Early-stage gastric cancer can be almost cured, but it is still difficult to treat advanced, relapsed, or metastatic gastric cancer.

Patients with metastatic or advanced stomach cancer receive chemotherapy because surgery does not bring a great effect. However, new anticancer drugs, including targeted therapy, enabled personalized treatment recently.

The Korean Cancer Study Group is accumulating evidence for the optimal treatment option through a large-scale retrospective study to confirm the efficacy and safety of Cyramza (ingredient: ramucirumab) in real-world data of Korean patients who recently had been treated with the drug.

Korea Biomedical Review sat down with KCSG President Zang Dae-young, a professor at the Hematology-Oncology Department of Hallym University Sacred Heart Hospital, to learn about the latest findings in the treatment of metastatic or advanced gastric cancer and the implication of the real-world study results.

Question: What is the current status of Korean patients with metastatic or advanced gastric cancer?

Answer: About 70 percent of gastric cancer patients in Korea are diagnosed with advanced gastric cancer, and the disease can relapse during a five-year follow-up after radical dissection. Among the total patients with relapsed gastric cancer, 50 percent had recurrence within two years after surgery, 70 percent within three years, and 90 percent within five years.

Metastatic or advanced gastric cancer patients have a poor prognosis compared to those with early-stage gastric cancer. In the local stage, the five-year relative survival rate is 96.7 percent. But it drops sharply to 61.5 percent in the local metastasis stage and 5.6 percent in the distant metastasis stage. The median survival is seven to 11 months, and less than 10 percent of patients survive more than two years.

Q: The KCSG recently released the real-world outcomes of ramucirumab in patients with gastric cancer in Korea. What motivated the society to conduct this study?

A: Researchers compare the treatment group with the control group in a randomized phase 3 study required for marketing approval and reimbursement. They select patients in relatively good physical condition, prescribe the drug, and check whether the effect is good in the same homogeneous group.

But it is not known whether the efficacy and safety shown in the randomized trial will be consistent in real clinical settings.

So, patients, doctors, and the government are paying much attention to real-world data studies. If the effect is not significant, the government needs policy adjustment to consider the drug’s cost-effectiveness.

The KCSG conducted a nationwide retrospective study on whether the ramucirumab plus paclitaxel combination therapy, which became reimbursable in metastatic gastric cancer in May 2018, was effective in a real-world setting.

In a randomized RAINBOW trial on 665 patients, the ramucirumab plus paclitaxel therapy demonstrated the median overall survival at 9.6 months, reducing the risk of death by 19.3 percent compared to 7.4 months median overall survival in the paclitaxel monotherapy group.

Q: Can you elaborate on the study process and the results?

A: The study was the largest study in Korea that analyzed data of over 1,000 patients who received second-line ramucirumab plus paclitaxel. Also, it was the world’s first study where meaningful outcomes were obtained through statistical and epidemiologic verification on patients with the disease across the nation.

Oncologists investigated all the medical records of gastric cancer patients in Korea who were treated with ramucirumab+paclitaxel from May 2018 to December 2018, and 92 medical institutions screened 1,460 people.

We excluded very small clinics with three or fewer prescriptions in one year, hospitals with no IRB (institutional review board) or non-medical research personnel, and patients who received prescriptions before insurance coverage.

Finally, we analyzed data from 1,063 patients who met the criteria.

We found that the median progression-free survival was 4.03 months, and the median overall survival was 10.3 months. In addition, the objective response rate and disease control rate were 15.1 percent and 57.7 percent, respectively.

We had expected that the median overall survival could be shorter than that of the RAINBOW study, but the actual data was over 10 months, longer than 9.6 months shown in RAINBOW. This is very meaningful because the data are second-line treatment outcomes of nearly all Korean patients.

Q: How was the safety of ramucirumab+paclitaxel in the real-world study?

A: The real-world data study included many patients who had poor Eastern Cooperative Oncology Group (ECOG) performance scores. However, the combo therapy caused low non-hematologic toxicity such as anorexia, nausea, vomiting, asthenia, stomatitis, and diarrhea.

Unlike randomized clinical trials that strictly check for adverse reactions, doctors often omitted reports of mild adverse events because patients did not remember them. This is why we had expected that serious side effects would be similar to those shown in the randomized trial. Instead, as we expected, serious side effects were at low levels, just like in the RAINBOW study.

Hematologic toxicity was similar between the real-world data study and the RAINBOW trial.

Q: What is the significance of this real-world study?

A: The study targeted all the patients who received the combo in Korea. It even included data from a small hospital that treats five patients with advanced gastric cancer a year. If we had looked into a few patients, we would have had a selection bias. But Korea provides universal health insurance. So, we could find all the patients who received the reimbursed combo therapy.

It is meaningful not only for doctors but patients that the ramucirumb+paclitaxel combo therapy was effective in real patient care, rather than in a clinical trial where patient selection and research environment are well controlled.

There was a pronounced difference between patients in a clinical trial and those in real clinical settings who were mostly weak and aged.

However, there was no significant difference in the effect and safety profile in this real-world study compared to the randomized RAINBOW trial. This means that we confirmed the clinical value of ramucirumab+paclitaxel standard therapy once again.

Also, it is meaningful that the expensive anticancer therapy helped improve treatment results in reality, and the therapy could save socio-economic costs.

Q: Is there anything that should be improved to revitalize real-world studies in Korea?

A: In this study, we had to pass IRBs in all medical institutions, which was the most difficult task for us. Every hospital has a different medical record system, and we had limited access to individual patients’ information at the hospitals. It was a six-month project, and we didn’t have much time, but some hospitals spent three months for IRB approval.

In the future, I hope that if an institution leading the study passes IRB, other hospitals could approve it as a joint study. But, unfortunately, every hospital’s review of clinical study and revision is too much work, which hampers a study's progress.

Another problem is a follow-up loss of patients after hospital visits. For example, suppose a patient moves from one hospital to another. In that case, it is difficult to track the patient’s survival period because each hospital system is different, and it is not easy to access the death data of the National Health Insurance Service.

For a state-run study in the future, I hope that government agencies could share data.