‘Imfinzi combo therapy increases survival benefits in proportion to treatment period’

Immuno-oncology drugs have been recognized as a global standard of care for treating advanced biliary tract cancer, notorious for poor prognosis by demonstrating improved survival rates in combination with conventional chemotherapy.

In particular, the combination therapy of Imfinzi (durvalumab) and gemcitabine/cisplatin' (GemCis), the first immuno-oncology drug to be approved for treating biliary tract cancer, has attracted attention for its success, as Professor Oh Do-youn of the Department of Hematology/Oncology at Seoul National University Hospital served as the principal investigator of the approval clinical trial (TOPAZ-1 study).

Recently, the third-year overall survival (OS) data of the TOPAZ-1 study were released, attracting global attention once again. This was the first time that a three-year OS had been evaluated in a large clinical trial of advanced biliary tract cancer patients.

According to data presented at the Cholangiocarcinoma Foundation Conference in Salt Lake City, Utah, on April 18, the Imfinzi combination had a three-year OS of 14.6 percent, more than double that of the control arm (6.9 percent). At a median follow-up of 41.3 months, the Imfinzi combination reduced the risk of death by 26 percent compared to the control arm.

As such, the Imfinzi combination therapy has repeatedly achieved “firsts” in treating biliary tract cancer and has become the first standard of care recommended by leading guidelines. However, since its approval by the Ministry of Food and Drug Safety in November 2022, it has not been covered by insurance, and Korean patients could not benefit from the treatment.

Korea Biomedical Review interviewed Professor Oh to learn about the implications of the recently updated three-year survival results of the TOPAZ-1 study, the clinical value of Imfinzi combination therapy, and the treatment environment for biliary tract cancer patients in Korea.

Question: What are the implications of the recently announced three-year survival results from the TOPAZ-1 study?

Answer: Until now, no large global trials have looked at three-year overall survival (OS) in advanced biliary tract cancer. The prognosis of biliary tract cancer is so poor that long-term survival of three years has not even been discussed. Therefore, the identification of a three-year OS is of significant clinical value.

The Imfinzi combination had a three-year OS of 14.6 percent, more than double the 6.9 percent of the standard of care. Most notably, the mortality risk reduction benefit of the Imfinzi combination increased as treatment continued.

In the initial analysis, the Imfinzi combination was associated with a 20 percent reduction in mortality risk compared to the standard of care, which increased to 24 percent at six-month follow-up and 26 percent at three years, meaning that the clinical benefit was increasingly evident as the data matured over longer follow-up.

Q: Besides Imfinzi, the Keytruda (pembrolizumab) combination was recently approved in Korea for the first-line treatment of advanced biliary tract cancer. We are curious to know if there are any data differences between the two immuno-oncology agents and, if so, why.

A: The Keytruda combination showed a 17 percent reduction in the risk of death compared to the standard of care in the KEYNOTE-966 study, and an additional follow-up analysis showed a 16 percent reduction in the risk of death. In contrast, the Imfinzi combination showed an increasing mortality risk reduction benefit as the trial progressed, with a 26 percent mortality risk reduction at three years.

The exact reasons for this difference are difficult to explain, but it is likely due to differences in the patient's baseline characteristics and the drugs used. We can conclude from both studies that adding immuno-oncology drugs such as Imfinzi and Keytruda improves patient survival compared to traditional cytotoxic chemotherapy alone.

Q: What is the current status of treatment benefits for biliary tract cancer patients in Korea? Since March this year, Imfinzi has been revised to be fully self-paid (100/100), but the companion drug GemCis is covered by insurance (5/100). Has the treatment environment improved?

A: Even if conventional chemotherapy is covered, Imfinzi's drug price is prohibitive, so currently, only patients who can afford the treatment through private insurance or reimbursement programs run by pharmaceutical companies can consider Imfinzi combination therapy.

Q: There is also a view that the government underestimates the benefits of Imfinzi combination therapy based on the median OS in the TOPAZ-1 study when reviewing benefits. What is your opinion on this?

A: In clinical trials with immuno-oncology agents, it is expected to see a "delayed separation" effect, where the effect of adding an immuno-oncology agent to a conventional cytotoxic anticancer agent tends to come on slowly so that the difference in the actual survival curves is not seen until later. Therefore, it is appropriate to interpret the effect of an immuno-oncology agent in terms of how much it reduces the overall risk of death, not just how much it improves median survival.

In a global phase 3 trial, the Imfinzi combination therapy significantly improved the risk of death compared to the control group. Long-term follow-up studies have shown that the mortality risk reduction benefit increases over time. It is hoped that Korean biliary tract cancer patients will be able to receive this benefit through insurance coverage.