Lilly’s Cyramza (ingredient: ramucirumab), an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2), became the first second-line treatment for patients with metastatic or advanced gastric cancer. Before the arrival of Cyramza, the disease had to be treated only with chemotherapy.

In Korea, Lilly obtained regulatory approval for Cyramza in April 2015 and health insurance benefits in May 2018. The drug is used in combination with paclitaxel as the standard secondary therapy for local patients with metastatic or advanced gastric cancer.

Korea Biomedical Review recently sat down with Professor Kang Seok-yun at the Department of Hematology-Oncology of Ajou University Hospital to learn the status of the local treatment for metastatic or advanced gastric cancer and the clinical implication of Cyramza as the standard second-line therapy.

Professor Kang Seok-yun at the Department of Hematology-Oncology of Ajou University Hospital speaks during an interview with Korea Biomedical Review.

Question: What kind of characteristics do you see in Korean patients with metastatic or advanced gastric cancer?

Answer: Compared to early-stage stomach cancer, metastatic or advanced gastric cancer has a poor prognosis. When the cancer is localized, the five-year relative survival rate is 96.7 percent. But in the local metastasis stage, the survival rate falls to 61.5 percent, and in the remote metastasis, it plummets to 5.6 percent. The average survival is seven to 11 months, and only 10 percent of the patients survive longer than two years. With the advanced cancer detection system in Korea, an increasing number of patients discover stomach cancer early and the survival rate is gradually going up. But, to achieve better treatment results, it is important to treat metastatic or advanced gastric cancer.

Q: How do you treat metastatic or advanced gastric cancer?

A: We can’t expect to have a great result with local surgery for metastatic or advanced gastric cancer. Instead, we need a systemic treatment that can kill cancer cells spread throughout the body. So, we use chemotherapy either through an injection or oral medicine. If the patient's systemic performance is well, we use a combo of chemotherapies as the primary treatment. We usually combine fluoropyrimidines such as S-1, capecitabine, and 5-FU with platinum-based drugs such as cisplatin and oxaliplatin. If the patient tests positive for HER2, the standard treatment is to use a three-drug therapy, adding trastuzumab to the combination of the two chemotherapies mentioned earlier. For HER2 negative patients, we use only the chemotherapy combo.

Q: How do you treat patients who failed the first-line therapy or who relapsed?

A: In patients with advanced gastric cancer, the response rate after the first-line chemotherapy is reported to be less than 50 percent. In the West, only 20-50 percent of patients receive secondary treatment. In Korea, 70-80 percent receive second-line therapy. When we consider a secondary treatment, we look at the patient's systemic condition, age, accompanying diseases, the type of anticancer drug used in the primary therapy and response, and disease progression.

Just a few years ago, physicians had different opinions on the therapeutic effect of second-line anticancer drugs. But now, with medical advancement, more patients receive secondary treatment with safe and effective therapies. After trastuzumab, ramucirumab arrived in the market as another targeted therapy. Recently, an immune checkpoint inhibitor has emerged, too.

Among them, the combo therapy of ramucirumab plus paclitaxel offers the best treatment results, and these are recommended as the standard treatment in the recently revised domestic treatment guidelines. In the second-line treatment of patients with locally advanced, unresectable or metastatic gastric cancer, whose systemic performance and major organ functions are preserved, physicians recommend the ramucirumab-paclitaxel combo first.

In the RAINBOW study, the ramucirumab in combination with paclitaxel reduced the death risk by 19.3 percent, compared to paclitaxel alone. The combo treatment group’s median of overall survival was 9.6 months, meaningfully longer than 7.4 months in the paclitaxel-alone group. The progression-free survival of the combo group was 4.4 months, longer than 2.9 months of the paclitaxel-alone group, and the combo therapy lowered the risk of disease progression and death risk by 36.5 percent.

Also, the patients treated with the ramucirumab-paclitaxel therapy maintained the ECOG (Eastern Cooperative Oncology Group) systemic performance longer, and kept the quality of life better, compared to those with the paclitaxel alone.

It is very encouraging and significant for patients that the combo therapy did not worsen adverse reactions and gave 2.2 months of survival benefit.

Q: The combo treatment extended the average survival by about 2.2 months only. Can you say that the result is impressive?

A: Unlike breast cancer where therapies can extend survival by about five to 10 years, it is difficult to expect a significant improvement in survival with the secondary therapy in gastric cancer. Although extending the overall survival by 2.2 months may seem unsatisfactory, it is well worth using it, given the time when the patient struggles with side effects or complications during survival. Twenty years ago, if a person was diagnosed with stage 4 gastric cancer, it was not easy to survive for more than six months. Many died without even getting treatment properly because there was no treatment. Now, such patients can survive for one and a half years to two years.

Q: The ramucirumab-paclitaxel combo therapy is adding a targeted therapy to chemotherapy. Is there any toxicity concern?

A: As ramucirumab targets VEGFR2, the toxicity is mild compared to the combined therapies of other anticancer drugs. Targeted therapy aims to minimize side effects while promoting efficacy. Ramucirumab is a good treatment option because it can offer improved treatment effect without significantly increasing fatigue and hair loss, which are the adverse reactions of general anticancer drugs.

Q: Are there any remaining unmet medical needs in metastatic or advanced gastric cancer treatment?

A: There should be more therapies to extend survival. In lung cancer and breast cancer, there are many treatments and responses are good. So, even if a patient has a metastasis, many patients live for a long time. But in gastric cancer, even with the primary and secondary therapies, patients live for about one and a half years only. To prolong survival, researchers have to find the “unknown target” of targeted therapy.

If we use the combo treatment for a patient with poor gastric function or without a stomach due to recurrence after surgery, the patient often suffers a lot due to cytotoxicity. So, we need to develop a treatment that can minimize side effects to improve patients’ quality of life.

kym@docdocdoc.co.kr

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