Discussion
HER-2-negative, neutropenia, proteinuria, intestinal type tumors, tumors
REGRESSION, METASTASIS, NEUTROPENIA, POSITIVE, HYPERTENSION, ADVERSE EVENTS, ADVERSE EVENT, CPS, LIVER METASTASIS, HYPOTHYROIDISM, TUMORS
This study explored the combination of sintilimab plus apatinib and chemotherapy. With an ORR reaching 53.6% and a long median PFS (8.5 months), this prospective trial met the primary endpoint. The median OS time was > 1 year, reaching 12.5 months. These results indicate a significant improvement over previous second-line treatments, suggesting that the combination of a PD-1 inhibitor, VEGFR inhibitor, and chemotherapy has a certain synergistic effect.For the first-line treatment of advanced GC, the anti-PD-1 combination therapy has been listed in the latest treatment guidelines. The CheckMate 649 study showed that nivolumab combined with chemotherapy improved the OS compared with chemotherapy alone [Previous studies have also shown a synergistic effect between chemotherapy and apatinib [Our study of the combination of sintilimab plus apatinib and chemotherapy (irinotecan or paclitaxel) in an unselected population showed an ORR of 53.6%, median PFS of 8.5 months, and median OS of 12.5 months. These results are better than those of ramucirumab combined with paclitaxel in the RAINBOW study (ORR of 28%, median PFS of 4.4 months, and median OS of 9.6 months) [Although recent studies have indicated that PD-L1 levels are related to the efficacy of PD-1 inhibitors, the CheckMate 649 study showed that nivolumab combined with chemotherapy improved the OS, especially in patients with a Combined Positive Score (CPS) of ≥ 5[33]. In the unselected population from the ATTRACTION-4 study, nivolumab combined with chemotherapy failed to improve OS compared with placebo combined with chemotherapy, and advantages only existed in terms of the ORR and PFS [The univariate Cox regression analysis of this study showed that the Lauren classification and liver metastasis were potential prognostic factors affecting both PFS and OS, whereas the multivariate analysis showed that liver metastasis was an independent prognostic factor for PFS and OS. Patients with liver metastasis had significantly better PFS and OS and significantly better ORR than those with non-liver metastasis. This result suggests that patients with liver metastasis are more likely to benefit from the treatment regimen in this study. However, Tumeh et al. [The ORR obtained by patients with intestinal type tumors according to the Lauren classification was significantly better than that of patients with diffuse type, mixed type, or unknown tumors, and there was also a significant difference in the median PFS (11.3 vs. 4.1 months, No unexpected adverse events occurred in this study. Most of the adverse events were grade 1 and 2. The most common grade 3–4 treatment-related adverse event was neutropenia, which was mainly caused by irinotecan. The most common adverse event caused by sintilimab was increased liver transaminases, followed by hypothyroidism; most of these cases were grade 1 and 2. The most common adverse events related to apatinib were proteinuria and hypertension, most of which were also grade 1 and 2. The overall tolerance of this treatment regimen was good, likely because of the reduced dose of chemotherapy drugs and apatinib used in this study compared with the standard dose when used as monotherapy, on account of that we thought they were more important to play an immunomodulatory role in the combination therapy.This study has some limitations. Firstly, this was a single-arm, single-center study without a randomized control group; thus, it lacked sufficient persuasiveness. Secondly, patients enrolled in this study were HER-2-negative and had a proficient mismatch repair status; however, the lack of more molecular feature detections may bring some limits for further mechanism analysis, such as PD-L1 levels and so on. In addition, the number of patients was small, which may lead to some bias in the study results. A prospective expansion study of this regimen is underway.