Hope for Patients With Metastatic Bladder Cancer
- A new immunotherapy and chemotherapy combination has been given accelerated approval as treatment for patients with metastatic bladder cancers who cannot receive cisplatin-based treatment.
- The unique combination is of enfortumab vedotin (also known as Padcev) and the drug pembrolizumab (also known as Keytruda).
- Patients who cannot receive cisplatin for their cancer have historically fared very poorly.
- In a study of the combination, the new treatment achieved a response in 64.5% of the patients.
- Earlier approval of drugs that treat serious conditions can happen because of FDA’s Accelerated Approval Program.
Cisplatin is a very common type of chemotherapy drug and has been the standard-of-care for advanced bladder cancer. However, about half of patients with advanced bladder cancer are ineligible to receive this treatment. So the approval of this combination meets a major need and can bring hope to many people.Read More
How Common Is Bladder Cancer?
Bladder cancer is the sixth-most common type of cancer overall in the United States, according to the National Cancer Institute, though it is the fourth-most common for men.
Approximately 81,000 new cases of bladder cancer are expected to be diagnosed in 2022 in the U.S., which will result in about 17,000 deaths.
Around 17% of these cases will be ones in which cancer has spread to the tissues surrounding the bladder, termed locally advanced, or has spread to other parts of the body, termed metastatic.
Most of these cases occur in people older than 55 years of age. At five years, only 5% will survive.
These advanced bladder cancers have usually been treated with the chemotherapy drug cisplatin. Cisplatin is very efficacious but comes at the cost of significant toxicity. It can be particularly harmful for the kidneys.
Given that bladder cancers most often afflict the older population with likely impaired kidney function, cisplatin is not a suitable choice. Historically, such cisplatin-ineligible patients (around 50%) have been treated with drugs that are not as effective. Thus, treatments that can prolong the survival for these patients are greatly needed.
Both of the enfortumab vedotin and pembrolizumab drugs have previously demonstrated success in treating metastatic bladder cancers on their own. Researchers hypothesized that combining these drugs may yield even better results, which was shown by the study results.
Dr. Arjun Balar, the vice president of global clinical development of Loxo Oncology at Eli Lilly, explains current treatment options for later stage bladder cancer.
How Do These Drugs Combat Cancer?
Enfortumab vedotin is an antibody-drug conjugate, or compound treatment. The antibody portion of this drug targets Nectin-4, which is a molecule liberally expressed on the surface of bladder cancer cells. This molecule helps cancer cells stick to one another. It also helps them proliferate.
After the antibody binds to Nectin-4, the chemotherapy drug MMAE (monomethyl auristatin E) is injected into the cancer cells. MMAE decimates the scaffolding on which the cancer cells are built, in turn stopping the tumor from growing and killing it.
Enfortumab vedotin had previously only been approved as a second or later-line agent, meaning that patients had to first fail more traditional therapies before being offered this antibody-drug conjugate.
Pembrolizumab is an immunotherapy drug, which means it primes the patient’s own immune system in the fight against their cancer.
Cancer cells can learn to evade detection by the immune system. They can essentially hijack the PD-1 (Programmed Death Receptor-1) and PD-L1 (Programmed Death Ligand-1) pathways to survive.
PD-1 is a protein on the surface of immune cells. PD-L1 is a protein on the tumor cells, which can bind to PD-1 and prevent the immune system from killing the cancer cell. Pembrolizumab interrupts this process by binding to PD-1, allowing the immune cells to exterminate cancer.
Pembrolizumab had been approved by itself for patients with advanced or metastatic bladder cancer who cannot receive cisplatin or if cisplatin fails to stop their cancer from spreading.
Dr. Arjun Balar, the vice president of global clinical development at Loxo Oncology at Eli Lilly, explains the potential side effects of immunotherapy for bladder cancer.
The study recruited 149 patients with advanced or metastatic bladder cancers. These patients were randomly assigned to either receive Enfortumab vedotin with Pembrolizumab combination or just Enfortumab alone. It was a phase 1b/II trial, which means that it was not designed to compare the two treatment groups with each other. Thus, the results should not be taken to recommend one treatment over the other.
For the patients who received the combination treatment, the investigators saw an objective response rate (ORR), or measurable decrease in tumor burden without a complete disappearance of the disease, of 64.5%.
About 10.5% of patients achieve a complete response (CR), or the disappearance of all signs of cancer in response to treatment with the combination treatment.
Those who had Enfortumab vedotin only had an ORR of 45.2% and a CR of 4.1%. When reviewing these results, it must be reiterated that the trial was not designed for a comparison of the two arms.
The trial also aimed to measure the progression-free survival (PFS) and overall survival (OS) of the two groups. Both PFS and OS are additional measures of treatment efficacy. OS can be defined as the length of time patients live after they’re diagnosed with cancer. PFS represents the time a patient is alive without a progression of their disease. For the combination treatment, the median PFS was not reached due to the preliminary nature of these findings. Their OS was 22.3 months. For the single immunotherapy arm, the PFS was 8 months, and the OS was 21.7 months.
At the time, Dr. Gary Steinberg, director of the urology bladder cancer program at NYU Langone’s Perlmutter Cancer Center and a professor of urology at NYU Grossman School of Medicine, said, “The results while preliminary and require additional follow-up are extremely encouraging and appear to demonstrate real progress over EV or pembrolizumab alone. The nearly 65% response rate is impressive.”
He continues, “the numbers are a significant improvement over carboplatin gemcitabine or alternative chemotherapy regimens. The combination is significantly better than pembrolizumab alone. We have not approached the median duration of response yet. The only caveat is the increased grade 3-4 dermatologic adverse events.”
Toxicity Of Treatment
Enfortumab vedotin combined with pembrolizumab naturally exhibits the toxicities associated with both drugs. In the combination arm, the most frequently observed toxicities were skin reactions, tingling of nerve endings within the arms and legs, and eye symptoms (blurry vision, dry eyes, etc.). Therefore, providers who aim to use this treatment for their patients in the future must be versed in managing these side effects.
“51.3% of patients experience some peripheral neuropathy, with 1.3% experiencing grade 3 or higher neuropathy. Any grade of a skin rash was seen in 46%, with 17% of patients experiencing a rash of grade 3 or more. 23.2% of patients presented with serious treatment-related adverse events, and 3.9% had treatment-related deaths… these side-effects need to be [evaluated] in the context of long-term benefits of this drug combination,” notes Dr. Bellmunt.
Are These Drugs Available To Patients?
Enfortumab vedotin with pembrolizumab for the treatment of locally advanced or metastatic bladder cancer is not offered as a first treatment option for patients within the community.
However, the U.S. Food and Drug Administration (FDA) has granted the Padcev/Keytruda combo an accelerated approval in the U.S. as a combination therapy for the treatment of adult patients with locally advanced or metastatic bladder cancer who are not eligible to receive cisplatin-containing chemotherapy.
Earlier approval of drugs that treat serious conditions can happen because of FDA’s Accelerated Approval Program.
Drug companies are still required to conduct studies to confirm the anticipated clinical benefit. If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug.
If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.
What Does This Mean For Patient Care?
Advanced or metastatic bladder cancer tends to be a devastating disease, which can result in patient death within a couple of years of diagnosis. Cisplatin is one of the most effective treatments available, yet up to half of the patients will not qualify for it given its various toxicities. This lack of other robust treatment options means that there is a large need for efficacious treatments for these patients.
RELATED: Exploring the Treatment Options for Metastatic Bladder Cancer
The combination of Enfortumab vedotin and pembrolizumab may offer these patients hope with an effective treatment option.
The Next Steps
This new combo is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication is contingent upon verification and description of clinical benefit in the EV-302 confirmatory trial, which is still underway.
The EV-302 trial is a phase III trial, which means its results will be highly scientifically rigorous. This study compares the chemotherapy/immunotherapy treatment combination with traditional chemotherapies, such as cisplatin, carboplatin, and gemcitabine.
The results will likely be available in early 2024. If the results show a positive response with the enfortumab vedotin and pembrolizumab, then this treatment combination will, most likely, receive FDA’s final approval and become an evidence-backed, effective treatment option in the fight against bladder cancer.
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