Apatinib in the treatment of gastric cancer in Henan Province: a multicenter prospective real-world observational study (Ahead-HAP01)

Introduction

Gastric cancer is one of the most common malignant tumors of the digestive system in Asia. Unfortunately, most patients present with advanced incurable disease where the goals of treatment is palliative to control symptoms and improve survival (1). Gastric cancer incidence is unevenly geographically dispersed, with an unusually high incidence in East Asia, South America, and Eastern Europe (2). Henan is a populous province in China, and gastric cancer is the second most common malignancy with significant morbidity and mortality in the region.

Targeting angiogenesis has played a significant role in the treatment of several malignancies (3) . In gastric cancer, the role of Anti-angiogenic therapy has been limited until October 17, 2014, where the China Food and Drug Administration (CFDA) officially approved a small-molecule tyrosine kinase inhibitor (TKI) that selectively inhibits the vascular endothelial growth factor receptor-2 (VEGFR2), as a national class 1.1 new drug to treat advanced gastric cancer patients who failed second-line treatment (4,5). However, the effectiveness of Apatinib under real-world condition has not been evaluated and the drug performance under ideal and controlled circumstances has not been validated (6). In fact, genetic factors, diet, poor healthcare access, social economic status, comorbidities compliance and other factors play significant role in drug performance under “real-world” conditions.

Clinical trials usually have strict inclusion criteria, and the enrolled patients typically have, among other characteristics, better performance status than real-world patients. That is why efficacy can overestimate drug performance compared to clinical practice. Additionally, gastric cancer populations in different regions have distinct clinical characteristics. Consequently, therapeutic interventions’ efficacy and adverse reactions may also vary. The efficacy and safety of apatinib in real-world scenarios remain unexplored (7,8). The population included in the phase III clinical study of apatinib is the population with more than second-line treatment. However, in the real world, due to the patient’s constitution or personal will, some first-line and second-line treatment people also received apatinib treatment. In addition, apatinib was studied as a single drug for the treatment of advanced gastric cancer before it was marketed, but there are many patients in the real world who are treated with chemotherapy or immunotherapy. Therefore, clinical practice urgently needs to see the real world application, efficiency and safety data as a reference for the treatment of gastric cancer with apatinib.

We present results from a prospective study conducted in Henan province in china. A total of 943 gastric cancer patients treated with Apatinib between March 1, 2018, to March 1, 2019 were included. The aim of the study was to better examine the efficacy and the toxicity of apatinib in an unselected population in order to optimize its future use. We present the following article in accordance with the STROBE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5995/rc).

Methods

Patients

Patients with gastric cancer treated with apatinib from March 01, 2018, to March 01, 2019, who satisfied the following inclusion criteria were enrolled:

• Patients of both sexes aged ≥18 years;
• Patients with gastric adenocarcinoma diagnosed by pathology or histology;
• Patients who volunteered to join the study and signed the informed consent form;
• Patients who were expected to benefit from the treatment according to the investigators.

The exclusion criteria were as follows:

• Patients confirmed to be allergic to apatinib mesylate tablets and/or its excipients;
• Pregnant or breastfeeding women;
• Patients with contraindications to apatinib;
• Patients not deemed suitable for inclusion by their physician.

Patients who meet the criteria are observed non-interventionally after signing an informed consent form, and are followed up regularly according to the protocol design. All enrolled patients were from 14 sub-centers in Henan Province (see Appendix 1). This study was registered on https://clinicaltrials.gov/ (ID: NCT03478943). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by Ethics Committee of Henan Cancer Hospital (No. 2018012). All participating institutions were informed and agreed the study. All patients provided written informed consent before enrollment.

Trial design

In this multicenter, prospective observational study, gastric cancer patients treated with apatinib, first-, second-, third line or beyond were recruited. Apatinib monotherapy, apatinib combined with chemotherapy, and different doses of apatinib (dose range, 250–850 mg q.d.) were included in the statistical analysis. The efficacy and safety of apatinib in this patient population were reported.

Efficacy evaluation

Efficacy was evaluated according to version 1.1 of the efficacy evaluation standard for solid tumors.

Observation of adverse events

According to the National Cancer Institute (NCI) “Common Acute and Subacute Toxicity Classification Standard” adverse events (AEs) are classified into grades 1–5, as detailed in the NCI Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE 4.0). AEs not listed in the NCI toxicity classification standard were documented according to the following criteria:

• Grade 1 (mild): asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated;
• Grade 2 (moderate): minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living;
• Grade 3 (severe): hospitalization or prolongation of hospitalization; disabled; or limited to performing self-care activities of daily living;
• Grade 4 (life-threatening): life-threatening consequences or urgent intervention indicated;
• Grade 5: (death): death related to an adverse event.

Follow-up

The follow-up period began after the last use of the study drug. The adverse reactions that have not been recovered will continue to be treated and followed up until they are recovered to grade 1 or completely recovered. The patients were followed up for a long time every 8 weeks (including telephone follow-up), and whether they used other anti-cancer treatments before the follow-up was collected. If other treatments are used, record the treatment plan, cycle number and outcome. Follow up until the patient dies and record the cause of death and specific time to obtain the overall survival (OS).

Statistical methods

The population included all available patients from the participating sites who received at least one dose of Apatinib. There was no formal sample size calculation. Quantitative data are presented as the number of cases, arithmetic mean, standard deviation, median, and range according to their distribution. Qualitative data are presented as frequency, ratio, or percentage. Baseline data related to the efficacy evaluation were defined as the data obtained during the case screening period. The Cochran-Mantel-Haenszel (CMH) χ² test, Fisher’s exact test, or Wilcoxon’s rank-sum test of graded data were used to compare categorical variables among the groups. The t-test or Wilcoxon’s rank-sum test was used for continuous variables. The χ² test was used to evaluate whether the baseline characteristics of the missing patients were similar to those of the statistical patients. The Kaplan-Meier method was used to estimate the progression-free survival (PFS) and OS curves and estimate the median PFS and median OS as well as their 95% confidence intervals. The objective response rates (ORRs) and disease control rates (DCRs) with their 95% confidence intervals were also calculated. All analyses were descriptive, performed in the overall population and in subgroups according to therapy setting. When P<0.05, it represents a statistically significant difference.

Results

Between March 2018 and March 2019, a total of 943 patients with gastric cancer treated with Apatinib were enrolled. The baseline characteristics are summarized in Table 1. There were 591 patients younger than 65 years of age (62.67%) with an age range of 19–93 years. There were 227 (24.07%) patients treated with apatinib in the first line, 389 (41.25%) in second-line, 280 (29.69%) in third-line, and 47 (4.98%) beyond third line. Of patients with measurable disease at baseline, 14 patients (1.48%) achieved complete response (CR), 75 (7.95%) achieved partial response (PR), 610 (64.69%) had stable disease (SD) as best response, and 149 (15.80%) had progressive disease (PD).A total of 95 patients (10.07%) could not be evaluated (imaging assessment was not available). The median PFS was 5.65 months (95% CI: 5.22–6.05 months), and the median OS was 11.47 months (95% CI: 10.41–12.52 months) (Figure 1A,1B).

Figure 1 Progression-free survival (A) and overall survival (B) curves of the subjects.

Overall, the most common treatment-emergent adverse events (incidence ≥20%) were anemia; anorexia; thrombocytopenia, leukopenia, neurtopenia malaise and nausea. Aminotransferase increase, abdominal pain, abdominal distension, vomiting, and constipation were reported in 10–20% of patients. Proteinuria, positive fecal occult blood, diarrhea, hypertension, and palmar-plantar erythrodysesthesia syndrome were observed in less than 10% of patients. Adverse events are reported in Table 2.

The probability of adverse events in the different starting dose subgroups (250, 375, 425, 500, and 750 mg) was 93.71%, 85.71%, 100.00%, 86.49%, and 91.30%, respectively. Among these, the incidence of ≥ grade 3 adverse events was 23.37%, 14.29%, 50.00%, 23.65%, and 8.70%, respectively. The majority of patients were treated with either 250 or 500 mg dose and interestingly, both group reported similar adverse events. We analyzed the incidence of adverse events in the first-, second-, third-line and beyond. The probability of adverse events in these subgroups was 93.83%, 90.49%, 87.86%, and 87.23%, respectively, and serious adverse events (≥ grade 3) occurred in 33.04%, 22.88%, 18.93%, and 14.89% of the patients, respectively (Table 3).

In the efficacy subgroup analysis, the ORRs of the first-, second-, third-line and beyond, were 14.85%, 10.08%, 8.50%, and 4.76%, respectively, and the differences were statistically significant. The DCRs was 80.20%, 83.19%, 81.38%, and 90.48% for first-, second-, third-line and beyond, respectively, and the differences were not statistically significant (Table 4). The median PFS of first-, second-, third-, and higher-line treatment was 7.00, 5.59, 4.90, and 5.68 months, respectively, and the difference was statistically significant. The median OS of first-, second-, third-, and higher-line treatment was 16.56, 11.50, 10.09, and 7.29 months, respectively, and the difference was statistically significant (Table 5).

Among all patients, 12 patients were treated with apatinib combined with programmed cell death protein 1 (PD-1) antibodies, and 349 patients were treated with apatinib combined with Teysuno (S-1) (33 patients could not be evaluated by imaging). There was no significant difference in PFS and OS between the two groups, which may be due to the small sample size of the PD-1 antibodies group. However, this requires further investigation with a larger sample size.

Discussion

This prospective study evaluated the efficacy and tolerability of rucaparib in patients with gastric cancer treated in a real-world setting. The use of Apatinib in real-life, either in the first, second, third and beyond treatment showed a favourable benefit-risk profile outside clinical trials in Henan China. The concept of a real-world study (RWS) originates from practical clinical research trials. It represented an early stage of pharmacoepidemiology and was first proposed by Williamson and Barrett in 1966 (9). The first published RWS was conducted by Kaplan et al. in 1993 on the efficacy evaluation of ramipril (10). The Cures Act of 2016 uses real-world evidence to approve new indications that meet post-marketing research requirements. Moreover, the US Food and Drug Administration (FDA) published an article in the New England Journal of Medicine titled “Real World Evidence - What is it and What does it tell us?” (11). Therefore, real-world evidence is critical for decision-making in clinical practice (12,13).

In this real-world study of apatinib in the treatment of gastric cancer, 943 patients were included in this analysis. The median PFS of the included patients was 5.65 months (5.22–6.05 months) compared to 2.8 months in previous phase III trial. Median overall survival in our analysis was 11.47 months (10.41–12.52 months) compared to 7.6 months in previous phase Ⅲ trial. In addition, the clinical study of apatinib combined with docetaxel in advanced gastric cancer carried out by Yang’s team showed a median PFS of 4.5 months (14). In contrast, Wang et al. reported a median PFS of 4.2 months and a median OS of 7.13 months (15). Therefore, compared with previous clinical studies (14,15), apatinib seems to have better efficacy and consistent safety results. However, interpretation from our study may be challenging due to the heterogeneity of the patient population, for that any comparison or conclusion drawn from these data should be interpreted with caution especially that in china, medical workers have greater flexibility in adjusting doses and frequency of administration as well as using different combination treatments in comparison to randomized clinical trials.

In addition, the data showed that the combination of apatinib and other therapies had higher ORRs and DCRs as well as longer median PFS and median OS than apatinib alone, and the differences were statistically significant. This suggests combining apatinib and other therapies may be more beneficial than apatinib monotherapy and possibly should be used at an earlier stage of the disease. However, as mentioned before, caution should be exercised when interpreting this data given the different variable and the retrospective nature of the data collected.

The overall safety profile of Apatinib in this real-life setting was acceptable and consistent with previously reported data. No new safety signals were identified (16-18). Interestingly, we observed a decrease in the incidence of adverse reactions in second and higher-line treatments compared with first-line treatment. This may be related to more aggressive symptoms control and the use of apatinib as a single agent in later-line therapy. However, this still needs in-depth observation and analysis in the follow-up study. Althought radiological images were not centrally reviewed and this may have influenced the response rate and PFS, in our study the median OS of patient treated with apatinib alone or in combination compared favourably with the median OS of those treated within the registrative TAGS trial, in which less than 15% of oriental patient were enrolled (19).

Conclusions

This study represents real-world evidence of patients treated with apatinib outside clinical trials in Henan, china. Efficacy results of apatinib, even in heavily pre-treated patients, are similar and in some cases better to those from pivotal clinical trials. The safety profile of apatinib in a real-life setting is manageable and predictable. In addition, our results suggested that, in the real world, the combination of apatinib with other therapies could provide more significant benefits. In addition, a lower initial dose was found to provide benefits. These results need to be confirmed in randomized trials. Even with more aggressive management of side effects in the real world, adverse events remain relatively high, which may be related to the poor performance status in patients in the real world. With the rapid development of immunotherapy, a combination of targeted therapy and immune check point inhibitors more common. At the time of this study, immune checkpoint inhibitors were not commonly used in the treatment of gastric cancer for the lack of data and the cost. The number of patients in this study with immune check point inhibitors was small, which could not reflect the real-world situation. Our team will focus on the effectiveness and safety of apatinib combined with immunotherapy in the real world in the follow-up study.

Acknowledgments

We thank all of the gastric cancer patients and the group members who participated in this research. The authors also appreciate the academic support from the AME Gastric Cancer Collaborative Group. The abstract of this study was accepted for Poster presentation by ASCO GI in 2021 (Abstract 32238).

Funding: This work was supported by grants from the National Natural Science Fund Youth Fund of China (No. 82003041), the Joint Funds of the National Natural Science Foundation of China (No. U2004132), the Key Scientific and Technological Projects in Henan Province (No. 202102310111), and the Project of Tackling Problems in Medical Science and Technology of Henan Province (No. LHGJ20190631).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-22-5995/rc

Data Sharing Statement: Available at https://atm.amegroups.com/article/view/10.21037/atm-22-5995/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5995/coif). The authors have no conflicts of interest to declare.

EthicaL Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Ethics Committee of Henan Cancer Hospital (No. 2018012). All participating institutions were informed and agreed the study. All patients provided written informed consent before enrollment.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: A. Kassem)