Gastric adenocarcinoma (GAC) and gastroesophageal junction adenocarcinoma (GEJA) are prevalent and dangerous malignancies worldwide, with more than 1 million newly diagnosed cases and over 0.7 million deaths in 2020 (1–3). It has been reported that the incidence of GAC has declined, while that of GEJA has steadily increased in recent years (4–6). Moreover, there is a large proportion of GAC and GEJA patients with advanced disease at diagnosis who lose the opportunity for potentially curative surgical resection (7, 8). According to the guidelines recommended by the Chinese Society of Clinical Oncology, the first-line systematic therapy for advanced GAC and GEJA is fluorouracil-based chemotherapy plus immunotherapy (combined with trastuzumab if the tumor presents human epidermal growth factor receptor 2 (HER2)-positive), while the second-line therapy is limited and merely includes paclitaxel, docetaxel, and irinotecan monotherapy or their combination, as well as paclitaxel and ramucirumab combination (9, 10).

Angiogenesis mediated by vascular endothelial growth factor (VEGF) has been identified as a key factor that facilitates the progression and metastasis of GAC and GEJA (11). Therefore, the application of antiangiogenic agents for the treatment of GAC and GEJA has received close attention. For instance, ramucirumab, a monoclonal antibody targeting VEGF receptor-2, has been approved by the Food and Drug Administration (FDA) for the treatment of advanced GAC and GEJA (12, 13). Meanwhile, apatinib, an oral tyrosine kinase inhibitor that also targets VEGF receptor-2, has been recommended as the third-line treatment for advanced GAC and GEJA in China since it dramatically prolongs progression-free survival in patients with advanced GAC and GEJA (9, 14). In the last two years, some clinical studies have shown that advanced GAC or GEJA patients who receive second-line apatinib plus chemotherapy present satisfactory response and survival, suggesting that apatinib plus chemotherapy may serve as a potential second-line therapy for advanced GAC and GEJA (14–21). In addition, a recent phase II study investigating ramucirumab plus irinotecan as second-line therapy in patients with advanced GAC also reveals the efficacy and safety of VEGF receptor-2 inhibitor plus irinotecan in those patients (22). However, more evidence is needed to facilitate the application of second-line apatinib plus chemotherapy for the treatment of advanced GAC or GEJA.

The current prospective, multicenter, phase II clinical study aimed to evaluate the treatment response, survival benefit, and adverse events of second-line apatinib plus irinotecan in advanced GAC or GEJA patients.

Irinotecan is one of the standard second-line chemotherapies for advanced GAC or GEJA, which could be metabolized into SN38, a DNA topoisomerase I inhibitor, thus suppressing the duplication of DNA and synthesis of RNA and exerting antitumor efficacy (24). Because of its spectral antitumor efficacy and wide application in digestive cancers, the current study chose irinotecan in combination with apatinib, a VEGFR-2 inhibitor that specifically represses angiogenesis to hinder tumor progression (25). In addition, a previous study suggested that irinotecan-based chemotherapy plus ramucirumab (another VEGFR-2 inhibitor) achieves a better treatment response than paclitaxel plus ramucirumab (26), which implied the potential superiority of irinotecan plus a VEGFR-2 inhibitor versus other chemotherapies plus a VEGFR-2 inhibitor. According to previous studies, the common dose of apatinib is 500 mg daily (15, 18, 19). Meanwhile, considering that advanced GAC or GEJA patients might be impossible to tolerate 150-180 mg/m² irinotecan on the first day every 2 weeks, the dosage in our phase I clinical trial (data not published) was set as 500 mg apatinib daily and 180 mg/m² irinotecan on the first day every 3 weeks (as a treatment cycle) to promote tolerability. However, all 3 patients experienced grade 3 adverse events, which mainly included diarrhea, hypertension, and granulocytopenia. The adverse events resulted in drug cessation in 2 of the 3 patients, and the dose of apatinib was reduced to 250 mg daily in the other patient. Therefore, in the current phase II study, the dose of apatinib was set as 250 mg daily and that of irinotecan was set as 180 mg/m² on the first day every 3 weeks to increase the tolerability.

The application of second-line apatinib plus chemotherapy for the treatment of GAC and GEJA has become a hotspot in recent years. For instance, it has been reported that in patients with advanced GAC or GEJA refractory to first-line chemotherapy, the ORR is 21.6%, and the DCR is 83.8% (18). Meanwhile, a randomized, controlled trial revealed that second-line apatinib plus docetaxel achieved an ORR of 18.4% and DCR of 60.5% in advanced GCA or GEJA patients who failed first-line chemotherapy (17). Moreover, in advanced GAC patients who receive second-line apatinib plus chemotherapy (including docetaxel, paclitaxel, oxaliplatin, capecitabine, and tegafur), a total of 18.5% of patients achieve an objective response, and 92.6% of patients achieve disease control (15). In addition, a recent retrospective, real-world study investigated second-line or above apatinib plus irinotecan in patients with advanced gastric cancer (27). The current study was a prospective, multicenter, phase II clinical study focusing on second-line apatinib plus irinotecan in patients with advanced GAC or GEJA, which could further verify the therapeutic potential of second-line apatinib plus irinotecan for the treatment of these patients. The data revealed that the ORR and DCR were 28.6% and 75.0%, respectively, in advanced GAC or GEJA patients who received second-line apatinib plus irinotecan, which was within the range of previous study-reported ORR and DCR (15–21). In addition, the ORR and DCR were numerically higher than those in advanced GAC patients receiving second-line chemotherapy (19). A possible explanation could be that apatinib inhibited the progression of GAC and GEJA by suppressing angiogenesis, while chemotherapy directly killed tumor cells (24, 28). Therefore, the combination of these two antitumor agents with different mechanisms of performance might exert good effects on treating GAC and GEJA. Thus, the treatment response was acceptable in patients receiving second-line apatinib plus irinotecan. In the current study, 3 patients were excluded from treatment response evaluation. The reasons were as follows (1): The first patient was nonlocal. He/she failed to be followed up due to COVID-19, and the treatment response was not evaluated in this patient. (2) The second patient had poor drug consistency after 2 cycles of treatment. In addition, treatment response was not evaluated in this patient. (3) The third patient died after 1 cycle of treatment, which was considered to be associated with disease progression but not the drugs. Treatment response was not evaluated in this patient.

The survival of patients with advanced GAC or GEJA is quite unfavorable; it has been reported that the 5-year survival rate in these patients ranges from 5% to 30% (6, 29, 30), which is partly caused by the limited treatment choice after failure of first-line therapy. Previous studies have shown that second-line apatinib plus chemotherapy achieves certain survival in GAC or GEJA patients. For instance, in advanced GAC or GEJA patients receiving second-line apatinib plus chemotherapy (including docetaxel, paclitaxel, oxaliplatin, capecitabine, and tegafur), the median PFS and OS are 3.06 and 6.51 months, respectively (15). Meanwhile, in advanced GAC patients who receive second-line apatinib plus S-1, the median PFS and OS are 143.1 days (approximately 4.77 months) and 211.6 days (approximately 7.05 months), respectively (20). In the current phase II clinical study, it was observed that the median PFS and OS were 4.5 and 11.7 months, respectively, in advanced GAC or GEJA patients receiving second-line apatinib plus irinotecan. The PFS in the current study was within the range in previously reported studies, while the OS was numerically longer than that previously reported (15–21), which could be explained by the fact that some of the patients were locally advanced in our study and might have longer survival. Another possible explanation might be that compared with other studies, patients in the current study tended to have milder disease conditions and better performance status, such as younger age, lower ECOG PS score, and fewer metastatic sites, which contributed to a longer OS. Additionally, data from multivariate Cox regression analysis revealed that male sex, liver metastasis, and peritoneal metastasis were independent risk factors for worse PFS or OS, which were all well-recognized risk factors for mortality in advanced GAC or GEAJ patients in previous studies (31, 32). However, patients with these factors should not be excluded from the upcoming trial since these factors were prevalent in patients with advanced GAC or GEJA. Conversely, clinicians should pay close attention to patients with these factors to achieve better management in those patients.

According to previous reports, the hematological adverse events of apatinib plus chemotherapy mainly refer to leukopenia, neutropenia, anemia, and thrombocytopenia, whose incidences range from approximately 15% to 60% (14–21, 33). Regarding the non-hematological adverse events of apatinib plus chemotherapy, the common ones are fatigue, nausea and vomiting, elevated transaminase, diarrhea, etc., whose incidence ranges from approximately 30% to 75% (14–21, 33). The current phase II clinical study showed that the category of hematological and non-hematological adverse events was in line with previous studies; meanwhile, the incidences of these adverse events were also within the range of previous reports (14–21, 33). Meanwhile, the incidence of febrile neutropenia was 3 (10.7%). Growth factors were allowed for the treatment, but not for the prevention, of neutropenia. In addition, there were 12 patients who continued the original treatment regimen until the end of the study, 5 patients who stopped treatment due to treatment-emergent adverse events, and 11 patients with dose reduction due to treatment-emergent adverse events. These findings suggested that second-line apatinib plus irinotecan was tolerated in advanced GAC or GEJA patients.

This study might serve as vital evidence for the use of second-line apatinib plus irinotecan in patients with advanced GAC or GEJA, while some limitations of this study should be clarified. First, the sample size of this study was not large enough; further studies should verify our findings in a larger cohort. The possible reasons for slow accrual for the trial are listed as follows: a. most patients with GAC or GEJA were resectable, and the number of patients with advanced GAC or GEJA was small; b. with the continuously widening application of PD-1 inhibitors in China, an increasing number of patients were willing to receive PD-1 inhibitors. Therefore, the current study only enrolled 28 patients. Second, this study was a prospective, single-arm study; thus, further randomized controlled trials or meta-analyses might be needed to validate the efficacy and safety of second-line apatinib plus irinotecan. Third, the patients in this study received different first-line treatments, which could be a potential confounding factor. Fourth, the underlying mechanisms of apatinib plus irinotecan in inhibiting GAC or GEJA should be further explored by in vitro and in vivo experiments.

Collectively, apatinib plus irinotecan as second-line therapy achieves a good treatment response and satisfactory survival with tolerable safety in patients with advanced GAC or GEJA, which could serve as a potential treatment option for these patients. However, these findings should be further verified in studies with larger sample sizes to provide more reliable evidence to support second-line apatinib plus irinotecan in patients with advanced GAC or GEJA.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the First Hospital of China Medical University Institutional Review Board (No. 2016-197-10) with the registration number NCT03116555 (https://clinicaltrials.gov). The patients/participants provided their written informed consent to participate in this study.

XQ and YLi contributed to the study conception and design. Material preparation was performed by JQ, XH and YLu. Data collection was performed by PY, YC and JL. Data analysis was performed by XW (7th author), CW and TL. YB, YH and LM were responsible for the interpretation of the data. The first draft of the manuscript was written by CL and CZ. LH and XW (16 author) contributed to manuscript revisions of the intellectual content. All authors contributed to the article and approved the submitted version.