For decades, platinum-based chemotherapy has been the gold standard for treating locally advanced or metastatic urothelial cancer. However, the advent of antibody-drug conjugates (ADCs) has changed the treatment of urothelial cancer.

In addition to providing a new option as a last resort to urothelial carcinoma patients whose cancer has progressed despite both platinum-based chemotherapy and immuno-oncology, ADCs have recently demonstrated therapeutic outcomes that outperform platinum-based chemotherapy in combination with immuno-oncology in first-line treatment, suggesting the possibility of a new standard treatment.

Padcev (enfortumumab vedotin), introduced by Astellas Korea this past March, is that treatment.

Padcep is the first ADC introduced for urothelial cancer treatment in Korea, winning approval for treating patients with locally advanced or metastatic urothelial cancer who have received prior treatment with PD-1 or PD-L1 inhibitors and platinum-based chemotherapy agents.

Currently, it is the only new drug option available for patients who have received both platinum-based chemotherapy and immuno-oncology. Given the unmet patient demand, Astellas immediately began applying for insurance coverage, which is considered by the Health Insurance Review and Assessment Service's (HIRA) Cancer Disease Review Committee.

Against this backdrop, Korea Biomedical Review met with Dr. Kim In-ho, a professor of oncology at the Catholic University of Korea Seoul St. Mary's Hospital, who has been treating patients with urothelial carcinoma, about the innovative value of Padcev in the treatment paradigm for urothelial carcinoma, and how it can be applied and improved in the Korean treatment environment.

Question: Despite remarkable advances in cancer treatment, platinum-based chemotherapy is still the standard of care for urothelial cancer. Why?

Answer: Before the advent of immuno-oncology, other cancers were heavily studied in clinical trials for new drugs, but urothelial cancer was not. There are many reasons for this, but urothelial carcinoma is the 12th most prevalent cancer in Korea and the 10th most common cancer in terms of incidence, accounting for about 2-3 percent of all cancers. Hence, the number of patients is small. Therefore, clinical studies show a wide gap with other cancers.

Recently, immuno-oncology drugs have shown good results in treating urothelial cancer, and several studies have been conducted on combining chemotherapy and immuno-oncology drugs in the first-line treatment. However, most results were the same, and some studies failed. Therefore, platinum-based chemotherapy is still used as a standard therapy, and immuno-oncology drugs are used for the next stage.

Q: Padcev was recently approved in Korea to be administered as a monotherapy in patients with advanced cancer who previously used platinum-based chemotherapy and immuno-oncology.

A: That was because we had very good results in the EV-301 study. The response rate was 41.3 percent for Padcev monotherapy vs. 18.6 percent for the control chemotherapy. Moreover, the response rate for Padcev was the same from phase 1 to phase 3 studies. Normally, when a drug shows good results in Phase 1 and a 50 percent response rate in Phase 2, it is considered very encouraging, but eventually, the response rate drops to 30-40 percent in Phase 3.

However, Padcev showed a response rate of 42.7 percent in EV-101, a Phase 1 study, 44.0 percent in Cohort 1 of EV-201 in Phase 2, and 41.3 percent in EV-301 in Phase 3. In addition, the results of the UNITE study, a real-world data (RWD) study in the United States, showed a consistent response rate of 52 percent, so we can say it is a very effective drug.

In addition, the median overall survival (mOS), the primary endpoint in the EV-301 study, was 12.91 months in the Padcev monotherapy arm and 8.94 months in the chemotherapy arm, showing a 30 percent reduction in the risk of death in the Padcev arm compared to chemotherapy. This is a very good result, even if the survival time is not very long, because it is used in patients who have failed platinum-based chemotherapy and immune checkpoint inhibitors.

Q: What is the ideal treatment strategy for urothelial carcinoma after introducing Padcev?

A: There are two strategies, but the context is the same. In patients whose cancer has progressed after first-line platinum-based chemotherapy, the immuno-oncology drug pembrolizumab is used as a second-line treatment. Then, Padcev is used as a third-line treatment in case of progression. In patients who have achieved a complete response (CR), partial response (PR), or stable disease (SD) after first-line platinum-based chemotherapy, the immuno-oncology drug avelumab is used as maintenance therapy. Then, Padcev is used as a second-line treatment in case of progression.

We don't know if it's better to start with Padcev immediately after immuno-oncology or do so after using paclitaxel in patients whose cancer has progressed. However, assuming cost is not a consideration, using Padcev first would be the ideal trial.

The patient's quality of life should also be considered in favoring Padcev. I had a patient who had very severe breathing problems due to lung metastases, and his shortness of breath improved significantly after using Padcev. Another patient had severe leg swelling due to lymph node metastases, and he was uncomfortable every time he walked into the clinic, but after using Padcev, the swelling improved, and he could walk more easily. Of course, there are side effects of Padcev. However, patients with recurrence or metastasis are already in a very bad condition at treatment, so managing the side effects is important. In the end, when the cancer gets better, the symptoms improve, and the patient's quality of life improves.

Q: At the recent European Society for Medical Oncology Annual Meeting (ESMO 2023), the EV-302 study comparing the combination of Padcev + pembrolizumab to platinum-based chemotherapy in the first-line treatment of urothelial carcinoma received a standing ovation.

A: The results of the EV-302 study were notable because they showed comparable effectiveness and survival to platinum-based chemotherapy and "overwhelmingly" superior results. In urothelial cancer, no other treatment strategy has surpassed the effectiveness of platinum-based chemotherapy in the last 40 years. In the EV-302 study, the combination of Padcev + pembrolizumab nearly doubled survival compared to platinum-based chemotherapy.

Of course, it remains to be seen how many patients will be able to benefit from the Padcev + pembrolizumab combination, even if it is approved in the U.S. unless the price issue is resolved. Nevertheless, in first-line treatment, prolonging survival as long as possible is most important, and we should also consider the results of the EV-302 study, which nearly doubled survival over the current standard of care.

Q: If so, will we be able to completely exclude platinum-based chemotherapy from the standard of care for urothelial cancer at some point in the future?

A: We don’t know. It was the EV-302 study that excluded platinum-based chemotherapy for the first time. However, platinum-based chemotherapy will remain an important option for years to come. It's been around for so long that there's still a patient group that needs it and a patient group that responds well to it. Immuno-oncology has gained traction in the last decade, but in terms of response rate, it's only 10-20 percent when used alone. I'm very encouraged by the newer agents, but there are still many cancers where chemotherapy is much more beneficial, so I don't think we can completely rule them out for the time being.

Q: The government is considering reimbursing Padcev. How do you expect this to proceed, as reimbursement reviews for ADCs have tended to be bumpy lately due to cost concerns?

A: Urothelial cancer has a shorter life expectancy than other cancers. It is a very severe and urgent cancer with a life expectancy of only six months to one year at the third-line treatment. It is also important to note that there are no effective alternatives to Padcev in urothelial cancer. There are some alternatives for other cancers, even if they are not covered. However, there are no alternatives to Padcev.

The available treatments in Padcev's position are either paclitaxel, Pemetrexed, or platinum-based chemotherapy, which have low response rates of 10-15 percent. So, there is no alternative to Padcev, which has a response rate of over 40 percent. The disease is severe, but the lack of alternatives makes Padcev’s use even more urgent.

In the past, if a patient's cancer progressed after using avelumab as first-line maintenance or pembrolizumab as second-line treatment, there was nothing to talk about. There are treatment options, but the cost prevents patients from accessing them. As a physician treating these patients, it's very frustrating. It would greatly help patients if the reimbursement issue were resolved.