New Contenders Enter the Bladder Cancer Arena: Can Novel Therapies Challenge Keytruda's Dominance?

With MSD's Keytruda (K drug), the new "blockbuster drug," already dominating the NMIBC field, can newcomers get a share of the market?

Market Size Expected to Double

Bladder cancer is the fifth most common cancer, typically affecting people over 70 years old, more commonly men, and is the fourth most common cancer in men. If diagnosed early, patients generally respond well to treatment, but the recurrence rate is also relatively high.

Approximately 90% of bladder cancers start in the cells lining the inner surface of the bladder, a type known as urothelial carcinoma. Most urothelial carcinomas are non-muscle-invasive, with NMIBC being the most common type.

Typically, the first sign of bladder cancer is blood in the urine. Other symptoms may include pain or a burning sensation during urination, or changes in urination habits. More severe symptoms of bladder cancer may include lower back pain on one side of the body, feelings of fatigue or weakness, loss of appetite, and weight loss.

NMIBC Detection Methods Include Blood Tests, Urine Cytology, Cystoscopy, and Computed Tomography. Multiple Guidelines Recommend Intravesical BCG Instillation as the First-Line Treatment for Intermediate- and High-Risk NMIBC. However, Individual Differences Exist in Patient Response and Tolerance Rates; It Is Ineffective in Approximately 30%-40% of Patients, and the Recurrence Rate Among Those Initially Responsive Is Also High.

According to data provided by market research firm Expert Market Research, in 2023, the global bladder cancer treatment market reached sales of nearly US$4.03 billion. During the forecast period from 2024 to 2032, this market is expected to grow at a compound annual growth rate (CAGR) of 9.31%, reaching sales of US$8.98 billion by 2032.

Sustained Efficacy Challenges the "King of Drugs"

Anktiva is a superantagonist of interleukin-15 (IL-15) and is expected to become the next-generation immunotherapy surpassing immune checkpoint inhibitors. Evaluate, an industry media outlet, predicts that sales of this immunotherapy could reach nearly $900 million by 2028. Patrick Soon-Shiong, Executive Chairman of ImmunityBio, and Richard Adcock, CEO of the company, believe that Anktiva’s advantage lies in its ability to induce "durable complete remission." Patrick Soon-Shiong pointed out that Anktiva will be the first next-generation immunotherapy to go beyond killer T-cells, primarily exerting long-term remission effects by activating natural killer cells and, more importantly, CD8+ memory T-cells.

In Cohort A of the pivotal QUILT-3.032 trial, 82 high-risk, BCG-unresponsive NMIBC CIS patients were treated with the Anktiva-BCG combination therapy. Of these, 58 patients showed no detectable tumors after a median follow-up of approximately two years. According to data published in late 2022 in The New England Journal of Medicine – Evidence, the complete response rate for these patients was 71%, with a median duration of complete response lasting 26.6 months.

Although clinical research data were positive, the FDA rejected the approval of Anktiva (N-803) in May 2023 due to deficiencies found during a pre-licensing inspection by its third-party contract manufacturer. Now, ImmunityBio, Inc. has submitted longer follow-up data showing that the complete response rate of the Anktiva-BCG combination therapy was 62% among 77 evaluable patients. As of the data cutoff in November 2023, the longest duration of complete response exceeded 47 months, and the trial is still ongoing. Among patients with complete responses, 58% had a response lasting at least one year, and 40% had a response lasting at least two years.

By contrast, in the KEYNOTE-057 trial that led to the approval of Keytruda (K药) for NMIBC at the beginning of 2020, the complete response rate induced by Keytruda reached 41%. Among the 39 patients who achieved a complete response, the median duration of response was 16.2 months. However, it should be noted that the two complete response rates correspond to different trials, and these were not head-to-head clinical trials; therefore, it cannot be simply concluded that the Anktiva-BCG combination drug is more effective than Keytruda.

Moreover, at the end of December 2023, the combination of K drug and Astellas' antibody-drug conjugate (ADC) Padcev for metastatic bladder cancer caused a sensation. However, Patrick Soon-Shiong believed that Pfizer's plans for Padcev currently do not include NMIBC, and since ADCs are essentially cytotoxic drugs with tumor-targeting properties, the Anktiva-BCG combination still has advantages.

Another advantage of Anktiva is that its treatment course is almost the same as existing therapies, with minimal disruption.

New Therapies Poised for Launch

Besides K drug, the Anktiva-BCG combination drug also faces challenges from emerging pharmaceutical companies.

CG Oncology (raised $380 million), which topped the list of European and American financings in the first quarter of 2024, is one such company. The company’s oncolytic virus therapy, cretostimogene, achieved complete remission in approximately three-quarters of treated patients.

On May 3, CG Oncology reported that in a late-stage trial involving 105 evaluable NMIBC patients, the complete response rate of cretostimogene reached 75.2%.

According to data reported in early May at the annual meeting of the American Urological Association, no patients who reported complete remission required bladder removal; 29 patients maintained complete remission for up to 1 year, and another 22 patients were awaiting evaluation. No patients reported grade 3 or higher adverse events.

CG Oncology Plans to Submit New Drug Application to U.S. FDA in the Second Half of 2025. In addition to its significant efficacy, the company also plans to combine cretostimogene with Keytruda to enhance sustained efficacy, with data expected to be released later this year.

Ferring's gene therapy Adstiladrin is also a strong competitor in this field. A Phase III trial showed that the gene therapy achieved complete response in 51% of patients within 3 months. Among those with complete response, 46% remained free of high-grade recurrence at 12 months.

Combination Drug Production Capacity Bottleneck

Externally, there are veterans and new players catching up. The Anktiva-BCG combination therapy still needs to overcome its own commercialization challenges — the ongoing global BCG shortage could very likely become the "Achilles' heel" of this combination therapy's commercialization. As strong competitors to this combination therapy, Keytruda, Adstiladrin, and cretostimogene do not require combination with BCG. Notably, Merck & Co., Inc. (MSD) remains the sole BCG supplier in the United States.

To this end, ImmunityBio has decided to sign an exclusive agreement with the Serum Institute of India (SII) to collaborate on the global production of BCG. SII is the world’s largest producer of BCG vaccines and has two BCG products used in the field of oncology, one of which is a traditional BCG called Onco-BCG that has already been commercialized outside the United States. According to the agreement, once the FDA approves the trial protocol, SII will immediately provide standard BCG for ImmunityBio’s clinical trials. ImmunityBio also plans to submit the trial protocol to other regulatory agencies worldwide.

SII's Second Product is a Recombinant BCG Undergoing Mid-Stage Testing in Europe. This product involves two genetic modifications to enhance its properties. Reportedly, compared to conventional BCG, this recombinant BCG demonstrates superior immunogenicity and safety. The two companies are also actively advancing the research on this BCG.

Preview of Ongoing Projects

Over the past 40 years, chemotherapy has been the standard treatment for patients with tolerable bladder cancer. The chemotherapy regimen has been based on cisplatin for decades without change. However, the efficacy of chemotherapy is limited and lacks durability. In response, researchers have been exploring new treatment methods and have achieved some success.

A report published by market research firm DelveInsight shows that currently, more than 80 pharmaceutical companies are developing drugs for bladder cancer, with over 100 drugs in the pipeline.

Sustained-Release Formulation UGN-102: This drug, developed by UroGen Pharma, is a reverse thermogel containing mitomycin. It is a hydrogel-based sustained-release formulation designed to expose bladder tissue to mitomycin for an extended period, enabling non-surgical treatment of tumors. UGN-102 is delivered using a standard catheter in an outpatient setting and is currently in Phase III clinical trials for the treatment of bladder cancer.

Oral Targeted Agent APL 1202: This drug, developed by Asieris Pharmaceuticals, is an orally available, reversible Met AP2 inhibitor with anti-angiogenic and anti-tumor activity, and can also modulate the tumor immune microenvironment. APL 1202 is currently undergoing registrational clinical trials in China as a monotherapy for first-line treatment of intermediate-risk NMIBC patients or in combination with chemotherapy as a second-line treatment for intermediate- and high-risk, chemotherapy-refractory NMIBC patients. The drug is currently being evaluated in Phase III trials for the treatment of bladder cancer.

Intravenous Drug Trilaciclib: Developed by G1 Therapeutics, it is a “First-in-Class” therapy designed to improve the prognosis of cancer patients undergoing chemotherapy. It is a short-acting intravenous CDK4/6 inhibitor administered prior to chemotherapy, temporarily halting cell cycle progression. Currently, the drug is being evaluated in Phase II trials for bladder cancer treatment. Trilaciclib was approved by the FDA in February 2021 for use in preventing chemotherapy-induced myelosuppression in small cell lung cancer but previously failed in Phase III studies for first-line colorectal cancer and triple-negative breast cancer.

Catumaxomab’s Market Launch: Developed by Linton Pharm, catumaxomab is a bispecific antibody that binds to the epithelial cell adhesion molecule (Ep-CAM) on tumor cells and CD3 on T cells, recruiting immune accessory cells through Fcγ receptor binding. Catumaxomab kills tumor cells via T-cell and accessory cell-mediated cytotoxicity and has the potential to induce long-term vaccine effects. It is currently in Phase I/II trials for bladder cancer treatment. Notably, it was the world's first bispecific antibody drug to reach the market but was withdrawn in 2017 due to poor market performance and side effects associated with cytokine release syndrome. In 2017, the drug's inventor co-founded Linton Pharm to continue its development.

Oncolytic Therapy VAX 014: Developed by Vaxiion Therapeutics, it is a novel oncolytic immunotherapy based on recombinant bacterial minicells (rBMC). VAX 014 functions by specifically targeting and directly delivering a novel, fast-acting, pre-formed oncolytic protein toxin into tumor cells. The drug is currently in Phase I trials for the treatment of bladder cancer.