Early mortality factors in immune checkpoint inhibitor monotherapy for advanced or metastatic non-small cell lung cancer

Purpose Immune checkpoint inhibitors (ICI) are a promising treatment, but may cause hyperprogressive disease and early death. The present study investigated early mortality factors in ICI monotherapy for lung cancer. Patients and methods We retrospectively reviewed all patients diagnosed with advanced or metastatic non-small cell lung cancer (NSCLC) and treated with ICI monotherapy (nivolumab, pembrolizumab, and atezolizumab) between March 2016 and August 2021 at National Hospital Organization Kochi Hospital and Tokushima University. Early death was defined as patients who died within 60 days of ICI treatment. Results A total of 166 patients were included. The majority of patients (87%) had an Eastern cooperative oncology group (ECOG) Performance status (PS) of 0/1. There were 21 early deaths. Significant differences were observed in ECOG PS, the histological type, liver metastasis, tumor size, the white blood cell count, neutrophils (%), lymphocytes (%), the neutrophil-to-lymphocyte ratio in serum (sNLR), C-reactive protein (CRP), and albumin between the groups with or without early death. Univariate logistic regression analyses identified ECOG PS score ≥ 2, liver metastasis, tumor size ≥ 5 cm, neutrophils ≥ 69%, lymphocytes < 22%, sNLR ≥ 4, CRP ≥ 1 mg/dl, and albumin < 3.58 g/dl as significant risk factors for early death. A multivariate logistic regression analysis revealed that liver metastasis (Odds ratio [OR], 10.3; p = 0.008), ECOG PS score ≥ 2 (OR, 8.0; p = 0.007), and a smoking history (OR, 0.1; p = 0.03) were significant risk factors for early death. Conclusion Liver metastases, ECOG PS score ≥ 2, and a non-smoking history are early mortality factors in ICI monotherapy for advanced or metastatic NSCLC.


Introduction
Immune checkpoint inhibitors (ICI) have caused a paradigm shift in the treatment of various cancer types. ICI monotherapy has been used as a first-line treatment for advanced or metastatic untreated non-small cell lung cancer (NSCLC) (Reck et al. 2016;Mok et al. 2019). Among patients with advanced, previously treated NSCLC, overall survival (OS) was shown to be significantly better with ICI monotherapy than with chemotherapy (Borghaei et al. 2015;Brahmer et al. 2015;Herbst et al. 2016;Rittmeyer et al. 2017). On the other hand, ICI have been implicated in the development of hyperprogressive disease (HPD) and early death (Champiat et al. 2017;Abbar et al. 2021;Ferrara et al. 2018). Although the risk factors for and mechanisms underlying HPD have been examined (Lo Russo et al. 2019;Kim et al. 2020Kim et al. , 2021Castello et al. 2020;Passaro et al. 2021;Chen et al. 2021;Ku et al. 2021;Kamada et al. 2019), current knowledge is still insufficient. The selection of suitable patients for ICI monotherapy is essential. OS is the most robust indicator of cancer treatment outcomes. On the other hand, few studies have examined early mortality factors in ICI monotherapy for advanced or metastatic lung cancer in real-world settings. To the best of our knowledge, only one study investigated early death in real-world settings (Inoue et al. 2018). Therefore, the present study attempted to identify early mortality factors in ICI monotherapy for advanced or metastatic NSCLC.

Patients
We retrospectively reviewed all patients diagnosed with advanced or metastatic NSCLC and treated with ICI monotherapy (nivolumab, pembrolizumab, and atezolizumab) between March 2016 and August 2021 at National Hospital Organization Kochi Hospital and Tokushima University. Early death was defined as patients who died within 60 days of ICI treatment.

Data collection
We collected data on age, sex, smoking history, the Eastern cooperative oncology group performance scale (ECOG PS), white blood cell count, neutrophil count, lymphocyte count, eosinophil count, C-reactive protein (CRP), albumin, histological type, the genotypes of mutations, type of ICI, line of ICI, date of ICI initiation, number of ICI administered, and the status of death. We also examined data obtained on the primary lesion size (maximum diameter measured on chest computed tomography), the number of metastatic sites (count of involved solid organs, not all sites), the status of specific metastasis (non-regional lymph nodes, contralateral lung, pleura, brain, liver, kidney, adrenal gland, and bone), and stage (according to the eighth edition of the tumor-nodemetastasis [TNM] staging system). A computed tomography scan was performed for a radiological evaluation before ICI therapy.

Statistical analysis
Categorical and continuous variables were summarized using descriptive statistics. The independent samples t test was used to test for differences between continuous variables. Pearson's chi-squared test and Fisher's exact test were employed to analyze relationships between categorical variables. Univariate and multivariate logistic regression analyses were performed to identify predictive factors associated with early death with ICI. The neutrophil-tolymphocyte ratio in serum (sNLR) was calculated as the ratio of the neutrophil count to the lymphocyte count. The cut-off value for sNLR was set at 4 based on previous studies (Kim et al. 2019b;Sacdalan et al. 2018). We conducted all statistical analyses using SPSS statistics version 27.0 (IBM, Armonk, USA). P values are presented without adjustments for multiple comparisons in an exploratory manner.

Multivariate analysis of factors associated with early death
A multivariate logistic regression analysis for the prediction of early death was performed using the following variables: a smoking history, ECOG PS, the histological type, liver metastasis, tumor size, neutrophils, lymphocytes, sNLR, CRP, and albumin (Table 3). A multivariate analysis with a multivariate logistic regression model showed that liver

The number of early mortality factors and percentage of early deaths
Liver metastases, ECOG PS score ≥ 2, and a non-smoking history were early mortality factors in ICI monotherapy against advanced or metastatic NSCLC. The number of early mortality factors and percentage of early deaths are shown in Fig. 1. One patient had all three early mortality factors, and the early mortality rate was 100%. Eight out of 11 patients (73%) with two early mortality factors and 7 out of 48 patients (15%) with one early mortality factor died within 60 days. Furthermore, 5 out of 106 patients (4.7%) with no early mortality factors died early.

Discussion
The present results identified liver metastases, ECOG PS score ≥ 2, and a non-smoking history as early mortality factors in ICI monotherapy for advanced or metastatic NSCLC. Few studies have examined early mortality factors in ICI monotherapy for advanced or metastatic lung cancer in realworld settings. To the best of our knowledge, only one study investigated early mortality in real-world settings (Inoue et al. 2018). ICI has caused a paradigm shift in the treatment of various cancer types, but have also been implicated in the development of HPD and early patient death (Champiat et al. 2017;Abbar et al. 2021;Ferrara et al. 2018). Although the risk factors for and mechanisms underlying HPD have been examined (Lo Russo et al. 2019;Kim et al. 2020Kim et al. , 2021Castello et al. 2020;Passaro et al. 2021;Chen et al. 2021;Ku et al. 2021;Kamada et al. 2019), current knowledge is still inadequate. Although PD-L1 and the tumor mutation burden (TMB) have been used as predictive biomarkers for ICI therapy, there are currently no established predictive biomarkers (Brody et al. 2017;Zou et al. 2021). The selection of suitable patients for ICI monotherapy is essential in real-world settings, and OS is the most robust indicator of cancer treatment outcomes. Therefore, we examined early mortality factors in ICI monotherapy for advanced or metastatic NSCLC in real-world settings.
In a system review, liver metastasis, previous metastatic sites > 2, a Royal Marsden Hospital score ≥ 2, higher ECOG PS, and a lactate dehydrogenase (LDH) level greater than the normal upper limit were associated with the development of HPD ). In another system review, liver metastasis, LDH, more than two metastatic sites, and a Royal Marsden Hospital score of 2 or higher correlated with Fig. 1 The number of early mortality factors and percentage of early deaths HPD (Kim et al. 2019a). A previous study also implicated hepatic metastases, more than two metastatic sites, ECOG PS ≥ 2, and an LDH level higher than the normal upper limit in the development of HPD . Furthermore, liver metastasis was the only variable associated with HPD in a multivariate analysis (Abbar et al. 2021). The presence of tumors within the liver was previously shown to significantly reduce systemic tumor-specific immunity, and immunosuppression was dependent on regulatory T cells (Tregs) ). The number of circulating Tregs was significantly higher than the baseline in patients with HPD (Kang et al. 2022). The balanced expression of PD-1 between CD8 + T cells and Tregs is essential in programmed cell death 1 (PD-1) inhibitory immunotherapy (Aksoylar and Boussiotis 2020;Kumagai et al. 2020). In a mouse model of liver metastasis due to colorectal cancer, Treg numbers were elevated, and the hepatocyte growth factor/hepatocyte growth factor receptor signaling pathway was up-regulated (Huang et al. 2020). Lactic acid has been shown to promote the expression of PD-1 in Tregs in highly glycolytic tumors, such as liver metastases (Kumagai et al. 2022).
In the present study, a non-smoking history was a significant early mortality factor. OR was 0.1 (P = 0.03) when six patients with a missing smoking history were assumed to have a smoking history and 0.2 (P = 0.03) when they were hypothesized to have a non-smoking history, indicating that non-smoking history is a risk factor regardless of the presence or absence of missing data. The reason for this result is not apparent. In adenocarcinoma, a non-smoking status was predictive of a low TMB (Sharpnack et al. 2020). The probability of EGFR mutations and ALK rearrangements was previously shown to be significantly higher in patients with a non-smoking history than in those with a smoking history (Chapman et al. 2016). Furthermore, TMB was lower in EGFR-mutant lung cancer than in EGFR wild-type lung cancer (Offin et al. 2019). EGFR mutations and ALK rearrangements are generally associated with low response rates to ICI therapy in NSCLC (Gainor et al. 2016;Lee et al. 2017). Therefore, ICI may be less effective in patients with a non-smoking history. However, in the present study, only 2 out of 21 patients who died early had EGFR mutations and no ALK rearrangement. No significant differences were observed in genetic abnormalities between the groups with and without early death (Table 1). Specific molecular alterations (MDM2/MDM4, KRAS, and serine/threonine kinase 11) have been associated with HPD (Kato et al. 2017;Kim et al. 2019b). Therefore, these genetic abnormalities in patients with a non-smoking history may be related; however, only a few have been examined to date.
The limitation of the present study is that it was a twocenter retrospective analysis conducted with heterogeneous data from patient cohorts. Therefore, the results obtained are speculative and not definitive. Furthermore, since the number of cases was small, OR was significant, but CI was also large; therefore, reliability was not high. The frequency of early death within 60 days of ICI monotherapy for advanced or metastatic NSCLC was not high. Therefore, multicenter studies are needed. Although we need to consider these limitations when interpreting the present results, this study is of value because early mortality factors in ICI monotherapy against advanced or metastatic NSCLC were identified in real-world settings. Simple clinical parameters may easily predict early mortality with single-agent ICI against advanced or metastatic NSCLC and are clinically useful. Early mortality rates were 73 and 100% in patients with 2 and 3 early mortality factors, respectively. ICI-based combination therapy may be a better treatment option for patients with multiple mortality factors than ICI monotherapy for advanced or metastatic NSCLC.

Conclusion
Liver metastases, ECOG PS score ≥ 2, and a non-smoking history were identified as early mortality factors in ICI monotherapy against advanced or metastatic NSCLC. otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.