“85% of stage 4 stomach cancer patients already have limited treatment options, but the health insurance criteria for immune checkpoint inhibitors are excessively strict, leading many patients to forgo treatment.”
Professor Ra Sun-young of the Yonsei Cancer Center noted on the 28th of last month at Severance Hospital in Seoul, “Even though research has shown that immune checkpoint inhibitors are effective for patients with low PD-L1 expression, they still do not qualify for health insurance coverage.”
PD-L1 is a protein used by cancer cells to disguise themselves as normal cells. Only patients with high PD-L1 combined positive score (CPS) who express PD-L1 on both cancer cells and immune cells can receive health insurance benefits for the latest immune checkpoint inhibitors.
South Korea's annual stomach cancer incidence rate ranks third in the world, following Mongolia and Japan. Stage 1 stomach cancer can be mostly cured through surgery when detected early. Stages 2 and 3 stomach cancer have already metastasized to lymph nodes, requiring chemotherapy after surgery.
In contrast, stage 4 stomach cancer is already in a state of metastasis to other organs, making surgery challenging, and only drug treatment is possible. Their five-year survival rate is 7.5%, meaning even 1 out of 10 does not survive. Complete recovery is out of reach, and extending the period of survival is the best they can hope for.
Professor Ra stated, “With the introduction of targeted therapies and immune checkpoint inhibitors, a treatment path has opened for stage 4 stomach cancer patients,” adding, “We need to change the insurance criteria to give them hope.”
In the past, the only treatment available for stage 4 stomach cancer patients was cytotoxic chemotherapy. This type of chemotherapy was usually administered in combinations of two or three to enhance treatment efficacy, but it also carried significant side effects, killing normal cells.
Recently, new therapies like trastuzumab (Herceptin) and immune checkpoint inhibitors such as pembrolizumab (Keytruda) and nivolumab (Opdivo) have emerged, evolving into combinations with cytotoxic chemotherapy.
Targeted therapies selectively attack only cancer cells that have specific proteins. They minimally affect normal cells, leading to fewer side effects; however, only patients with protein targets on their cancer cells can benefit from these treatments. In contrast, immune checkpoint inhibitors work by strengthening the body’s immune system to eliminate cancer cells and can be used for a relatively broad range of patients.
However, for stage 4 stomach cancer patients, the available medications vary based on the expression of the human epidermal growth factor receptor 2 (HER2) protein, which is a major cause of the disease. HER2-positive patients, who account for 15-20% of stage 4 stomach cancer patients, can use a combination of targeted therapies and immune checkpoint inhibitors. However, the majority, or 85%, who are HER2-negative, cannot use targeted therapies.
Professor Ra said, “Targeted therapies are designed to attach to proteins that are overexpressed on the surface of cancer cells to inhibit their growth, but in the case of HER2-negative patients, there is either low or no HER2 protein,” noting, “Since there are no targets for the drug to attach to and attack, the effect of targeted therapies is nonexistent.”
Ultimately, the only alternative for HER2-negative stage 4 patients is the combination of immune checkpoint inhibitors. However, among these patients, only those with PD-L1 targets can use immune checkpoint inhibitors. Another screening process is necessary.
Professor Ra stated, “HER2-negative patients tend to have better efficacy with immune checkpoint inhibitors if they have higher levels of PD-L1 protein,” adding, “All HER2-negative patients undergo PD-L1 testing for screening purposes before receiving immune checkpoint inhibitor prescriptions.”
The criteria for health insurance support based on PD-L1 levels are due to the same reasons. It is not possible to support high-cost medications for patients who do not respond effectively. Currently, the cost of combined therapy with immune checkpoint inhibitors for stage 4 HER2-negative patients amounts to 5.5 to 6.6 million won every three weeks, with a total expense of 200 million won for the standard treatment duration of two years.
The Health Insurance Review and Assessment Service applied coverage for the immune checkpoint inhibitor Opdivo in September 2023, and established coverage standards for Keytruda last February, but the coverage is limited to patients with PD-L1 scores of 5 and 10 or higher. The patient group with scores of 1 to 4 cannot receive prescriptions for the only remaining treatment option, the immune checkpoint inhibitor, representing about 40% of the total.
However, clinical trial results involving Professor Ra have demonstrated that immune checkpoint inhibitors were effective across the entire PD-L1 score range from 1 to 10. Professor Ra noted, “Currently, patients with scores below 5 are not covered by health insurance, which causes elderly patients, who do not want to burden their children, to refuse treatment,” emphasizing the need for practical coverage criteria that reflect the realities of clinical practice and patients.
The Korean Gastric Cancer Association recommended in its gastric cancer treatment guidelines released last January that metastatic HER2-negative and positive stomach cancer patients with any detected PD-L1 protein receive immune checkpoint inhibitor combination therapy with Keytruda as the first-line treatment. The medical community recognizes the need for methods to increase patient benefits while not worsening health insurance finances. There may also be realistic options for health insurance and pharmaceutical companies to apply differentiated costs for low-income patients.
Professor Ra's emphasis on practical coverage criteria reflects over 30 years of experience in patient care. She graduated from Yonsei University College of Medicine, receiving both master's and doctoral degrees, and has worked as a specialist at Yonsei Medical Center Cancer Center for over 30 years since 1990. She has been the principal investigator (PI) in over 50 clinical trials of anticancer drugs targeting stomach cancer and various other cancers.
Since June of last year, she has also served as the chairperson of the Korean Cancer Association. She is currently conducting comprehensive research from cancer prevention to early diagnosis, treatments for stages 1 to 4, palliative care, and hospice services. She leads a coalition involving 25 cancer-related associations and is spearheading collaborative research with the National Cancer Center on senior cancer data analysis.
Professor Ra stated, “Stomach cancer has complex biological characteristics and relatively low drug responsiveness, making it difficult for various drugs to be effective. Nonetheless, I hope that many patients in the country can benefit from treatments, given the numerous studies conducted over the years that have led to approvals for usage in stomach cancer.”