Is Chemo The Best Bladder Cancer Treatment For All?

DR. SCOTT TAGAWA AND DR. BISHOY FALTAS

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The bladder is a muscular organ made up of several layers of cells. This image outlines the bladder, ureters and surrounding vessels.

State-of-the-art cancer care continues to evolve due to advances in all aspects of patient care – including diagnosis, and personalized treatment and management. By incorporating novel diagnostics, systemic therapies, molecular targeted therapies, immunotherapies, and other biotechnological strategies into treatment paradigms, patient outcomes continue to improve along the cancer continuum.

For patients with bladder cancer and other urothelial cancers (cancers of the bladder, renal pelvis and ureter), cisplatin-based chemotherapy remains the standard of care. This is based on decades of research through a series of randomized clinical trials showing that chemotherapy regimens containing cisplatin consistently lead to the best overall survival rates. Importantly, some patients with metastatic urothelial cancer who are treated with cisplatin-based regimens are cured.

However, cisplatin is hard on not just the cancer cells, but the body overall. As a result, not all patients are “fit” for cisplatin. There are standard criteria that are used to define patients for whom cisplatin is not a viable treatment option. These include kidney (renal) function as measured by a blood test and sometimes urine tests, performance status (a measure of how physically functional patients are), hearing loss, nerve damage (neuropathy/numbness), and heart failure. Some of the time, there may be trade-offs. For instance, some patients would trade off the risk of needing a hearing aid for a higher chance of tumor shrinkage (or even cure).

While it is well-known among physicians that not all bladder cancer patients are candidates for this treatment option, questions linger regarding what the best treatment option should be for these patients. To get to the bottom of this question, we reviewed the scientific evidence and Dr. Scott Tagawa recently presented our findings to a large group at the 34th annual Chemotherapy Foundation Symposium (CFS). This conference brought together over 2,000 cancer care clinicians across a multidisciplinary spectrum to provide updates on the most cutting-edge new agents, ongoing clinical trials and emerging developments in cancer treatment and diagnosis.

What did the science show?

According to recent data presented at the 2016 European Society of Medical Oncology (ESMO) meeting, the most common alternative treatment regimen for patients who are well enough to tolerate chemotherapy is the combination of carboplatin and gemcitabine chemotherapies. This was based on the review of data from 1426 patients with advanced urothelial carcinoma who were treated with chemotherapy.

Interestingly, there were some other global trends in the types of chemo prescribed. Centers that treated fewer patients with urothelial cancers were more likely to give alternative (non-cisplatin) chemotherapy to patients that did not meet any standard criteria for being unfit. The most common reason for being deemed unfit for cisplatin was the patient’s current level of kidney function. Unfortunately, data showed that patients who were fit for cisplatin, but received alternative chemotherapy lived much shorter than those who received cisplatin, and none of those patients in the study were alive at the 5-year mark.

One setting where cisplatin-based chemotherapy is very important is in the pre-operative setting where the goal is cure rather than just prolongation of life by months to years. Physicians should be aware of some “tricks of the trade” to optimize kidney function and other parameters to maximize the chance for cisplatin administration and cure. For patients, it’s important to consider at least getting a consultation at a center of excellence before making a treatment decision.

We also recently wrote an editorial in The Lancet outlining the value of immunotherapy for patients with advanced urothelial cancers who are unfit for cisplatin, and in particular checkpoint inhibitor immunotherapy. While not currently FDA-approved for this indication, a study using atezolizumab (Tecentriq) was published in this prestigious journal with a second supportive study utilizing pembrolizumab (Keytruda) presented at the ESMO meeting in October. Both studies used monoclonal antibodies that enable the immune system to become activated and fight cancer, and both demonstrated substantial responses in a subset of patients. Studies of the tumor and surrounding tissue testing for PDL1 expression are able to predict those with a higher likelihood of response, but even those with “negative” testing can respond. Tests of tumor genomics are also able to group tumors into those with a higher likelihood of response, but again, even those in the lower immune responding group can have a long-term response to immune treatment. Ongoing studies are needed to help predict response in a more powerful manner. One issue that we’ve recently examined is the difference in tumor genomics before and after chemotherapy highlighted by Dr. Faltas’ high-impact publication on the clonal evolution of urothelial cancer. Among other things, this highlights the importance of obtaining recent tissue from metastatic sites to gain the most accurate understanding of an individual patient’s tumor biology.

In summary, it is important for physicians to recognize when a patient may or may not safely receive certain chemotherapy regimens, such as cisplatin combinations in the case of urothelial carcinoma. In addition, research is ongoing for patients that are unfit for certain types of chemotherapy to prove whether or not immunotherapy should be used in patients who have not yet received chemotherapy. Several immunotherapy drugs are currently being tested in randomized clinical trials and these include patients that are unfit for cisplatin. Additionally, other drugs such as antibody-drug conjugates or monoclonal antibodies have shown promising activity in patients with advanced urothelial carcinoma, and these studies included patients unfit for cisplatin.

Immunotherapies for Advanced Bladder Cancers

Cancer MicroscopeImmunotherapy is a very encouraging approach for treating bladder cancers and other tumors arising from the renal pelvis and ureters. There are a number of different types of bladder cancer immunotherapies currently available:

1. Atezolizumab (brand name Tecentriq) is an FDA-approved immunotherapy for urothelial carcinoma, the most common form of bladder cancer. Atezolizumab is an immune checkpoint blockade or “checkpoint inhibitor.” It selectively binds to cancer cells based on the presence of PD-L1, a protein on the tumor surface.

PD-L1 is more strongly expressed on certain types of tumors, including urothelial cancers arising from the bladder, renal pelvis, and ureters. PD-L1 prevents the body’s immune system from being able to recognize the cancer and attack it. It had been more than two decades since the FDA approved a new bladder cancer treatment.

Atezolizumab is only approved for urothelial carcinoma that has grown or recurred after previous chemotherapy, and we offer this treatment at Weill Cornell Medicine. We are also currently testing another PD-L1 checkpoint inhibitor alone or in combination with another immune checkpoint antibody versus standard chemotherapy through an open phase III clinical trial.

2. Ramucirumab is a monoclonal antibody that binds to the Vascular Endothelial Growth Factor (VEGF) receptor-2. This is a receptor found predominantly on blood vessels. Angiogenesis is a process where vessels grow to feed tumors and blocking this pathway can be helpful at stopping the growth of these vessels, particularly in combination with chemotherapy. We previously completed a randomized phase III trial which demonstrated that patients who got docetaxel (Taxotere) chemotherapy plus ramicurimab had more than twice the tumor shrinkage and double the time until tumor growth compared to docetaxel chemo alone; This study was recently published in the Journal of Clinical Oncology. Based upon our results, we recently opened a phase III trial using this drug in combination with chemotherapy. People who have already received chemotherapy, and those who have received chemo followed by atezolizumab or other checkpoint inhibitors are eligible for this clinical trial.

3. IMMU-132 (also known as Sacituzumab Govitecan) is an antibody drug conjugate that leverages the capability of monoclonal antibodies to attach to specific targets on cancer cells. By attaching a drug to the monoclonal antibodies, treatments are able to “hitch a ride” into the cancer cells.

This treatment is a potential good treatment fit for adults with metastatic bladder cancers who have not responded to chemotherapy or who have relapsed after chemotherapy or PL-1/PD-L1 checkpoint inhibitor immune treatment.

Initial positive results in the phase I trial led to a phase II clinical trial that is currently open to enrollment. Learn more about how this drug works in the body and get more information about our open IMMU-132 clinical trial by checking out our recent blog post, “Doing Better on Behalf of Bladder Cancer Patients.”

4. REGN2810 is a monoclonal antibody – a type of protein that works by blocking the programmed death receptor 1 (PD-1), a cell receptor on immune cells that is involved in preventing the immune cells from destroying other cells. Through our open clinical trial, patients with bladder and other urothelial cancers who have received prior treatment with checkpoint inhibitors (such as atezolizumab) can get the combination of the REGN2810 drug with immune boosters.

Cancer: A Wolf in Sheep’s Clothing

Immunotherapy wolf in disguiseCancer cells can be pretty sneaky, altering their make-up or microenvironment to avoid detection by our body’s immune system. As a result, the immune system, which is designed to fight off “invaders,” can’t detect cancer as foreign and doesn’t have its guard up.

Earlier this month, NewYork-Presbyterian Hospital kicked off a new ad campaign highlighting how immunotherapy is working to change just that. Immunotherapy treatments are designed to help activate the immune system and kick it into high gear, helping it fight the very cancer it was previously unable to detect.

New scientific discoveries happening right here at Weill Cornell Medicine are making this possible. Our physician-scientists and researchers at the Meyer Cancer Center have found ways to help the immune system better recognize and destroy cancer cells by designing new immunotherapy drugs, cancer “vaccines,” and combination treatments. Through precision medicine and an individualized approach to cancer care, we are developing new ways to treat cancer more successfully than ever before. And, we’re accomplishing these results with less toxicity.

Over the past decade, the U.S. Food and Drug Administration (FDA) has approved several new immunotherapy drugs for advanced cancers. At the Weill Cornell Genitourinary (GU) Oncology Program, we have greatly contributed to the efforts to obtain FDA-approval for immunotherapies for GU cancers, including kidney cancer, bladder cancer, and prostate cancer.

For kidney cancer, we have been involved in many studies of drugs utilizing the immune system to fight cancer, including the phase 2 clinical trial that formed the basis for the large trial leading to the FDA approval and general availability of nivolumab (Opdivo) for renal cell carcinoma. Nivolumab is an immunotherapy that works by allowing the body’s existing immune system to kill tumors. Our team is now working on ways to improve this drug and other types of drugs.

For bladder and other urothelial cancers, we have been instrumental in the development of several antibodies that can be used with and without chemotherapy. Sacituzumab Govitecan (IMMU-132), an antibody-drug conjugate, has had remarkable preliminary activity. It works by leveraging the immune system and bringing a powerful drug directly to the interior of cancer cells in order to kill them from the inside out. We are continuing to use this drug as well as other immunotherapeutic agents to improve outcomes for patients with these types of cancer.

Based upon several scientific properties, prostate cancer is a good tumor type for immunotherapy, and in fact, the first therapeutic cancer vaccine (used to treat cancer rather than prevent cancer) was approved for prostate cancer. At Weill Cornell Medicine, exploiting the immune system remains a focus in fighting prostate cancer, with a number of ongoing and upcoming clinical trials. Weill Cornell Medicine continues to be a worldwide leader in work with monoclonal antibodies, which are proteins (like a “key”) that very specifically target cancer cells (with a specific “lock” that is not present on normal cells). In particular, our work with antibodies against prostate-specific membrane antigen (PSMA) has led to the development of several targeted therapies for prostate cancer. These antibodies can be linked to powerful radioactive particles or drugs that seek out prostate cancer cells (like a smart bomb). For men with prostate cancer whose PSAs rise despite hormonal therapy, we are leading a study of targeted radioimmunotherapy that aims to prevent metastatic disease. In addition, the antibody itself may be able to generate an immune response in prostate tumors and lead to clearance of circulating tumor cells. We are also working on developing vaccines for men with rising PSAs following surgery or radiation.

We continue to examine many promising, cutting-edge immunotherapies through our robust clinical trial program. Click the below links to learn more about eligibility and open clinical trials across the spectrum of GU cancers:

Open Immunotherapy-Based Clinical Trials

Prostate Cancer

Kidney, Bladder and Urothelial Cancers

To search our complete list of our open clinical trials, click here.