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Expert Discusses Challenges With Checkpoint Inhibition in the Frontline Treatment of Metastatic Bladder Cancer

Nichole Tucker
Published Online:8:00 PM, Wed October 2, 2019
Nicholas J. Vogelzang, MD, FACP, FASCO
Nicholas J. Vogelzang, MD, FACP, FASCO
Although checkpoint inhibitors are being studied in ongoing clinical trials for the treatment of metastatic bladder cancer, 2 challenges continue to prevent checkpoint inhibition from becoming the standard frontline therapy for these patients, according to Nicholas J. Vogelzang, MD, FACP, FASCO.
 
The FDA has placed enrollment limitations for studies that give checkpoint inhibition in the front-line setting for the disease, said Vogelzang. Patients are required to be platinum ineligible and have high PD-L1 expression to enroll. This excludes many patients who could benefit from checkpoint therapy. Another challenge is the cost of molecular testing, which limits patient access to testing, although it could help determine a patient’s likelihood to respond to treatment.

“If the opposing team has all left-handed batters, you're going to want to have some right-handed pitchers, and you won't know that without knowing the genetics of the cancer,” said Vogelzang.
 
There are solutions to the challenges that exist in the bladder cancer treatment space. For patients who do not meet the FDA’s strict criteria, chemotherapy continues to be the frontline treatment with an overall response rate of 70%, said Vogelzang. These patients can also receive checkpoint inhibition in the second-line setting and novel agents in the third-line setting, if needed.
 
To improve upon access to molecular testing, there needs to be prospective research proving that genetic testing can improve the management of the disease, so that insurance companies will be more likely to cover costs.
 
In an interview with Targeted Oncology, Vogelzang, medical oncologist, Comprehensive Cancer Centers of Nevada, explained the need for updates to clinical trial criteria to make checkpoint inhibition more widely available to patients with metastatic bladder cancer.

TARGETED ONCOLOGY: How is the frontline treatment of bladder cancer changing?

Vogelzang: It's very confusing to most doctors, and it's very distressing to most patients. It's frustrating because of all the restriction being placed upon us regarding both clinical trials and insurer guidelines.

TARGETED ONCOLOGY: What are some of the emerging therapies for bladder cancer?

Vogelzang: There are 2. There's the FGFR3 inhibitor, erdafitinib (Balversa) is on the market and enfortumab vedotin is not on the market yet, but it has a fast track designation. Then there’s the Immunomedics anti–Nectin-4 drug [IMMU-132] that is coming along nicely. There are currently 2 general categories and then there's one FGFR3, which is restricted to a molecularly defined subset. There are also 2 new agent opportunities that will bring the total available drugs for patients up to 5.

TARGETED ONCOLOGY: Is there any trial data you've seen that indicates which emerging therapy is the most promising for patients with bladder cancer?

Vogelzang: The FDA has already made it clear that enfortumab is high on their priority for approval. Seattle Genetics has a proven track record of getting these types of immuno-toxins approved. This is a drug that is reasonably expected to be FDA approved within 3 to 6 months, or sooner. 

This idea that drugs can improve upon checkpoint inhibitor therapy is seeing ongoing excitement and traction. The immunotherapies, of which there are 5, are virtually all in [combination] trials looking for enhancing drugs to make them more effective.
 
In my practice, I have LEAP-1, which has complicated eligibility criteria. It essentially says that if [a patient] is first line and ineligible for platinum-based therapy, you are then to receive either pembrolizumab (Keytruda) with or without lenvatinib (Lenvima). That's an important trial.
 
Mirati Therapeutics has a trial of a checkpoint inhibitor nivolumab (Opdivo), along with their TKI, sitravatinib. There are studies underway of cabozantinib (Cabometyx) combined with checkpoint inhibitors. There's a really exciting trial from USC in which patients who've had prior chemotherapy are given a checkpoint inhibitor and ephrin inhibitor, which is also exciting.
 
This whole field is confusing to patients and complicated for doctors to navigate because all of these trials have strict eligibility criteria and they include renal function issues, hemoglobin, and extent of prior therapy and that leads to a great deal of frustration in patients. Many times, for obscure reasons, they are excluded from these trials and the obscure reasons mostly stem from the FDA's decision to say that the only patients who can get first-line checkpoint inhibitors are those who have clear criteria, like, platinum ineligibility and they have to have a high PD-L1 expression. That has put a cloud over the clinical trial field because these are arbitrary decisions that are based upon a preliminary evaluation of clinical trials that are just now being reported, rather than [actual] science.

TARGETED ONCOLOGY: Will there continue to be a role for chemotherapy in treatment of bladder cancer?

Vogelzang: Yes. Chemotherapy has an immediate, and in some cases, dramatic effect on almost all cases of bladder cancer. It has a 70% objective response rate, although some might argue that it is lower than that. In general, when you include complete response, partial response, and stable disease, well over 70% of patients have a response. It is also pain-relieving and life-extending. Studies have long shown the important role of chemotherapy compared with placebo or even compared with single-agent chemotherapy. Chemotherapy continues to be a safety net for patients for whom these newer agents are not effective or curative.

TARGETED ONCOLOGY: What criteria do you use to decide patient selection for some of these therapies?

Vogelzang: [It should be genetic testing.] There is widespread failure of the insurance and third-party community to approve genomic testing. With that very high barrier to obtain genomic profiling comes an inability for most doctors to use the FGFR3 inhibitors, of which there are approximately 5. The FGFR3 inhibitors, which have been reviewed in several journals, all depend upon a molecular profile to be obtained, and if the treating doctors can't get the molecular profile, then that whole class of drugs is not available to the patients. That's what leads to high levels of frustration. 

TARGETED ONCOLOGY: For patients who are considered to be ineligible for these clinical trials with checkpoint inhibitors, what treatment do you typically give?

Vogelzang: Chemotherapy. As a good example, I recently saw a patient who has explosive bladder cancer. The patient is very healthy with no comorbidities and minor renal dysfunction, but he has liver metastases, which are notorious for their ominous prognosis. I cannot take the time to get him into LEAP-1, even though he might qualify because of his renal dysfunction. He has a creatinine level of 1.7. I don't want to risk his cancer worsening while I'm trying to get him into a clinical trial.

My plan for him is to start him on chemotherapy immediately to put out the fire, which is the burning cancer in the liver that's putting his life at risk. Then, I'll move him onto one of the checkpoint inhibitor trials along with an agent that will hopefully enhance the checkpoint inhibitor. I would have liked to give him a checkpoint inhibitor first, but I don't want [to risk it], and besides, I don't have the PD-L1 staining. The FDA seems to think that these patients can just wait to get PD-L1 staining. I can't wait because it takes another week to get PD-L1 staining. Then, the clinical trials folks want to get tissue samples to send off for their research.

It's easiest to just give every patient chemotherapy first line, even though I don't want to do that. Then, I'd give a second-line checkpoint therapy. In the third line, it would be the newer agents. By that time, I will have a variety of genetic testing done if their insurance providers let us do those.

TARGETED ONCOLOGY: What is your overall view of the treatment landscape for bladder cancer?

Vogelzang: It's an exciting time for bladder cancer research and clinical investigation. It's an exciting time for patients. They have more options now than they've ever had before. The Bladder Cancer Advocacy Network has become very active and there are large-scale clinical trials available throughout the United States and the world that allow almost all patients if they wish to participate. I would encourage every doctor to find a clinical trial for their patient, even if that means referring that patient to one of their colleagues doing bladder cancer trials.

TARGETED ONCOLOGY: As the field continues to advance, what advice would you give to community oncologists treating these patients?

Vogelzang: The first thing you should do when you see a patient with metastatic bladder cancer is immediately try to obtain molecular profiling. You're looking for the FGFR3 patients. You may also be looking for DNA repair deficiency. Those patients tend to do very well with cisplatin-based therapy.

Number 2, oncologists should correct or preserve renal dysfunction. Patients with bladder and transitional cell carcinoma of the upper tract frequently have renal dysfunction. They either have obstructive neuropathy and are in need of stents, or have preexisting renal dysfunction due to age, prior nephrectomy, or prior urothelial damage.

Third, [oncologists] should lay out a plan in your mind and with the patients about the direction you're going to go. We all hope that chemotherapy will be wonderful and [patients] will be cured. That occurs 5% of the time. We also hope that checkpoint inhibitors will be highly effective and curable. That occurs 10% of the time. Be realistic and set realistic goals with the patients, you'll have to say, "we'll start with this (namely chemotherapy) and we'll move to a checkpoint inhibitor, perhaps on a clinical trial.” It depends on the trial criteria. Hopefully, by then you'll have molecular genetics so that you'll know if you can do FGFR3 inhibition. And if they don’t have FGFR3 alterations, by then [we should also have] enfortumab and maybe Immunomedics’ [drug approved].

I compare it to a baseball game where a manager is not only thinking about his starting pitcher but also about who his middle reliever and closer will be. You need to have a complete game plan in your mind before you begin treating these patients.

TARGETED ONCOLOGY: What role does molecular testing play in improving outcomes for patients with bladder cancer? 

Vogelzang: The difficulty is that molecular testing is very expensive. It’s a bit of a frustration because most genetic profiles of patients with bladder cancer show that the tumor is driven by p53, or we see some other bad genetic finding that doesn't lead to any specific therapy. If you do genetic testing on 10 patients with bladder cancer, you may find 1 or 2 that have FGFR3. You're also looking for things that predict the need for checkpoint inhibition. You want to know their PD-L1 status, tumor mutational load, and their DNA repair deficiency. If they have BRCA, CHEK2, or one of the other genetic profile abnormalities, then you have a clue as to what your next step should be.

Reverting to the baseball analogy, if the opposing team has all left-handed batters, you're going to want to have some right-handed pitchers and you won't know that without knowing the genetics of the cancer.

Soon there will be more agents that are commercially available [aimed at] various subsets of patients with bladder cancer. These subsets were first identified from MD Anderson Cancer Center and other institutions like North Carolina and the University of Michigan. Each one of these groups of patients with bladder cancers are similar to the subsets of breast cancer—luminal, basal, neuroendocrine, etc. These subsets may also predict who is most likely to benefit from chemotherapy and who is most likely to benefit from immunotherapy.

That first genetic profile gives you a plan for where your treatment will go. A genetic profile can help assess whether the patient should be getting chemotherapy, immunotherapy, or an FGFR3 inhibitor.

We don't have a prospective trial to prove that genetic profiling improves outcomes yet. That is part of the issue. Insurance companies are asking us to show them the proof that molecular profiling changes the management of this disease and we don't have those data. Therefore, they don't approve it.

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