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The immuno-oncology and antibody-drug conjugate (ADC) combination therapy of Keytruda (pembrolizumab) and Padcev (enfortumab vedotin) is changing the treatment paradigm after it won approval as the first-line treatment of urothelial cancer in July last year.
Bladder cancer, the most common form of urothelial carcinoma, is the leading cancer type, with about 520,000 cases diagnosed annually worldwide, ranking 10th in cancer incidence and 13th in deaths, and is a serious disease.
Notably, 10-15 percent of bladder cancers metastasize at the first stage of diagnosis, about 50 percent of muscle-invasive bladder cancers, and the survival rate drops sharply to 14 percent for distant metastases. The disease is three to four times more common in men, and 85 percent of bladder cancer patients in Korea are aged 60 years or older, often facing treatment difficulties due to declining renal function and decreased systemic performance, creating an urgent need for effective treatment alternatives.
The Keytruda-Padcev combination, which emerged in response to this clinical unmet need, has garnered significant attention from the scientific community since its first data presentation in 2023, with nearly 30 months of follow-up data from the phase 3 EV-302/KEYNOTE-A39 study presented at the American Society of Clinical Oncology's Genitourinary Cancers Symposium (ASCO GU 2025) in February.
Results showed that the Keytruda-Padcev combination reduced the risk of death by 49 percent compared to conventional chemotherapy (15.9 months) with a median overall survival (OS) of 33.8 months (HR=0.51, 95 percent CI, 0.43-0.61). It also demonstrated a high objective response rate (ORR) of 67.5 percent, a complete response rate of 30.4 percent, and a duration of response (DOR) of 23.3 months, demonstrating superior efficacy and durability compared to chemotherapy (44.2 percent, 14.5 percent, and 7.0 months, respectively).
Korea Biomedical Review interviewed Professor Beom Seung-hoon of the Department of Medical Oncology at Severance Hospital about his experience in the real-world clinical application of the Keytruda-Padcev combination, the clinical implications of the latest findings, and future strategies for the treatment of urothelial cancer.
During a recent interview with Korea Biomedical Review, Professor Beom Seung-hoon of the Department of Medical Oncology at Severance Hospital stressed the need for expanding reimbursement for Keytruda-Padcev combo therapy for people with urothelial cancer. (Credit: KBR)
During a recent interview with Korea Biomedical Review, Professor Beom Seung-hoon of the Department of Medical Oncology at Severance Hospital stressed the need for expanding reimbursement for Keytruda-Padcev combo therapy for people with urothelial cancer. (Credit: KBR)
Question: Please explain the highlights and implications of the EV-302/KEYNOTE-A39 study results presented at ASCO GU 2025.
Answer: The new analysis includes follow-up data that extends about one year beyond the original data. With a median follow-up of 29.1 months, the Keytruda-Padcev combination reduced the risk of death by 49 percent compared to the current standard of care, chemotherapy. Median overall survival more than doubled to 15.9 months with chemotherapy and 33.8 months with Keytruda-Padcev, a vital finding demonstrating the combination's sustained benefit.
The excellent treatment outcomes seen at the original 17-month follow-up were maintained in the new 30-month data. It is also important to note that patients who achieved a partial response (PR) or complete response (CR) continued to benefit for two years, during which time they survived without further treatment.
Q: What do these findings mean for patients with urothelial cancer?
A: The EV-302/KEYNOTE-A39 study was a large phase 3 trial, and the treatment benefit seen in this large number of patients provides further support for the efficacy and safety of the Keytruda-Padcev combination. In particular, median overall survival more than doubled compared to conventional chemotherapy, and the complete response rate increased from 14-15 percent to 30 percent. The median duration of response also increased from seven months to two years, further supporting the powerful effectiveness of the combination.
Five years of complete remission is typically associated with a higher likelihood of cure in cancer treatment, and these data significantly boost that expectation. The Keytruda-Padcev combination can be summarized as “a treatment that improves survival by nearly three years in patients with urothelial carcinoma with less than a year to live.”
Q: How does the safety of the Keytruda-Padcev combination compare to conventional chemotherapy, and how are adverse events managed?
A: There were no additional new adverse events in this presentation compared to the 2023 data, and there was no significant change in the frequency of grade 3 or higher serious adverse events. The rate of grade 3 or higher serious adverse events in the Keytruda-Padcev combination arm was about 57 percent, which is lower than that of conventional chemotherapy (70 percent).
However, adverse events are different due to the different mechanisms of action. Certain side effects, such as neurotoxicity, dermatologic toxicity, blood glucose elevation, and interstitial pneumonia, can occur and need to be well understood and closely monitored by healthcare providers. The management of these adverse events is shared at meetings and conferences, and the U.S. and European guidelines outline what to do if they occur. In the Keytruda-Padcev combination, Keytruda is dosed every three weeks, and Padcev is dosed on days 1 and 8 of a 21-day cycle, so patients are initially seen weekly and closely monitored for unexpected adverse events.
Q: How many adverse events have resulted in the discontinuation of the Keytruda-Padcev combination?
A: While not specifically mentioned in the ASCO GU 2025 presentation, a 2023 NEJM (New England Journal of Medicine) issue reported that about 35 percent of patients receiving the Keytruda-Padcev combination discontinued due to treatment-related adverse events. However, there was no difference in patient quality of life compared to conventional treatment, and adverse events were considered manageable.
Q: What is the Korean and international level of recommendation for the Keytruda-Padcev combination?
A: It is currently recommended as a Category 1 Preferred regimen in the U.S. NCCN (National Comprehensive Cancer Network) and is recommended at the same level in the European Society of Medical Oncology (ESMO) guidelines. In Korea, the NCCN and ESMO guidelines are followed.
Q: We want to know about the Korean patient experience with the Keytruda-Padcev combination.
A: One patient in the EV-302/KEYNOTE-A39 trial was a 67-year-old man who presented with recurrent ureteral cancer. At the time, he had multiple lymph node metastases and was considered incurable, but after treatment with Keytruda-Padcev, he has been in complete remission for three years and is doing well. During treatment, he developed interstitial pneumonia as a drug-related adverse event, which was detected early and treated appropriately.
Q: What goes into prescribing the Keytruda-Padcev combination in practice, and how does it differ for patients compared to conventional treatment?
A: The schedule is similar to conventional chemotherapy, so prescribing it has no significant challenges. It is more comfortable for patients because it takes less time to administer than conventional treatments and does not require additional fluid therapy to preserve kidney function. In addition, the time spent in the hospital for dosing is reduced, likely to improve overall convenience. In this respect, the Keytruda-Padcev combination may be less burdensome for patients than conventional therapy.
Q: Which patients are eligible for the Keytruda-Padcev combination?
A: A significant proportion of patients with urothelial carcinoma are elderly patients with declining renal function and comorbidities. Cisplatin, a conventional cytotoxic anticancer drug, is limited to patients with a certain level of renal function. This leaves about 30-40 percent of patients ineligible for cisplatin. Carboplatin is the next best option, but it is difficult to administer to patients with further declining renal function. These patients have traditionally been considered for immuno-oncology monotherapy, with limited response rates of around 20 percent.
In contrast, the Keytruda-Padcev combination is not limited by renal function and can be applied to a broader patient population, making it an effective alternative for difficult-to-treat patients. In addition, Korean patients participated in the EV-302/KEYNOTE-A39 trial, and the same efficacy and safety were confirmed as in the global trial, so Korean patients are expected to benefit from the treatment. However, the current lack of reimbursement is a significant challenge that needs to be addressed.
The principle is to prioritize the use of therapies that are effective in first-line treatment and have a high response rate. While there may be other agent-specific adverse events compared to traditional cytotoxic anticancer drugs, we believe that the Keytruda-Padcev combination should be a priority based on the principles of chemotherapy to improve initial response rates and help patients stay healthy for longer.
Q: The strategy of using Padcev monotherapy after avelumab maintenance therapy is sometimes considered. What are the characteristics of this approach, and how does it differ from the Keytruda-Padcev combination?
A: One current treatment strategy for urothelial carcinoma is to use a cytotoxic agent in first-line therapy, followed by avelumab maintenance if a response is maintained, and then follow-up with other agents, including Padcev, if cancer progresses.
While it is covered for first- and second-line treatment, the only proven follow-up treatment, Padcev, is not covered for third-line treatment, making it difficult to use. In terms of effectiveness, the response rate is about 40 percent, and the duration of treatment is only about six months on average. In addition, third-line treatment requires that the response to first and second-line treatment is maintained, side effects are tolerated, and health status is maintained. However, many patients do not have the opportunity to receive a third-line treatment due to cancer progression, side effects, and other reasons.
Unique adverse events may also occur when Padcev is administered alone.
Therefore, patients are expected to benefit more from the combination of Padcev with Keytruda in the early stages than as a second-line treatment.
Q: How will urothelial carcinoma treatment evolve, and what studies should we watch for with Keytruda-Padcev?
A: The urothelial cancer treatment landscape continues to evolve. Existing immuno-oncology agents have proven their effectiveness, new targeted agents targeting FGFR mutations have been approved, and ADC-based therapies continue to be developed. With these advances, new treatment options are likely to emerge, and the outlook for treatment remains positive.
In particular, the Keytruda-Padcev combination is effective regardless of clinical characteristics. Still, advances in genomic analysis are helping to predict whether it will be more effective in certain patient populations. Furthermore, if there is evidence that certain adverse events can be predicted or detected early enough to address them proactively, it will allow for more precise personalization of treatment in the clinic.
Q: What efforts are needed to expand patient access to the Keytruda-Padcev combination?
A: The current lack of reimbursement, which limits patient access to treatment, is a significant challenge that needs to be addressed. The relevant academic societies are actively voicing their opinions, and efforts are needed from the government, academic societies, and pharmaceutical companies. From the patient's point of view, alleviating the cost burden is a key factor in expanding access to treatment, so we all need to work together. It will take a concerted effort, including efforts at the societal level and clinicians actively voicing their opinions. It's a matter of prioritization, but when it comes to metastatic urothelial cancer treatment alone, reimbursement is a must.
Q: What is your message to people with urothelial cancer?
A: Cancer treatment can vary in outcome depending on the patient's condition, willingness to treat, and management of side effects. Good treatments are being developed, and the clinic has many positive outcomes, so stay hopeful. Cancer is still not completely conquered, but good treatments have been developed recently, and the clinic has had many positive results. Therefore, I encourage you to be hopeful and work together toward the best possible treatment.
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Kim Chan-hyuk kch@docdocdoc.co.kr
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