This is the first study of PD-1 blockade combined with anti-angiogenic drug and chemotherapy for untreated advanced gastric cancer. Since no MTD was observed, dose 3 was determined to be RP2Ds. Among the 34 patients who were administered the study treatment, the confirmed ORR stood at 76.5%, the median PFS reached 8.4 months, the median EFS reached 22.3 months, and the 2-year OS rate stood at 62.8%. As a result of the multidisciplinary team (MDT) evaluation, ten patients proceeded to surgical intervention. Surgically treated patients had longer survival outcomes versus non-surgical patients (median EFS: 23.1 vs 8.4 months; median OS not reached vs 19.6 months). The combination therapy exhibited a manageable safety profile.

In the present study, we observed that 35.3% of patients presented with PD-L1 CPS ≥ 1, 20.6% indicated CPS ≥ 5, and 14.7% recorded CPS ≥ 10. These percentages fall below those reported in the CheckMate 649 trial (82.0% for CPS ≥ 1 and 60.4% for CPS ≥ 5) and the KEYNOTE-859 trial (78.2% for CPS ≥ 1 and 34.9% for CPS ≥ 10).3,8 However, the confirmed ORR in this study surpassed numerically the results of the nivolumab or pembrolizumab plus chemotherapy groups in the CheckMate 649 trial (58%) and the KEYNOTE-859 trial (51.3%).3,7 A phase 2 study evaluating camrelizumab alongside chemotherapy followed by camrelizumab plus apatinib for untreated advanced gastric cancer reported a confirmed ORR of 58.3%.24 Additionally, nivolumab plus chemotherapy yielded a median OS of 13.8 months in the CheckMate 649 trial and 17.5 months in the ATTRACTION-4 trial. In the KEYNOTE-859 and ORIENT-16 trials, pembrolizumab or sintilimab combined with chemotherapy yielded a median OS of 12.9 and 15.2 months, respectively.3,7,27,28 In contrast, this study showed substantial clinical benefits. Therefore, the integration of apatinib with camrelizumab and chemotherapy could potentially enhance both short-term and long-term results.

Notably, the addition of apatinib to camrelizumab plus chemotherapy demonstrated encouraging efficacy, specifically among the group with low PD-L1 CPS scores. The combination therapy yielded a confirmed ORR in the PD-L1 CPS < 1 (70.6%) and CPS < 5 (72.7%) subsets. In contrast, the confirmed ORR was 51% and 55% for these subgroups in the CheckMate 649 trial.3 Moreover, peritoneal metastasis is an adverse prognostic factor. Unfortunately, none of the patients with peritoneal metastasis showed tumor reduction with combination therapy.

Given the poor prognosis of patients with late-stage gastric cancer, multiple studies investigated curative surgery as a potential solution for cases with limited non-curable factors.29,30,31 The phase 3 REGATTA study recruited individuals diagnosed with clinical stage IV and a single incurable metastasis (located in either peritoneum, liver, or para-aortic lymph nodes). The study did not demonstrate a survival advantage from palliative gastrectomy followed by chemotherapy compared to chemotherapy alone.30 In the AIO-FLOT3 study, 60 patients with limited metastatic gastric cancer received induction chemotherapy followed by surgery with the aim of curing or prolonging their lives. Among 36 patients who were given curative surgery, the R0 resection rate stood at 80.6%, and these patients exhibited enhanced survival relative to patients who did not receive surgery.31 However, the impact of curative surgery in managing metastatic gastric cancer remains unclear, particularly regarding suitable candidates and optimal treatment approaches before surgery. In this study, ten patients received combination therapy with camrelizumab, apatinib, and chemotherapy followed by curative surgery. Of these patients, nine had distant lymph node metastases and five had liver metastases. Impressively, 80% of patients achieved a partial response to the combination regimen, and 90% attained R0 resection. Pathological complete responses (pCR) were observed in three patients (30%), while five patients (50%) achieved major pathological responses (MPR). These findings are comparable to a phase 2 clinical trial of neoadjuvant camrelizumab plus apatinib and chemotherapy for treatment of resectable gastric cancer, which reported an ORR of 28.6%, an R0 resection of 72.7%, and a pCR and MPR of 12.5% each, among 14 patients with cT4bN+ clinical stage, which overlapped with inclusion criteria in this study.25

In a subset of patients, multiplex immunofluorescence analysis demonstrated a significant increase in TLS after treatment. TLS was linked to improved outcomes and heightened response to immune checkpoint inhibitors in cancer treatment.32,33,34 This finding may underpin the favorable efficacy of the combination therapy. Elevated infiltration of CD3+ or Foxp3+ T cells was linked to improved survival in gastric cancer.35,36,37 Similarly, in this study, patients receiving combination therapy exhibited an association of elevated levels of CD3+ cells or Foxp3+ cells with extended OS. However, the study failed to definitively identify specific immune cell types. In colon cancer, Foxp3+ Tregs were classified into two subsets: CD38+Foxp3+ Tregs linked to negative prognosis, and CD38-Foxp3+ Tregs linked to positive survival.38 Given the distinct functions of each immune cell type, further research is crucial for accurately interpreting the immune results highlighted in this study.

The safety characteristics identified in this study were in line with those detailed in the phase 2 clincal trial investigation of neoadjuvant camrelizumab in combination with apatinib and chemotherapy for locally advanced gastric cancer.25 Additionally, it was consistent with the phase 2 study of first-line camrelizumab plus chemotherapy followed by camrelizumab and apatinib for advanced gastric cancer.24 The latter phase 2 study reported that 68.8% of patients developed treatment-related adverse events (TRAEs) of grade 3 or above, 75.0% experienced treatment interruption because of TRAEs, and 41.7% experienced dosage decrease because of TRAEs. In comparison, in this study, TEAEs grade 3 or above were experienced by 52.9% of patients, TEAEs resulted in dose delay or interruption in 55.9% of patients, and TEAEs resulted in dosage decrease in 61.8% of patients. Thus, preliminary results suggest that this combination regimen may be a tolerable treatment approach.

This phase 1 trial investigated the dosage, safety, and antitumor activity of camrelizumab plus apatinib and chemotherapy for a small number of participants. Additionally, without pharmacokinetic and pharmacodynamic analyses, this study did not succeed in shedding light on the pharmacological processes of the combined treatment. Furthermore, biomarker analysis was performed on a subset of patients, and only relied on multiplex immunofluorescence staining without comprehensive molecular analyses such as transcriptomic or proteomic profiling. As such, the study’s findings warrant careful and prudent interpretation. Further studies with larger sample sizes, control groups, and more extensive molecular analyses are necessary to fully evaluate the efficacy and potential biomarkers of this combined treatment.

In conclusion, camrelizumab plus apatinib and chemotherapy demonstrated a tolerable safety profile in patients with untreated advanced gastric cancer. Additionally, this combination therapy exhibited antitumor activity, including a notable rate ORR and extended PFS and OS. Notably, patients exhibiting lower PD-L1 expression (CPS < 1 and CPS < 5) also achieved a high ORR. Nevertheless, additional clinical trials are indispensable for confirming the efficacy of this combination therapy.