presciently.

TME is a complex system which contains tumor cells, immune cells [T-cells, B-cells, dendritic cells, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs)], carcinoma-associated fibroblasts (CAFs), vascular system and extracellular matrix components [8]. In contrast to traditional chemotherapy, the immunotherapy mainly take effect through the immune cells within or outside the TME to specially recognize and attack the tumor cells, which theoretically makes the immunotherapy higher specificity and lower side effect [9]. Anti-PD-1/PD-L1 could interrupt multiple signal pathways which relate to the function of T cells and enhance anti-tumor immunity [10]. Anti-VEGF, antibody act on an angiogenesis stimulator, enhance tumor immunity by accelerating the maturation of dendritic cells, and inhibit immunosuppressive cells such as regulatory T cells [11]. Current combination therapies with ICI and anti-VEGF showed favorable changes in the TME.

Traditionally, neutrophils, despite widespread in the TME, are seemed to be an indicator of innate immune response [12]. In our study, high neutrophils represent high risk in the prognosis of NSCLC patients. Contrary to previous view, neutrophils may play an important role in tumor progression. Lin et al. demonstrated that tumor-infiltrating neutrophils promote tumor growth in Pancreatic ductal adenocarcinoma. Especially, they took high intratumor neutrophils and high IL-8 levels for poor outcomes of immune checkpoint inhibitors therapy and worse survival in patients with advanced cancers [13]. In other study, Farnaz et al. explained the role of neutrophils as a pro-metastatic agent in breast cancer and considered the increasing neutrophils in tumors as a failed immune response to cancer [14]. In another large 16-year cohort, high neutrophil-to-lymphocyte ratio was closed to increased risk of lung cancer mortality in low-risk individuals [15].

Lymphocyte is always closed related to immune system. High lymphocyte is to be a positive prognostic factors of a NSCLC patients in our research. Likewise, Kobayashi et al. reported that low lymphocyte was a more valuable predictor of poor prognosis in node-negative NSCLC [16]. And the results of Huang' study suggested that a high absolute peripheral lymphocyte count is an independent protective factor, and it had a high clinical benefit for patients with lung cancer [17].

As a member of CD4 + T cells, Tregs express special markers including CD25 and regulate suppressive signals. Indeed, Tregs are on behalf of a risk sign to cancer patient. Several studies revealed the regulatory function of Tregs in tumor behavior in the TME [18, 19]. While suppressing the over-reactive immune response in autoimmune disease, Tregs in TME prevent the effective response of cytotoxic T lymphocytes (CTLs) on tumor cells. Xu et al. considered the function of Tregs is closely associated with the prognosis of patients [9].

CD19 is the most specific and common marker of B cells. B cell is a protective factor in NSCLC patients in our study. It is generally accepted that B cell produces antibody and cytokines to regulate immune responses and inflammation as well as inducing T cell activation and proliferation via antigen presentation [20]. A study which conducted a single-cell RNA-seq analysis demonstrated that the naïve-like B cells suppress the growth of lung cancer cells in NSCLC patients [21]. Another recent study has revealed B cells are related with favorable prognosis of NSCLC [22].

Pleural invasion is always seemed to be an independent risk factor and an important prognostic factor of NSCLC [23]. In the 8th edition of the TNM classification for NSCLC, if a tumor shows ipsilateral pleural dissemination, it increases the T descriptor from T1 to T2 and upstages a tumor from stage IA to stage IB, no matter how small the size is [24]. Studies from different groups showed that NSCLCs with pleural transfusion is more likely to be poor differentiated, more invasive and have larger tumor size [25‐27]. These results accord closely with our analysis.

This study had several limitations. Firstly, the volume of NSCLC patients is large in our hospital but the number of patients using bevacizumab is limited so that the subjects included is limited. Secondly, it was a retrospective study. This may have influenced the power of the analysis to build model. Further prospective studies are needed.

In conclusion, to our knowledge, this is the first study in China to set a model to predict the prognosis of NSCLC patients treated with anti-PD-1/PD-L1 plus bevacizumab, which provides a useful basis for the treatment of NSCLC patients. Compared with the commonly used TNM stage, we established a particular model for certain people. Compared to conventional testing techniques, such as immunohistochemistry, which is expensive and time-consuming, we selected clinicopathological factors and hematological indicators. Physicians could rapidly predict the prognosis of patients and propose prognosis-based therapeutic protocol for NLCSC patients. Additional studies would be required to explore whether the nomogram can also be applied to predict the effective of treatment.

In summary, our study pay attention to NSCLC patients treated with PD-1/PD-L1 antibody plus antiangiogenic drugs and build a new nomogram to predict long-time OS of these patients. The nomogram may help clinicians to accurately estimate long-time OS of NSCLC patients treated with PD-1/PD-L1 antibody and antiangiogenic drugs in the early stage of treatment.