Urothelial carcinoma, which is a type of bladder cancer, accounts for 90% of all bladder cancers and is considered a typical cancer type in the field.

However, unlike other cancers like lung and breast cancer, where the standard of care changes quickly with the introduction of new drugs, UC has remained a barren area for decades, leaving a large unmet need for first-line treatment options. For the past 30 years, platinum-based chemotherapy has remained the first-line standard of care for UC.

# Recently, new drugs, including immuno-oncology drugs and antibody-drug conjugates (ADCs), have been introduced for UC in Korea, shifting the treatment paradigm. However, until the health insurance reimbursement issue is resolved, their active use on-site seems unlikely.

According to the medical and pharmaceutical industries on the 16th, platinum-based chemotherapy using gemcitabine, cisplatin, carboplatin, etc. had been used as a first-line treatment for UC.

However, the median overall survival (OS) was only 12-15 months with their use due to toxicity, with patients often having to take a drug holiday from chemotherapy after 3-4 months of treatment, and disease progressing around 6-9 months after initiation.

However, in the past year or two, the treatment paradigm for UC has been rapidly shifted with global pharmaceutical companies introducing treatments based on clinical research to Korea.

One of the first treatments to receive attention is Merck's immuno-oncology drug Bavencio (avelumab). Bavencio is a fully human monoclonal antibody specific for PD-L1 and has demonstrated prolonged survival as a first-line maintenance therapy for UC. Since August last year, its use as first-line monotherapy has been reimbursed by Korea’s health insurance and is being used in practice.

Bavencio’s efficacy was confirmed through the long-term follow-up Phase III JAVELIN Bladder 100 trial, which involved 700 patients with locally advanced or metastatic urothelial cancer in 29 countries, including Korea, for over 38 months. The trial results showed a median OS of 29.7 months with Bavencio+maintenance therapy. This is over 9 months longer than the 20.5 months found in the maintenance monotherapy arm.

In July this year, the combination of the ADC cancer drug Padcev (enfortumab vedotin, Astellas) and the immuno-oncology drug Keytruda (pembrolizumab, MSD) was approved in Korea, marking another shift in the first-line UC treatment paradigm.

The Phase III EV-302/KEYNOTE-A39 trial, which became the basis of its approval, showed a median OS of 31.5 months in the Padcev+Keytruda arm compared to 16.1 months in the control arm, which was a significant difference. Median progression-free survival (PFS) was 12.5 months in the Padcev+Keytruda arm versus 6.3 months in the control arm

Around the same time the Padcev+Keytruda combination was approved, BMS and Ono Pharmaceutical’s immuno-oncology drug Opdivo (nivolumab) received approval in Korea as the first-line treatment for UC as well.

The approval was based on results from the CheckMate 901 trial, which evaluated Opdivo versus the standard of care gemcitabine+cisplatin (GemCis) in 608 patients with metastatic UC. Results showed that at a median follow-up of 36 months, the primary endpoint, median OS, was 21.7 months with the addition of Opdivo versus 18.9 months in the control arm, resulting in improved treatment outcomes.

The treatment paradigm for UC, which had remained unchanged for 30 years, has changed dramatically in the past 1-2 years after 30 years of unchanged treatment.

Based on the results of the study, Padcev+Keytruda is expected to rise to the forefront among first-line treatment options on-site.

“Based on the efficacy seen in the studies, the Padcev+Keytruda combination would be my first choice,” said In-Keun Park, Professor of Medical Oncology at Asan Medical Center in Seoul. ”The Opdivo+GemCis combination that has been approved at a similar period, has proven to be less effective. Also, we need to consider the availability of the cisplatin option and utilize drugs with caution, so I would consider using the Opdivo+GemCis option for patients with uncontrolled diabetes.”

“The currently reimbursed Bavencio has fewer side effects and proven efficacy, but is indicated for patients who have not progressed after receiving platinum-based chemotherapy as a first-line treatment,” explained Professor Park. ”If Padcev+Keytruda or Opdivo+GemCis becomes a common first-line treatment option, Bavencio may lose more ground.” 

Now that the first-line treatment options for UC have been approved in Korea, attention is now focused on how quickly they will be available on-site.

As Bavencio is covered as a maintenance therapy for first-line urothelial cancer, the industry is eyeing whether the Padcev+Keytruda combination will also be granted reimbursement.

However, the Padcev+Keytruda combination presents a dilemma for pharmaceutical companies. This is because 2 different companies - Astellas and MSD - own the drugs that are included in the combination.

In order for a combination therapy to be reimbursed, both companies must apply for reimbursement and participate in the process for the agenda to be discussed with the government.

However, it is currently difficult for such discussions to take place due to the headquarters policies of global pharmaceutical companies and the possibility that discussions with other pharmaceutical companies may be judged as 'collusion' under domestic and international fair trade laws.

In other words, both pharmaceutical companies must separately apply for reimbursement. If one of the companies is not interested in applying for reimbursement, reimbursement of the combination therapy is effectively off the table.

This is the case for Padcev+Keytruda, and Astellas and MSD are known to be separately reviewing the need for reimbursement. However, the 2 companies are doing so at their discretion, as discussions between them could be regarded as collusion.

As a result, the pharmaceutical industry has recently called for the need to establish regulations in the health insurance reimbursement process to address the combination therapy research being conducted between pharmaceutical companies.

In other words, the industry has pointed out that a system needs to be established so that if one of the combination therapy developers applies for reimbursement, government agencies such as HIRA can notify the other companies so that the other companies can decide whether to participate in the reimbursement application process.

A pharmaceutical industry official said, “If the developers of drugs used as combination therapies are different companies, the Fair Trade Act forbids the companies from discussing insurance reimbursement and insurance prices on their own. It is difficult for the government to proceed with the reimbursement process if one of the drug developers applies for health insurance benefits and the other does not show any willingness for its drug’s reimbursement.”

This is why the industry sees it difficult for combination therapies to be applied reimbursement benefits.

“Even though the number of first-line treatment options for UC has increased, it is difficult to actively utilize them on-site unless the cost issue is resolved,” said a professor of oncology at a tertiary hospital. ”It takes longer for combination therapies to be reimbursed. It may even be impossible if two separate pharmaceutical companies need to receive reimbursement together for one combination therapy regimen.”