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New Agents in Bladder Cancer
Beyond Chemotherapy: Checkpoint Inhibitors Are Changing My Approach to Bladder Cancer

Released: December 14, 2017

Expiration: December 13, 2018

Matthew Galsky
Matthew Galsky, MD
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For decades, the standard first-line treatment for metastatic bladder cancer has been chemotherapy, starting with the development of cisplatin-based combination regimens. It was soon realized that not all patients with bladder cancer are suitable for cisplatin-based treatment, as this disease occurs more commonly in older patients who often have comorbidities and are typically not candidates for aggressive chemotherapy; the median age of diagnosis in the United States is 73 years. Patients with bladder cancer often have tobacco-related comorbidities as well as renal impairment, and many have had subclinical ureteral obstruction from their tumor. Due to these and other factors, administering cisplatin-based chemotherapy safely has been challenging.

This challenge led to the development of alternative cytotoxic regimens for patients who are not eligible cisplatin, most of which have largely been carboplatin-based chemotherapy. In particular, the combination of gemcitabine/carboplatin is widely used in patients with metastatic bladder cancer who are considered ineligible for cisplatin treatment. This is based on results from a randomized phase III trial comparing carboplatin/gemcitabine with a combination of 3 drugs: methotrexate, vinblastine, and carboplatin (M-CAVI). Findings from that study demonstrated that carboplatin/gemcitabine led to a slightly higher ORR (41% vs 30% with M-CAVI; P = .08) and was somewhat safer compared with M-CAVI. That said, patient outcomes with carboplatin/gemcitabine were not optimal, with no statistically significant differences in OS and PFS, and the regimen was still associated with substantial toxicity.

The need to develop better regimens for this patient population persists. In this commentary, I discuss how I see immune checkpoint inhibitors improving outcomes for patients with metastatic bladder cancer.

New First-line Strategy for Cisplatin-Ineligible Patients
As new strategies to treat all patients with bladder cancer are developed in clinical trials, there have been efforts to better define patients who are ineligible for cisplatin; consistency is important in clinical trials, particularly for patient populations with unmet needs. This happened concurrently with the introduction of immune checkpoint blockade into clinical trials in bladder cancer, which, of course, dramatically changed the treatment landscape. Of importance, the vast majorities of studies exploring immune checkpoint blockade, specifically with PD-1 and PD-L1 inhibitors, in patients with metastatic bladder cancer have enrolled patients who progressed on platinum-based chemotherapy (ie, second line or beyond). To date, 5 immune checkpoint inhibitors have been approved by the FDA for patients with advanced urothelial carcinoma who have progressed on platinum-based chemotherapy: atezolizumab, pembrolizumab, nivolumab, durvalumab, and avelumab.

In addition to the clinical trials of immune checkpoint inhibitors for patients with bladder cancer who progress on platinum-based chemotherapy, and because of the great unmet need, additional studies also explored immune checkpoint inhibitors as first-line treatment of patients ineligible for cisplatin. The criteria defining “cisplatin ineligibility” in these studies included performance status and kidney function (typically calculated creatinine clearance < 60 mL/min), as well as baseline neuropathy and hearing loss.

Immune Checkpoint Blockade for Cisplatin-Ineligible Patients: Clinical Trials
Favorable activity and lower toxicity of immune checkpoint inhibitors vs historical data with first-line gemcitabine/carboplatin in large single-arm phase II trials led to FDA approvals in 2016 and 2017. Both the PD-1 inhibitor pembrolizumab and the PD-L1 inhibitor atezolizumab have been approved for first-line therapy of patients with metastatic cisplatin-ineligible bladder cancer based on response rates of approximately 25% to 30%. As seen in other disease states, these responses appear durable. However, we do not yet have data from randomized phase III trials of first-line checkpoint inhibitors vs chemotherapy in patients with metastatic bladder cancer.

There are at least 4 randomized phase III trials exploring immune checkpoint blockade as first-line treatment for metastatic urothelial cancer, both cisplatin-eligible and cisplatin-ineligible patients. These trials have 2 general designs:

  1. Comparison of PD-1/PD-L1 blockade alone vs chemotherapy alone vs combination PD-1/PD-L1 blockade plus chemotherapy (KEYNOTE-361, IMvigor130)
  2. Comparison of PD-1/PD-L1 blockade alone vs combination PD-1/PD-L1 blockade plus CTLA-4 blockade vs chemotherapy alone (CheckMate 901, DANUBE)

Checkpoint inhibition may also have merit as a maintenance strategy after first-line chemotherapy. Two trials are exploring this strategy: a randomized phase II study being run through the Hoosier Cancer Research Network and the JAVELIN Bladder 100 phase III trial . Although these data will be interesting, the role of a maintenance approach is unclear if immune checkpoint inhibitor combination regimens become the first-line standard of care for metastatic bladder cancer.

How I Am Applying Checkpoint Inhibitors in the Clinic
In my practice, I use PD-1 or PD-L1 blockade as our first-line treatment of choice for patients with metastatic urothelial cancer who are ineligible for cisplatin treatment, unless there is a specific contraindication to the use of those drugs (eg, active autoimmune disease). Not only has immune checkpoint blockade become our preferred first-line treatment rather than chemotherapy for these patients, but it has also allowed us treat some patients who are not optimal candidates for chemotherapy.

Although immune checkpoint blockade is expanding the range of patients with bladder cancer who can be treated, defining “chemotherapy-ineligible” patients is challenging, and similarly immune checkpoint blockade may be associated with a suboptimal risk:benefit proposition in such patients. Expanding our understanding of the role of immune checkpoint inhibitors through observational data in real-world populations underrepresented in clinical trials will be important. Furthermore, regardless of the patient population, minimizing risk by understanding the spectrum and management of unique immune-related adverse events is critical. For practical guidance on managing immune-mediated toxicities associated with immune checkpoint inhibition, try CCO’s interactive algorithm tool, "Managing Immune-Related Adverse Events: An Interactive Algorithm Tool." This tool provides evidence-based, expert-recommended management strategies for immune-related adverse events based on the type and severity of the event.

A New Tool to Help Guide Treatment Decisions for Patients With Urothelial Cancer
To help you address challenges with treatment decisions for your patients with bladder cancer, my colleagues—Matthew I. Milowsky, MD; Daniel P. Petrylak, MD; Elizabeth R. Plimack, MD, MS; and Jonathan E. Rosenberg, MD—and I are creating a treatment decision tool for bladder cancer. This online tool will help you select among the various treatment options for your patients by showing you recommendations from each of the experienced faculty listed above specifically for the patient information you enter into the tool using a variety of pull-down menu options. Check back in on the CCO Web site soon for this online tool, along with additional commentaries from the experts.

How have you used immune checkpoint inhibitors to treat your patients with advanced and metastatic bladder cancer? Share your thoughts in the comment box below.

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In your clinic, have you used immune checkpoint inhibitors as first-line therapy for patients with advanced, unresectable bladder cancer?
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