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Padcev combo therapy shows excellent effect on Asian patients with urothelial carcinoma. What's next?

The combination of Padcev (enfortumab vedotin) and Keytruda (pembrolizumab) in treating urothelial cell carcinoma showed excellent results in Asian patients, according to a new study.

![Professor Eiji Kikuchi of the Department of Urology at Keio University School of Medicine presents research results during the genitourinary tumors research presentation session at the European Society for Medical Oncology Asia Annual Congress (ESMO Asia 2024) at the Suntec Convention & Exhibition Center in Singapore on Sunday. (KBR photo)](https://cdn.koreabiomed.com/news/photo/202412/25993_27315_4612.jpg)

Professor Eiji Kikuchi of the Department of Urology at Keio University School of Medicine presents research results during the genitourinary tumors research presentation session at the European Society for Medical Oncology Asia Annual Congress (ESMO Asia 2024) at the Suntec Convention & Exhibition Center in Singapore on Sunday. (KBR photo)

Last Saturday, Professor Eiji Kikuchi of the Department of Urology at Keio University School of Medicine presented the results of the Asian sub-analysis of the EV-302 trial at the European Society for Medical Oncology Asia Annual Congress (ESMO Asia 2024) in Singapore. 

The analysis included 176 patients from six countries -- China, Japan, Singapore, Korea, Taiwan, and Thailand.

The EV-302 study, a phase 3 trial evaluating the efficacy and safety of the combination of Padcev-Keytruda in patients with previously untreated locally advanced or metastatic urothelial carcinoma, was also highlighted as a landmark result at ESMO 2023.

In the Asian sub-analysis, the Padcev-Keytruda combination arm demonstrated a 66 percent reduction in the risk of death compared to chemotherapy (HR 0.34; 95 percent CI: 0.18-0.65), consistent with the overall study results of a 53 percent reduction in the risk of death (HR 0.47; 95 percent CI: 0.38-0.58).

At 15.6 months of follow-up, median progression-free survival (mPFS) was 6.3 months in the combination arm vs. 6.3 months in the chemotherapy arm, with consistent improvements in the Asian sub-analysis (HR 0.30; 95 percent CI: 0.19-0.48) and the overall study (HR 0.45; 95 percent CI: 0.38-0.54).

Notably, the objective response rate was 72.2 percent in the combination arm and 35.0 percent in the chemotherapy arm, a difference of 37.2 percentage points. It was 13.9 percentage points greater than the response rate difference in all-patient studies (67.7 percent vs. 44.4 percent, resulting in a gap of 23.3 percentage points). Disease progression rates were also significantly different, with 5.6 percent in the combination arm and 22.5 percent in the chemotherapy arm.

Regarding treatment persistence, 49 percent of patients in the combination arm are still in treatment, with a median duration of nine months (12 cycles) for Padcev and 10.2 months (15.5 cycles) for Keytruda. The main reasons for treatment discontinuation were disease progression (28 percent) and adverse events (14 percent).

Grade 3 or higher treatment-related adverse events (TRAEs) were 64.9 percent in the combination arm and 68.4 percent in the chemotherapy arm. The main adverse events in the combination arm were rash (12 percent), hyperglycemia (10.6 percent), and neuropathy (7.4 percent), while neutropenia (25 percent), anemia (20 percent), and neutropenia (18.4 percent) were the main adverse events in the chemotherapy arm. Some 51 percent of the chemotherapy arm received immune checkpoint inhibitors as maintenance or second-line treatment.

The Asian patient population was characterized by a higher proportion of nonsmokers and upper urinary tract cancers and a lower proportion of liver metastases compared to the overall study population. The frequency of skin reactions and hyperglycemia was slightly higher than in the overall population, and pembrolizumab-related pneumonia was more frequent.

“The results of this sub-analysis are consistent with the overall EV-302 study results and demonstrate the superiority of the Padcev combination as a first-line treatment in the Asian patient population,” Professor Kikuchi said.

On the sidelines of ESMO Asia, Korea Biomedical Review had an interview with Professor Jo Jeong-min of the Department of Hematology-Oncology at Ewha Womans University Mokdong Hospital to learn more about the combination's clinical significance and its application in real-world practice.

“The Padcev combination therapy is a very meaningful treatment option in that it overcomes the limitations of conventional chemotherapy and nearly doubles overall survival (OS),” Professor Jo said.

Here’s a one-in-one interview with Professor Jo.

![Professor Jo Jeong-min](https://cdn.koreabiomed.com/news/photo/202412/25993_27316_4652.jpg)

Professor Jo Jeong-min

**Question: How did the Asian subgroup fare in the EV-302 trial?**

**Answer:** In the EV-302 data presented today, the Asian subgroup had an effect consistent with the overall study results. Response rates were even higher, but this may be due to many factors and is difficult to generalize.

**Q: What are the limitations of chemotherapy, which has been used for 30 years as a first-line treatment for urothelial cell carcinoma?**

**A:** Despite their favorable response rates of around 50 percent, platinum-based chemotherapy regimens, such as cisplatin and carboplatin, have some important limitations. The short duration of response (two to three months) and severe renal and hepatic toxicity make repeat use difficult, especially in older patients. In addition, many patients are unable to tolerate or fail platinum-based regimens early on, limiting treatment options.

**Q: What are the key benefits of the new cancer therapy demonstrated in the EV-302 study?**

**A:** The EV-302 study showed consistent efficacy in all subgroups with liver metastases, decreased renal function, and various histologic variants. Compared to conventional therapies, the duration of response was longer, and the response rate was higher, especially overall survival, which nearly doubled. Albeit somewhat costly, the treatment outperformed any existing agent in terms of efficacy.

**Q: How does the long-term toxicity of the Padcev combination compare to conventional chemotherapy?**

**A:** The toxicity of the Padcev combination is different from that of conventional chemotherapy. Instead of hematologic adverse events, neuropathy, and skin toxicity are the main concerns, especially skin toxicity, which occurs in about 15 percent of patients initially and can be fatal. Glucose control problems may also occur initially, and neuropathy and pulmonary inflammation are concerns with long-term use. However, these side effects can be managed with dose adjustment or temporary discontinuation, and the therapeutic effect tends to be maintained.

**Q: What are the advantages and disadvantages of the Padcev combination compared to the less toxic initial maintenance therapy of avelumab (Bavencio)?**

**A:** Maintenance therapy with avelumab after a highly toxic chemotherapy regimen can significantly improve patients' quality of life but is limited in its applicability. That’s because it is only applicable to a subset of patients who respond to both platinum-based chemotherapy and avelumab and have a long-lasting response. In contrast, the Padcev combination is effective across the entire patient population, including advanced patients, but toxicity management and cost remain a challenge with long-term use.

**Q: What is your assessment of the Padcev combination's significant limitations, namely the cost and limited second-line treatment options?**

**A:** The Padcev combination is limited by its initial use in combination with an immuno-oncology agent, which reduces options beyond platinum-based chemotherapy. However, it is positive that the initial treatment is so effective in controlling disease progression that the number of patients requiring second-line treatment is reduced. This may be a preferable approach to a situation where all patients require follow-up treatment.

**Q: In the absence of biomarkers, what are the criteria for patient selection for the Padcev combination?**

**A:** There are several considerations for selecting patients for the Padcev combination. First, the cost may limit the use of Keytruda in patients with autoimmune disease. In patients with liver metastases, the efficacy of conventional platinum-based chemotherapy or immuno-oncology is limited, and the urgency of treatment should be determined by considering metastatic location, general condition, and histologic type. The EV-302 study demonstrated efficacy in all subgroups and may be considered first if the cost is not an issue, especially in patients expected to resist other therapies.

**Q: Why did Asian patients show better treatment responses but more skin toxicity and hyperglycemia?**

**A:** It is speculated that the current standard dose of 1.25 mg/kg may be too high for Asian patients. In clinical practice, lower doses are often used for cost reasons, and we observed less toxicity in these cases, suggesting a dose-to-toxicity relationship.

**Q: What is the current experience with monotherapy and combination therapy of Padcev and the management of toxicities?**

**A:** Padcev monotherapy has been used in patients who have failed platinum-based chemotherapy and immuno-oncology. The recently approved combination has limited experience but has shown some promise, notably complete remission in three to four of the patients with liver metastases treated with the combination, some of whom would have been unlikely to survive without the agent.

However, skin toxicity is a major challenge, which can present suddenly and progress rapidly, making early detection and response critical. Currently, some institutions manage it with their protocols, and guidelines are being discussed in Europe that require aggressive treatment, even in Grade 3 or less. In Korea, there is a need to establish society-level management standards.

**Q: How do you assess the reimbursement status and clinical need for the Padcev combination?**

**A:** Urothelial cell carcinoma is a highly aggressive disease with limited treatment options other than platinum-based chemotherapy, and the Padcev combination has shown excellent results. However, many patients don’t have access to treatment due to cost, making survival cost-dependent. While reimbursement of the combination is challenging, we hope that rapid reimbursement of at least one of the drugs will improve patient access to treatment.

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