In this study, we provided the largest data set concerning the efficacy of RAM and DOC in patients with advanced NSCLC in clinical practice. To the best of our knowledge, this is the first study to elucidate the impact of prior treatment and its effectiveness on RAM and DOC efficacy. Our findings demonstrated that prior ICI + was an independent factor significantly associated with better PFS in patients with NSCLC receiving RAM and DOC. Furthermore, we demonstrated that tumor response to prior ICI might predict survival benfits of RAM and DOC. There are several explanations for the results observed in our study.
We demonstrated that prior ICI + significantly increased anti-tumor responses and extended PFS in patients who received RAM and DOC compared to prior ICI−, whereas past ICI did not. This may be attributed to the duration from the final use of ICIs to RAM and DOC initiation.
In recent years, some clinical studies have shown that combination therapy with ICIs and antiangiogenic agents improves tumor immune response. Several studies have investigated this mechanism. The tumor microenvironment (TME) is composed of tumor and immune cells and several signaling molecules and contains several immunosuppressive cells, such as regulatory T cells (Bhome et al. 2015; Nishikawa and Sakaguchi 2014; Kumar et al. 2016; Pan et al. 2020; Ma et al. 2013). VEGF signaling can promote the immune suppression of the anti-tumor immune response in the TME and induces resistance to immunotherapy by promoting the differentiation and proliferation of these suppressor cells (Terme et al. 2013; Gabrilovich et al. 1998). VEGF also suppresses T cell infiltration into tumors by decreasing the expression of adhesion molecules, such as integrin ligand, which is termed tumor endothelial cell allergy (Huinen et al. 2021; Voron et al. 2015). Therefore, blocking VEGF signaling decreases the number of immunosuppressor cells in the TME and increases the number of effector T cells that can directly eliminate tumor cells. Thus, antiangiogenic agents restructure the immunosuppressive TME and enhance immunotherapy efficacy.
In addition, Osa et al. evaluated the duration of anti-programmed death-1 (PD-1) antibody binding to T cells and revealed that the bindings continued for more than 20 weeks after the last administration, and then the bindings were gradually uncoupled (Osa et al. 2018). Other clinical reports have also demonstrated that ICIs efficacy sustains for years after the discontinuation (Herbst et al. 2020).
Based on these reports, in the prior ICI + group, ICI-bound T cells can remain in the blood for a while, be reactivated by the administration of RAM, and infiltrate tumors again. The failure to show superiority in the past ICI group compared to the no ICI group may be due to the long duration from the final usage of ICIs to RAM and DOC initiation.
In recent years, clinical trials similar to our concept, using antiangiogenic agents immediately after ICI tolerance, have been reported one after another (Lee et al. 2022; Reckamp et al. 2022). In the future, sequential therapy with ICI and antiangiogenic agents will become an optimal treatment option, and further comparative studies are required to validate our findings.
We also demonstrated that tumor response to prior ICI might be a predict survival benefits of RAM and DOC. Tumeh et al. demonstrated that the number of tumor-infiltrating CD8+ T cells in ICI responders increased, but not in non-responders, following anti-PD-1 therapy using serial specimens from patients with melanoma (Tumeh et al. 2014). Hence, in conjunction with the report of Osa et al., anti-PD-1 antibodies bind to existing T cells for a while after immunotherapy discontinuation, and the more effective the ICIs are, the more such T cells may be present in the blood. Such anti-PD-1 antibody-bound T cells, different from finally differentiated exhausted T cells that have completely lost their proliferative potential and are refractory to immunotherapy, are memory-like exhausted T cells that retain their proliferative potential and can differentiate into T cells with anti-tumor effector activity (Henning et al. 2018). In short, in the prior ICI + group compared to the prior ICI − group, pre-existing ICI-bound T cells with anti-tumor activity may infiltrate into and eliminate tumors again with enhancement by RAM.
This study has some limitations. First, biases, including selection bias, were inevitable because of the retrospective design of the present study. However, confounding factors were adjusted using multivariate analyses. Second, the therapeutic efficacy by clinical response to prior ICI therapy was evaluated in a relatively small number of patients. Third, data on the treatment lines after RAM and DOC were not analyzed. Therefore, the OS may not have been accurately evaluated. Fourth, the efficacy of RAM and DOC immediately after ICI treatment was not directly compared to that of DOC monotherapy in this study. Therefore, it is difficult to elucidate the association between prior ICI therapy and RAM alone. Finally, this study evaluated efficacy alone, and safety was not assessed. In clinical practice, treatment decisions should be based on efficacy and safety. Further comparative studies are warranted to validate our findings.
In conclusion, prior ICI + significantly increased anti-tumor responses and prolonged PFS in patients who received RAM and DOC compared to prior ICI−, whereas past ICI did not. Therefore, RAM and DOC should be administered immediately after ICI tolerance. The tumor response to prior ICI may be a predictive factor for RAM and DOC efficacy. Prior ICI + showing CR + PR significantly prolonged PFS in patients with RAM and DOC compared with prior ICI−. RAM and DOC are expected to be more effective, especially when prior immunotherapy shows a good response. Further studies are warranted to confirm the results of this study.