We conducted a study on the efficacy of second-line combined immunization for advanced NSCLC patients receiving second-line immunization and chemotherapy in Yancheng First People's Hospital.mPFS and mOS were 7.0 and 11.0 months, respectively, with no significant increase in adverse reactions.Analysis of influencing factors showed that gender, age, smoking history, PS score, tumor stage, organ metastasis and other factors were not correlated with ORR, while PD-L1 was correlated with ORR (P =0.022). Kaplan-meier survival analysis of PFS and OS showed no statistically significant difference except for the expression of PD-L1 and the number of organs with metastasis. Considering the small sample size, there was no statistically significant difference between the expression of PD-L1 and the number of organs with metastasis (P =0.033/0.022).Pd-L1 expression was different in OS (P =0.014), indicating that PD-L1 expression had a great influence on the efficacy of second-line combined immunotherapy.
Chemotherapy is still the cornerstone of the treatment of driver gene-negative NSCLC [6-7].With the advent of immunotherapy, overall survival rate and quality of life were improved.The main mechanism of ICIs is to promote the viability of cytotoxic T lymphocytes (CTLs) in tumors and activate tumor-specific CTLs in lymphoid organs, thereby establishing anti-tumor immunity.Ideally, cancer immunotherapy is a sustained anti-tumor response initiated and supported by T cells, which is achieved by presenting corresponding antigens released by dead lysed cancer cells to the primary T cells of secondary lymphoid organs, and is synergistic when used in combination with chemotherapy [8]. Immune checkpoint inhibitors promote the anti-tumor response of CTL in patients by blocking CTL associated antigen 4 and programmed death protein-1 (PD-L1) of T cell coinhibitory receptor through an independent and complementary mechanism, which also confirms whether PD-L1 expression in PFS and OS is statistically different in this study. Positive PD-L1 expression results in better efficacy.PFS and OS of patients were improved to a certain extent.
For the second-line treatment of NSCLC with negative driver gene, second-line monotherapy is the main treatment. The topic of this study is second-line combination therapy. There is no prospective study of second-line chemotherapy combined with immunotherapy at present, but we have seen the advantages of combination therapy in this study.The Checkmate 017 study was conducted in patients with advanced lung squamous cell carcinoma following failure of first-line chemotherapy:Nivolumab was associated with a 41% lower risk of death (HR=0.59, 95%CI,0.44 to 0.79) in patients treated with second-line chemotherapy compared with docetaxel (9.2 months vs6.0 months).Nivolumab was also significantly better than docetaxel (ORR:20%vs9%, P =0.008,PFS:3.5 months vs2.8 months, p≤0.001).Checkmate 057 was administered in patients with advanced lung adenocarcinoma who had failed first-line platinum based chemotherapy and achieved the same efficacy advantage.In addition, Nivolumab showed consistent long-term benefits in 5-year survival and progression-free survival with longer follow-up, and no treatment-related adverse events were observed over the long term.Checkmate078 also confirmed the efficacy and safety of Nivolumab in the Chinese population..Subsequent keynote-010 and OAK trials further demonstrated that the immunotherapy drugs Pembrolizumab and Atezolizumab also had a significant advantage over chemotherapy, and again demonstrated the significant advantage of second-line ICIs in the treatment of advanced NSCLC [9-10].
The initial application of ICIs in patients had the problem of low efficiency. It was once thought [11] that chemotherapy drugs can be regarded as a "vaccine", which kills tumor cells and leads to the exposure and release of tumor antigens. Meanwhile, chemotherapy drugs also have an overall impact on the immune system, including the activation of DC cells.Activation (natural killer cell, NK) cells, natural killer cells reshape tumor associated macrophage (tumor – associated macrophages TAMs) cells, reduce Treg cells activity, etc.In theory, immunotherapy combined with chemotherapy can achieve the effect of 1+1>2. Due to the late introduction of immunotherapy in China, a large number of lung cancer patients did not receive immunotherapy at the initial treatment, but only received chemotherapy. How should they choose second-line therapy for these patients? What is the efficacy of second-line chemotherapy combined with immunization?
In this study, the median PFS was 7.0 months, pD-L1 expression > 1% mPFS was 7.5 months, mOS was 13.5 months, PD-L1 expression was 0% or unclear, mPFS was 6.5 months, mOS was 10.5 months,However, in CheckMate017 and CheckMate057 exploration of the efficacy of nivolumab in the second line treatment of advanced NSCLC, regardless of the expression of scales/glandular /PD-L1, nivolumab extended the benefit of OS by about 3 months, mOS 11.1 months and PD-L1 > 1% 13.4 months, which was similar to this study. In the study of Checkmate078 series nivolumab in 90% of the Chinese population for second-line treatment, the median OS was 12.0 months, the median PFS was 2.8 months, the mPFS in this study was 7 months, significantly longer, the median OS 11.0 months, slightly shorter,The Keynote010 study was about the efficacy of pembrolizumab in patients with advanced PD-L1 positive NSCLC who were treated. The median OS was 10.4/12.7 months and the median PFS was 3.9/4 months in non-PD-L1 positive patients. The median PFS and OS in this study were both improved.In addition, not all PDL1 expressions were positive in the study population and the sample size was small. From the comparison of data, we have reason to believe that second-line chemotherapy combined with immunization has further increased the efficacy, which needs to be verified by subsequent phase III clinical trials. It also gives us reason to believe that patients who are not treated with immunotherapy in the first line can be further considered in combination with immunochemotherapy in the second line.
Meanwhile, the results of this study showed that the incidence of adverse reactions such as fever, granulocytopenia and gastrointestinal reactions was not significantly increased in the treatment group.
In summary, through the real world data analysis of our center, we found that the ORR, PFS and OS of advanced NSCLC patients with second-line chemotherapy combined with immunotherapy were beneficial, and the positive expression of PD-L1 and the small number of organ metastases resulted in better efficacy.The deficiency of our study is retrospective study, with a small sample size and inconsistent protocol, which requires further confirmation by large-scale prospective clinical trials. For advanced NSCLC patients with high PD-L1 expression and no EGFR/ALK and other driver gene mutations, prospective clinical trials are necessary to explore the best treatment mode for such patients.