The role of immunotherapy in the treatment of NSCLC has been increasingly emphasized, and its application in clinical practice largely changes the treatment and prognosis of NSCLC patients.[4–6, 8] In this study, a total of 95 stage III/IV NSCLC patients treated with ICIs therapy was retrospectively analyzed. We found that both pretreatment ALC and post-treatment SIRI were useful predictors of outcomes in NSCLC patients receiving ICIs. Then we established a novel risk stratification based on these prognostic factors. To our knowledge, this is the first study to combine pretreatment ALC with post-treatment SIRI for predicting outcomes in patients treated with ICIs. Furthermore, our results showed that post-treatment NLR was a risk factor for the occurrence of IRP.
Currently, a growing body of studies illustrated that the clinical value of peripheral blood biomarkers which could be helpful for predicting treatment outcomes in different solid tumors, including NSCLC.[16–20] Lymphocyte is one of peripheral blood biomarkers which is a vital indicator of the immune system, reflecting the immune system activation, and play a fundamentally important role in tumor proliferation and migration.[23–26] Previous studies have reported that the lymphopenia correlated with worse outcomes in cancer patients.[27–29] Ryoko et.al. found that pretreatment ALC less than 1.5 associated with adverse survival.[28] Another analysis of patients with advanced breast cancer, sarcoma, and lymphoma, suggested that lymphopenia was an independent predictor of survival.[29] In our study, we found that pretreatment ALC less than 1.5 predicted adverse OS and PFS for patients treated with ICIs. The mechanism of cancer immunotherapy is to promote the activity of cytotoxic T lymphocytes (CTLs) and assist in the activation of tumor-specific CTLs in lymphoid organs, thus establishing an efficient and durable anti-tumor immune microenvironment for anti-tumor therapy.[30] Therefore, it is not difficult to understand that a higher pretreatment ALC is beneficial to improve the survival of patients receiving ICIs.
Another peripheral blood biomarker is the systemic inflammation response index (SIRI), which combined ANC, ALC, and AMC, has been proved to be an effective prognostic biomarkers in different cancers such as esophageal squamous cell carcinoma, non-small cell lung cancer, pancreatic cancer, gastric adenocarcinoma, clear cell renal cell carcinoma.[20, 31–34] Geng et al. suggested that SIRI was an independent prognostic indicator for ESCC patients after the radical surgery.[33] and Hu et al. proposed pretreatment SIRI was an independent predictor of outcomes in stage III NSCLC patients who undergoing chemoradiotherapy.[20] But few studies accessed the effect of SIRI for patients receiving immunotherapy. As far as we know, the present study was the first to demonstrate predictive roles of SIRI for prognosis of III/IV stage NSCLC patients treated with ICIs and revealed that high post-treatment SIRI was significantly associated with poor OS and PFS. Then, we established a novel risk stratification based on pretreatment ALC and post-treatment SIRI. Patients were classified into 3 categories: low-risk group: ALC > 1.5 and SIRI ≤ 1.69; medium-risk group: ALC > 1.5 or SIRI ≤ 1.69; high-risk group: ALC ≤ 1.5 and SIRI > 1.69. Survival analysis showed 1-year OS rates of 69.2%, 63.6%, 27.1% in low-risk, medium-risk, and high-risk group respectively (P = 0.001). In addition, PFS of high-risk group were also significantly shorter than that patients in low-risk or medium-risk group (P = 0.007). Given that ALC and SIRI are easily obtainable, a simple immune risk stratification based on these factors may easily predict survival in III/IV NSCLC treated with ICIs in clinical practice.
Although immunotherapy has brought hope to patients with advanced tumors in recent years, the immune-related adverse effects (irAEs) it brings have also drawn attention.[10] Immune-related pneumonitis (IRP) is a rare but potential fatal irAE that is related to poor outcomes.[11–14] It reported that the incidence rate of all-grade and grade 3 or more IRP were almost 5.4–19.0% and 2.6–12.2% respectively in the clinical setting.[35–37] Our study presented a real-world observation concerning the onset of IRP by ICIs therapy in clinical practice. 24 (25.2%) patients developed IRP attributed to PD-1/PD-L1 inhibitors. Among these patients, 12.5% (3/24) had grade 1 IRP, 66.7% (16/24) had grade 2 IRP, 12.5% (3/24) had grade 3 IRP, and 8.3% (2/24) had grade 4 IRP. Median OS and PFS were similar in patients who developed IRP compared with those who did not, however, patients with grade ≥ 3 IRP were associated with shorter OS (8 months versus 4 months, p = 0.04) and PFS (6.5 months versus 3 months, p = 0.054).
Given severity and worse outcomes of IRP, many scholars have tried to identify reliable predictors for the occurrence of IRP. They suggested that IRP may be associated with tumor histology types, smoking history, presence of preexisting interstitial lung disease.[38, 39] However, no reliable predictive biomarkers were currently used to predict the risk of IRP onset. Therefore, our study also explored an association between IRP and the peripheral blood biomarkers. Intriguingly, we observed that higher post-treatment NLR showed an increased the IRP onset. Patients with post-treatment NLR > 3 were corrected with a significantly higher risk for developing IRP than that post-treatment NLR ≤ 3 (HR: 2.917, 95%CI: 1.037–8.206, P = 0.043). There were few studies indicated that the NLR reflected the systemic immune status and may be regarded as a predictor of IRP in patients with ICIs therapy.[40, 41] A study by Ryosuke et.al. confirmed that NLR could well predict the onset and severity of IRP. They also showed that a considerable elevated NLR during the development of IRP.[40] Furthermore, Fujisawa et al. Also found similar results of elevated neutrophils and decreased lymphocytes in grade 3 and 4 IRP.[41] The precise mechanism of higher NLR associated with the development of IRP is still unclear, and further in-depth studies are needed to validate our results and elucidate the mechanisms it involved.
In addition, we also explored the correction between NLR and the time to IRP onset, and found that most of patients developed IRP within the first 3 months after the start of ICIs treatment, and the onset time in post-treatment NLR > 3 group was shorter than in post-treatment NLR ≤ 3 group. The median onset time in post-treatment NLR > 3 group was 1.5 months (range 1–16 months), and 6.5 months (range 1–18 months) in post-treatment NLR ≤ 3 group. Therefore, for those patients with post-treatment NLR > 3, we should be alert to the development of IRP in the first 3 months after ICIs therapy and adopt a timely treatment strategy.
The present study has several limitations. Firstly, this is a retrospective study, so there may be selective bias in our study. Secondly, there are small numbers of eligible patients, and all patients come from a single institution. Accordingly, larger prospective studies are needed to confirm our results. Third, our current study only explored parameters that are commonly used and easily accessible in clinical practice, but other relevant variables involving genomics and radiomics may provide more valuable information to improve the predictive accuracy of IRP as well as the prognosis of patients treated with ICIs.