Balar Shares Treatment Considerations in 2 Cases of Advanced Bladder Cancer

Arjun Balar, MD

Arjun Balar, MD

Arjun Balar, MD recently shared the treatment considerations and decisions he makes when treating patients with advanced bladder cancer. Balar, director of the Genitourinary Medical Oncology Program, NYU Langone Medical Center, explained his treatment decisions based on 2 case scenarios during aTargeted Oncologylive cased-based peer perspectives dinner.

Case 1

June 2016

A 66-year-old woman with a 40-year smoking history was referred by urology after an evaluation for gross hematuria. Her past medical history was remarkable for COPD, mild HTN and CAS with no prior MI.A cystoscopy revealed a nodular 8-cm mass along the posterior bladder wall. A transurethral resection of the bladder showed a high-grade urothelial carcinoma invading the muscularis propria. A CT scan of the abdomen and pelvis was shown negative for lymphadenopathy or distant metastases. Her initial diagnosis was stage cT2N0M0 muscle-invasive bladder cancer with urothelial origin.

TARGETED ONCOLOGY:What factors do you consider when deciding on a therapeutic approach for this patient?

Balar:Our first case is a 66-year-old woman with newly diagnosed muscle-invasive bladder cancer that is clinically localized. This is a young patient, with excellent performance status and with no significant medical comorbidities, so I generally favor an aggressive approach for curative treatment.

The reason these factors are important is because they really predict the patient’s ability to safely tolerate cisplatin-based chemotherapy. In fact, patients who have a very low performance status or have impaired kidney function do not tolerate cisplatin-based therapy well. For that reason, often a safe administration of cisplatin in these patients is not possible.

With regards to smoking history, the majority of patients with this cancer are either current or prior smokers. I strongly counsel patients that, if they are currently smoking, they discontinue smoking because this will significantly increase their risk for toxicities during chemotherapy. It is not something that would absolutely preclude that treatment, but it is something really important to consider.

There are other comorbidities that must be taken into account, in particular cardiovascular disease or diabetes. Again, the overall healthy of the patient is important to consider to make sure that treatment is administered in the safest way possible.

TARGETED ONCOLOGY:What is the best treatment approach for this patient?

Balar:The best treatment approach for this particular patient would be neoadjuvant cisplatin-based chemotherapy followed by definitive local therapy, usually with radical cystectomy.

The best cisplatin-based regimen is somewhat debated.. We have been using gemcitabine and cisplatin for quite some time now. This is largely based off randomized data from the metastatic study showing very similar outcomes with a better tolerable and safety profile compared to conventional MVAC [mothrexate, vinclastin, doxorubicin, cisplatin].¹For that reason, we have been using gemcitabine and cisplatin as the neoadjuvant chemotherapy of choice.

However, there is more recent data from the Fox Chase group, as well as Dana Farber, showing that MVAC given in an accelerated or dose-dense fashion is both safe and very effective, and can actually be a well-tolerated regimen, especially for patients who are otherwise young and fit [NCT02710734]. I consider dose-dense MVAC and gemcitabine and cisplatin as both very acceptable neoadjuvant chemotherapy regimens for patients with muscle-invasive bladder cancer.

Immunotherapy right now, whether it is with pembrolizumab [Keytruda], atezolizumab [Tecentriq] or any of the other checkpoint inhibitors, is currently exploratory in the muscle-invasive neoadjuvant setting and is not something that I would recommend outside of a clinical trial.

February 2017

Eight months later, the patient complained of shortness of breath. Her ECOG performance status is 0, but she continues to smoke 1+ packs per day. Liver function tests and creatinine clearance are within normal limits. A CT scan showed multiple bilateral pulmonary nodules and metastatic UC was confirmed by an IR biopsy.

TARGETED ONCOLOGY:What would your treatment approach be at this point?

Balar:This is a patient who, despite appropriate neoadjuvant chemotherapy and radical cystectomy, had residual muscle-invasive disease in the bladder and then, unfortunately, developed recurrence of bladder cancer as metastatic disease within a year after completing her initial treatment. Historically, for these patients, our treatment approach has generally been chemotherapy drugs we would reserve in the second-line setting. Those are most commonly taxane-based therapies, such as paclitaxel.

More recently, since the emerging data for immune checkpoint inhibitors has been reported, we have 5 new agents that are approved in this setting. These include: pembrolizumab, atezolizumab, durvalumab [Imfinzi], nivolumab [Opdivo], and avelumab [Bavencio]. They all target the PD-1 axis, and any of these agents would be reasonable options and are currently considered the standard of care for this particular patient. All of these agents in single-arm and randomized trials have shown very similar response rates and very similar safety profiles. Paclitaxel is also an acceptable option, but in general I would reserve paclitaxel as a treatment for after immunotherapy. 

In my opinion, I would not recommend re-treatment with the cisplatin-based chemotherapy regimen since she has developed recurrence in less than a year following completion of neoadjuvant chemotherapy. Mainly because this is a patient who has clearly shown to be resistant to cisplatin-based chemotherapy.

TARGETED ONCOLOGY:What factors influence the treatment options?

Balar:When you take a patient like this, I think it's critical to look at the entire patient--their individual make-up, their comorbidities, etc. For that reason, the prior treatment history this patient has fits into the classical description of a second-line metastatic bladder patient in my opinion, mainly because of their recurrence so soon after completing neoadjuvant chemotherapy.

Their comorbidities are important to consider mainly because this influences their potential toxicity risk with subsequent lines of therapy, especially with chemotherapy. PD-L1 tumor expression, I think, is less important. Mainly because even in the patients that are PD-L1—negative, based on the studies conducted so far, the response rates appear to be as good, if not better, than what would be expected with chemotherapy.

TARGETED ONCOLOGY:Is this patient a candidate for an immune checkpoint inhibitor?

Balar:I believe absolutely. Based on their prior treatment history, their comorbidities, and their disease recurrence of less than 1 year after treatment, the patient would fit an excellent candidate for immune checkpoint inhibitor therapy.

There is no specific checkpoint inhibitor I would use. I would probably choose the one that is available in my hospital formulary or one that fits the patient's preference, in terms of dosing schedule. There is some variability between the different agents. For instance, nivolumab is administered on a 2-week schedule, whereas atezolizumab and pembrolizumab are administered on a 3-week schedule. There is also insurance and reimbursements that have to be considered with the patient's individual financial situation. A lot of the logistical factors need to be considered, but the available data seems to be similar across all agents.

TARGETED ONCOLOGY:Is the patient a candidate for chemotherapy?

Balar:That is a consideration, but it would not be my first agent to consider. Chemotherapy would still be a potential option, but certainly after immunotherapy. I would generally consider agents that the patient did not receive previously. For this particular patient, reasonable treatment options would include: taxane-based therapy, either with paxlitaxel or doxetaxel [Taxotere], or another option would be single-agent gemcitabine, which the patient has not yet received.

Case 2

A 73-year-old man presented to her physician with hematuria and was diagnosed with metastatic urothelial bladder cancer with sites of metastases in the liver and lung. He had mild hepatic and renal impairment with AST and ALT levels at ~3x ULN and a creatinine clearance of 38 mL/min.The patient’s past medical history was remarkable for HTN and well-controlled on ARB. His ECOG performance status was 1. He had plaque psoriasis with no systematic manifestations.

TARGETED ONCOLOGY:What factors influence your options to treat this patient with an immune checkpoint inhibitor?

Balar:The patient in case number 2 is different from our initial case. This is a slightly older individual with metastatic urothelial bladder cancer, with extensive disease to the liver and lung and renal impairment and other medical comorbidities such as hypertension and plaque psoriasis. So, there are a lot of unique aspects to this particular case that are quite different from the initial case.

First and foremost, this is a patient who has metastatic disease and so our treatment that we are administrating is really not for curative intent and is more likely to be palliative in nature. One of the questions we ask is: what factors would influence your option to treat this patient with an immune checkpoint inhibitor? I think the first thing that I will touch on is: is this patient even a candidate for an immune checkpoint inhibitor as a standard of care? Given that this patient has a renal insufficiency with a creatinine clearance of 38 mL/min, this is a patient that I would consider ineligible for cisplatin-based chemotherapy on the basis of renal function and, therefore, would meet one of the indications for first-line immunotherapy with 1 of the currently 2 approved drugs agents: pembrolizumab or atezolizumab.

One of the considerations here is the sites of metastases. What we know is that patients with visceral metastatic disease tend to do poorly, particularly patients with liver metastases. This is an important consideration. Not only do patients with visceral metastases do poorly with chemotherapy, they actually do poorly with all therapies. In fact, the response rate with immune checkpoint inhibitors in patients with visceral metastatic disease, and in particular liver metastases, is particularly poor. It is estimated somewhere in the 8% to 17% range, as compared to the all-comer response rate for first-line immunotherapy, which is somewhere between 25% and 29%.

The other consideration here is the history of an autoimmune syndrome. Patients who have known autoimmune disease have been excluded historically from clinical trials of immunotherapy. Therefore, we do not know with reasonable certainty the safety of these agents in such patients. That being said, this is a patient who has plaque psoriasis without any systemic manifestations. If that is the case, then there is relatively low risk for significant immune-related toxicity, but it is not 0% risk. I think that needs to be a part of the shared decision making with the patient if they do choose to receive an immune checkpoint inhibitor.

The renal function is an important consideration because, for this particular patient, this is the major reason why they cannot safely receive cisplatin-based chemotherapy. For decades, we have been using carboplatin-based therapy for these patients until the recent approval of the immune checkpoint inhibitors.

The role of PD-L1 tumor expression in the first-line setting is an unanswered question. There are somewhat conflicting data as to the role of PD-L1 expression being able to sufficiently discriminate those who are most likely to respond to immune checkpoint inhibitors. There seems to be a trend at least towards higher responses in patients who have high PD-L1 tumor expression, but this needs to be more validated in larger studies and also to help us to make a decision about patients who should rather be treated with chemotherapy first.

TARGETED ONCOLOGY:Are there other biomarkers that point to a specific treatment?

Balar:The other biomarkers that are under consideration would include: tumor mutational burden and TCGA subtype gene expression profile. These are two additional biomarkers which seem to at least associate with response. Another biomarker is gamma-interferon T-cell signature, which is able to identify patients who have T-cell inflamed tumors. Patients with high gene expression profile for this gamma-interferon gene signature seem to have a high likelihood of response. Nonetheless, no single biomarker to date has been able to identify patients who have 0% response likelihood to immune checkpoint inhibitors. Until we have such a biomarker that really and reliably excludes patients from treatment, there is still significant work that needs to be done.

Reference:

Von der Masse H, Hansen SW, Roberts JT, et al; Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of large, randomized, multinational, multicenter, phase III study.J Clin Oncol. 2000;18(17):3068-3077. doi:2000.18.17.3068.