400,000 Patients Don’t Want to Lose Their Bladders: The Rise of Bladder-Preserving Therapies in NMIBC

To live or to live with dignity? For many cancer patients, this is a question that must be answered. This is especially true for bladder cancer patients, particularly those with non-muscle-invasive bladder cancer (NMIBC).

Although surgery can effectively treat patients with NMIBC, the recurrence rate remains an unavoidable issue. For a long time, they have faced a difficult choice: whether or not to remove the bladder.

Most patients may choose to refuse. After all, losing the bladder will significantly decrease their quality of life and might even affect their sense of dignity. However, this choice also means they may have to continue enduring the torment of the disease.

To protect the lives of NMIBC patients and preserve their bladders, more pharmaceutical companies need to get involved. Fortunately, we are welcoming an increasing number of strong participants. This year, two notable guardians for bladder preservation have emerged.

On April 22, Anktiva, the IL-15 superagonist developed by ImmunityBio, received FDA approval for use in combination with Bacillus Calmette-Guérin (BCG) to treat patients with non-muscle invasive bladder cancer (NMIBC) who are unresponsive to BCG, have carcinoma in situ (CIS), with or without papillary tumors.

In less than half a month, on May 3, CG Oncology announced that its investigational oncolytic virus therapy, Cretostimogene, for the treatment of high-risk NMIBC patients who are unresponsive to BCG, achieved positive results in a Phase III clinical trial. The company plans to submit a new drug application to the FDA in the second half of 2025.

With Anktiva in the lead and Cretostimogene striving to catch up, the global battle for bladder cancer treatment is becoming increasingly intense. This trend is set to continue, with China-based companies like RemeGen actively participating.

In the future, who will have the upper hand?

/ 01 / Bladder Defense Battle

Protecting the Bladder: A Topic Definitely Worth Attention from Pharmaceutical Companies

Bladder cancer is the 10th most common cancer globally, with over 614,000 new cases diagnosed worldwide in 2022. Approximately 70% of patients are initially diagnosed with non-muscle-invasive bladder cancer (NMIBC), representing a population of more than 400,000. Based on severity, NMIBC can be divided into carcinoma in situ (CIS) confined to the bladder surface, non-invasive papillary carcinoma (Ta), and tumors invading the lamina propria (T1).

Fortunately, bladder cancer has obvious early symptoms, which makes it easy to detect and treat early. For several decades, the standard therapy for NMIBC has been transurethral resection of bladder tumor (TURBT) plus postoperative adjuvant intravesical BCG instillation.

Unfortunately, bladder tumors are like leeks, cut them and they grow back, sometimes even taller.

TURBT is associated with a high recurrence and progression rate. Research data indicate that even in low-risk NMIBC patients, although the progression rate is very low, the risk of recurrence within 5 years is approximately 40-50%. For high-risk disease, despite an initial response to intravesical BCG in up to 80% of patients, the overall high recurrence or progression rate is about 50%. For T1 disease, especially upon re-resection, the progression rate approaches 80%. In cases unresponsive to initial intravesical therapy, the success rate of secondary bladder-sparing treatment ranges from 20-40%.

Ultimately, for NMIBC patients who are unresponsive to BCG, disease progression will lead to radical cystectomy (RC), which involves the removal of the bladder and surrounding organs. This is not an ideal option. On one hand, frail cancer patients are prone to losing their lives due to issues like infections; data shows that postoperative 90-day mortality and morbidity rates reach 3-6% and 28-64%, respectively. On the other hand, even if they survive, patients must live with a urine bag for life, resulting in a decreased quality of life.

Living is important, but living with dignity is a higher pursuit. This is also one of the reasons why many patients refuse RC and hope for alternative solutions that can preserve the bladder. Based on this unmet clinical need, the FDA pointed out in its 2018 guidelines that the treatment goal for BCG-unresponsive NMIBC patients is to avoid RC.

At this point, the development of drugs for NMIBC is crucial. The birth of any new drug is an extremely difficult process. The pathogenesis and biological characteristics of NMIBC are still unclear, and its significant heterogeneity makes it challenging to identify and validate therapeutic targets. The high recurrence and progression rates demand that new drugs not only effectively control tumors but also reduce the risk of recurrence and progression to muscle-invasive bladder cancer (MIBC).

The road is long and fraught with obstacles. But this has always been the case in the biopharmaceutical industry—where there is market demand, pharmaceutical companies will rush to develop new drugs. Competition drives the emergence of better medicines, offering patients greater hope for curing their diseases.

/ 02 / Tackling Non-Surgical Therapies

2024: A Year of Accelerated Breakthroughs in NMIBC Treatment

As mentioned above, in April, Anktiva, the first IL-15-based immunotherapy launched by ImmunityBio for the treatment of NMIBC, received FDA approval.

IL-15 has broad immunomodulatory activity, promoting the proliferation and activation of CD8+ cytotoxic T cells and NK cells, and is considered one of the most promising targets in cancer immunotherapy.

Natural IL-15 has a short half-life, so the balance between safety and efficacy needs to be considered during drug development. Anktiva is an IL-15 superagonist complex formed by the fusion of a mutated IL-15 with the IL-15 receptor α chain. Compared with natural IL-15, Anktiva demonstrates better pharmacokinetic properties, longer persistence in lymphoid tissues, and enhanced anti-tumor activity, offering patients an alternative option to avoid radical cystectomy (RC).

Of course, Anktiva is not the first non-surgical alternative therapy for NMIBC. At the beginning of 2020, Keytruda (K drug) was approved by the FDA as a monotherapy for high-risk non-muscle-invasive bladder carcinoma in situ (CIS) that is unresponsive to Bacillus Calmette-Guérin (BCG) treatment and where patients are unable or unwilling to undergo surgical treatment. In 2022, Adstiladrin, a gene therapy based on adenovirus, was approved for marketing, providing patients with a new treatment option.

However, Anktiva has potential advantages in terms of efficacy.

Data from the KEYNOTE-057 trial show that for BCG-unresponsive CIS patients, the 3-month complete response (CR) rate with K drug was 41%, with a median duration of response (DoR) of 16.2 months; for Adstiladrin in the same patient population, the 3-month CR rate was 51%, with a DoR of 9.7 months.

The results of the registrational clinical trial QUILT-3.032 for Anktiva showed that, with a follow-up time of 23.9 months, the CR rate was 71% for BCG-unresponsive CIS patients with or without Ta/T1 lesions, and the median DoR was 26.6 months.

Although these trials were not head-to-head comparisons and the data are not fully comparable, a DoR of up to 26.6 months is undoubtedly a significant advantage for Anktiva. The International Bladder Cancer Group (IBCG) sets the standard for a clinically meaningful DoR in the treatment of NMIBC at 24 months, and the target patients for this drug are precisely those who wish to control disease progression and avoid surgery.

In November 2023, updated follow-up data further confirmed the efficacy of Anktiva. The results showed that the CR rate remained at 61%, and the longest DoR has exceeded 47 months, with the possibility of further extension.

Of course, Anktiva is not without competition, as its formidable rival lies ahead.

/ 03 / An Increasing Number of Rising Stars

The contest between Anktiva, K drug, and Adstiladrin remains uncertain, and a new competitor has unexpectedly emerged.

Oncolytic virus therapy has long been highly anticipated in various cancer treatments due to its high selectivity and killing effect on tumor cells. CG Oncology has made a remarkable debut in the field of oncolytic virus treatment for NMIBC.

Since its inception, CG Oncology has been dedicated to developing oncolytic immunotherapies for cancer treatment, with Cretostimogene being its crowning achievement.

Cretostimogene, as an adenovirus oncolytic virus, can specifically recognize tumor cells and replicate within them. While directly lysing tumor cells, it releases tumor antigens and granulocyte-macrophage colony-stimulating factor (GM-CSF) expressed by transgenes, inducing an immune response. This "fighting poison with poison" strategy works in two ways, enabling Cretostimogene to exhibit strong anti-tumor potential.

More directly, according to the latest Phase III clinical data released by CG Oncology, the CR rate for BCG-unresponsive NMIBC patients was as high as 75.2%. By the data cutoff date, over half of the participants remained in remission, with the median DoR not yet reached but already exceeding 9 months.

At the cutoff time, the cystectomy-free survival (CFS) rate reached 92.4%, and the CFS for CR patients was 100%. For NMIBC patients, preserving the bladder as much as possible is undoubtedly the best news they want to hear.

Based on the outstanding clinical data of Cretostimogene, CG Oncology plans to submit a new drug application to the FDA in the second half of 2025. Meanwhile, the company also plans to use Cretostimogene in combination with Keytruda, which received FDA Breakthrough Therapy Designation in May 2023.

Phase II clinical data of the combination therapy also demonstrated significant potential for bladder-sparing therapy: the overall CR rate reached 83%, with a 12-month CR rate of 57% and a 24-month CR rate of 54%, among which 95% of patients maintained CR from 12 months to 24 months. The median DoR has not yet been reached but has exceeded 21 months. The 24-month CFS was 80%, and all CR patients (100%) did not require RC.

Whether used as a single agent or in combination therapy, and whether in terms of clinical data performance or indications, Cretostimogene has demonstrated strong competitiveness. In this battle for bladder protection, Cretostimogene holds great promise.

The clinical demand for NMIBC is substantial and remains unmet. Global pharmaceutical companies such as Johnson & Johnson and UroGen Pharma are accelerating the development of their pipelines, while pharmaceutical enterprises in China are also actively exploring new therapies. For instance, RemeGen's HER2 ADC drug, Disitamab Vedotin, is making headway, and LePu BioPharma has directly acquired the rights to Cretostimogene in China.

An increasing number of treatment options for NMIBC are bringing a ray of hope to patients. Who will prevail in the NMIBC field depends on who can better protect the patients' bladder.

       Title: 400,000 Patients, Don't Want to Lose Their Bladders