Discussion
tumor, neutropenia, fatigue, leukopenia, proteinuria, tumors, hand and foot syndrome
TUMOR, NEUTROPENIA, LEUKOPENIA, ADVERSE EVENTS, DISEASE, SOLID TUMORS, MALIGNANCIES, HYPOTHYROIDISM, TUMORS
The combination of immune checkpoint inhibitors with anti-angiogenesis drugs has previously shown synergistic efficacy in patients with several types of solid tumorsDespite of a high proportion of patients with RM-NPC can achieve a response with GP plus toripalimab or camrelizumab regimens during first-line treatmentThis study reported a similar safety profile of camrelizumab plus apatinib treatment that was consistent with previous studies for other solid tumors. The most common treatment­related adverse events of any grade were leukopenia, neutropenia, fatigue, proteinuria, hand and foot syndrome, increased ALT and AST level, and hypothyroidism. Notably, compared with camrelizumab monotherapyA key finding from cohort 1 of our study is that the immune microenvironment prior to treatment in baseline tumor tissues appears to drive the clinical activity of camrelizumab plus apatinib in RM-NPC. A consistent trend of increasing efficacy with increasing levels of PD-L1 and KDR expression both in cohort 1 and cohort 2. The positive and negative expression of PD-L1 and KDR and their associations with ORR in both cohorts suggest a strong interplay between the immune reaction and anti-angiogenesis in RM-NPC. Notably, our gene expression analysis found that the B cell-related gene signature further reinforced the clinical significance of B cells, indicating that B cell had a significant interaction with T cells in the tumor microenvironment (TME). More robust responses to the combination of camrelizumab and apatinib occur in patients whose tumors have higher levels of TLS, consistent with other malignancies treated with immune checkpoint inhibitor monotherapyLastly, intrinsic resistance and delayed resistance to anti-PD-1 and anti-VEGF combination therapy showed different evolutionary patterns during relapse. The increase of fibroblasts was the main reason for relapse of patients with intrinsic resistance. However, for the delayed resistance patients, the B cell density in the tissues decreased, while the number of cytotoxic T cells and fibroblasts increased, indicating that the decrease of B cells is the decisive inducement for the relapse. Without B cells’ synergetic promotion, the increased cytotoxic T cells cannot perform the function of killing tumor cells. Exhaustion may also be the reason why cytotoxic T cells do not perform their functions; this requires more detailed evidence from subsequent studies. An increase of fibroblasts was also observed in delayed resistance when the tumor relapsed, which suggests that the induction of fibroblasts is common consequence of camrelizumab plus apatinib therapy.This study has several limitations. First, it had a small sample size given the rarity of the disease. Second, the trial design of this exploratory trial did not allow us to assess whether antitumor activity of apatinib occurred primarily through a direct effect or by reversal of primary PD1 antagonists’ resistance. We did not compare the efficacy of this apatinib-camrelizumab regimen with those of anti-PD-1/PD-L1 monotherapies or more recent combined chemoimmunotherapy in this study. Further phase III randomized controlled trials are needed to directly compare apatinib in combination with camrelizumab versus camrelizumab monotherapy or with chemotherapy in treating RM NPC patients as the second or later line treatment therapy. In addition, the reliability and interpretability of biomarker selection may be limited due to the small sample size of sequencing. Although we found that the tertiary lymph structure was related to therapeutic efficiency, we did not detect the detailed characteristics of the tertiary lymph structure, such as its maturity and heterogeneity, which need to be confirmed in future research. Finally, for this study, the number of front-line treatments included in the population was not completely consistent, and the treatment plans for front-line therapy varied. Aside from discrepancies in chemotherapy plans, some patients also received anti-EGFR drugs, resulting in significant heterogeneity among the populations studied. Future studies will require further refinement of the characteristics of the study population to conduct large-scale studies.In conclusion, camrelizumab plus apatinib showed promising anti-tumor activity with a manageable safety profile in platinum-resistant and in PD1 antagonist-resistant RM-NPC. Patients with high expression of PD-L1, KDR and B-cell-related gene signatures will be important to predict which subsets of patients are more likely to benefit from this combination treatment strategy. This combination could be a potential second-line treatment option for patients with RM NPC and warrants phase 3 trials to validate the potential benefits of this regimen.