Peter O’Donnell, MD, associate professor of medicine, University of Chicago Medicine, discusses challenges with PD-L1 testing in patients with bladder cancer.

If a patient is cisplatin-ineligible in the frontline setting and is being considered for immunotherapy, PD-L1 testing should be incorporated into their workup, says O’Donnell. However, there are several challenges that remain in testing for the biomarker.

The biggest difficulty is that physicians have 2 FDA-approved diagnostic assays for use in practice and they both have different cut points in how they define the parameters of a positive patient. They also have different algorithms on how to calculate the percentage of positive cells. Moreover, both are linked to an individual drug—one assay is linked to pembrolizumab (Keytruda) use, and the other is linked to atezolizumab (Tecentriq) use. These variances can cause confusion among the medical community, says O’Donnell. If a patient is eligible for one of these therapies, the treating physician should be familiar with how to order each assay and do the proper corresponding scoring, he concludes.

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Dr. O'Donnell on Challenges With PD-L1 Testing in Bladder Cancer

Peter O’Donnell, MD, associate professor of medicine, University of Chicago Medicine, discusses the importance of identifying molecular subsets in urothelial cancer.

A lot of progress has been made in urothelial cancer, says O’Donnell, but the future is likely to rely more heavily on molecular subsets. At O’Donnell’s practice, every patient with metastatic disease is offered genomic sequencing in the frontline metastatic setting. Specifically, this occurs during the time they receive platinum-based chemotherapy as the identification of certain genomic targets may qualify patients for clinical trials.

 family alterations may be eligible for clinical trials, says O’Donnell. Data have been published that have shown promise for those patients. Additionally, PARP inhibitors can be used to target DNA repair mutations. Genomic sequencing may have a direct role in positioning a patient to receive a certain therapy if it becomes approved down the line, adds O’Donnell. Previously, patients with 

 alterations were eligible for trials and now have access to FGFR3 inhibitor therapy.

Dr. O'Donnell on the Importance of Identifying Molecular Subsets in Urothelial Cancer

Peter O’Donnell, MD, associate professor of medicine, University of Chicago Medicine, discusses ongoing immunotherapy trials in bladder cancer.

Physicians are eagerly anticipating trials of dual immunotherapy to see whether it will improve upon existing standards. There are 2 frontline trials where dual immunotherapy is being examined against chemotherapy as a standard backbone or single-agent immunotherapy, says O’Donnell. Moreover, triplets are being examined to see whether the addition of an immunotherapy agent can outperform a chemotherapy doublet. That could change the frontline standard, notes O’Donnell. Those combinations are on the near horizon, he says.

Aside from immunotherapy, there are many other targeted drugs that are in the pipeline. Even though immunotherapy has gained attention in the field, VEGF-targeted drugs are also being examined. An older trial looked at the combination of gemcitabine and cisplatin plus bevacizumab (Avastin), so there may be a role for a VEGF-targeted drug in bladder cancer.

Dr. O'Donnell on Ongoing Immunotherapy Trials in Bladder Cancer

Peter O’Donnell, MD, associate professor of medicine, University of Chicago Medicine, discusses PD-L1 testing in patients with bladder cancer.

PD-L1 testing is now required if a physician is considering using immunotherapy in the frontline setting for a cisplatin-ineligible patient with bladder cancer. It is also required if a physician plans on using immunotherapy in a patient who is chemotherapy-eligible, notes O’Donnell. However, if a patient is eligible to receive gemcitabine/carboplatin, O’Donnell tends to opt for that regimen over immunotherapy.

PD-L1 testing can also be used for patients who could receive either approach. If that type of patient is PD-L1—positive, O’Donnell recommends immunotherapy, whereas a patient who is PD-L1–negative might do better with gemcitabine/carboplatin, states O’Donnell.

Moreover, incorporating PD-L1 testing into practice is especially important following the FDA’s warning in May 2018 cautioning against the frontline use of single-agent immunotherapy, specifically pembrolizumab (Keytruda) or atezolizumab (Tecentriq), in PD-L1—low expressing platinum-eligible patients with advanced urothelial carcinoma.

Dr. O'Donnell on PD-L1 Testing in Bladder Cancer

Peter O’Donnell, MD, associate professor of medicine, University of Chicago Medicine, compares checkpoint inhibitors in the treatment of patients with bladder cancer.

Currently, immunotherapy agents can only be compared by extrapolation because there have not yet been head-to-head clinical trials in this space, O’Donnell says. In phase III clinical trials looking at the platinum-refractory setting, pembrolizumab (Keytruda) has shown a survival advantage against taxane-based chemotherapy. In the same comparison, atezolizumab (Tecentriq) did not show such benefit. As a result, O’Donnell says he finds himself using pembrolizumab because of its Level 1 designation in the platinum-refractory space. He concludes that more survival data are needed to fully distinguish between the available immunotherapies.

Both atezolizumab, a PD-L1 inhibitor, and pembrolizumab, a PD-1 inhibitor, are FDA approved for the frontline treatment of patients with metastatic urothelial carcinoma. The approvals were announced following the results of the IMvigor210 and KEYNOTE-052 studies.

Dr. O'Donnell Compares Checkpoint Inhibitors in Bladder Cancer

Peter O’Donnell, MD, associate professor of medicine, University of Chicago Medicine, discusses the evolution of immunotherapy in metastatic bladder cancer.

When immunotherapy first came to market in advanced bladder cancer, it was approved for patients in the platinum-refractory setting. Since then, it has transitioned to the frontline setting. In May, the FDA announced that immunotherapy should be used sparingly in the frontline setting, especially if a patient has yet to receive platinum-based chemotherapy, notes O’Donnell. Cisplatin-based therapy is still the gold standard in that frontline setting, states O’Donnell.

Based on the FDA announcement, patients who are cisplatin-ineligible should receive gemcitabine and carboplatin rather than immunotherapy monotherapy unless physicians know that that patient is PD-L1—positive. As a result, physicians are doing PD-L1 testing in the frontline setting to try to identify those patients where immunotherapy might be an option. For patients who are not eligible for chemotherapy, the new FDA guidance states that they are eligible to receive immunotherapy as opposed to no treatment at all, adds O’Donnell.

Dr. O'Donnell on the Evolution of Immunotherapy in Metastatic Bladder Cancer

Peter O’Donnell, MD, an assistant professor of Medicine at the University of Chicago Medicine, discusses the phase II IMvigor 210 study, which led to the approval of PD-L1 inhibitor atezolizumab (Tecentriq) in May 2016 as a treatment for patients with locally advanced or metastatic urothelial carcinoma (mUC).

The study included over 300 patients who were all treated with prior platinum-based therapy in the metastatic setting. All patients received atezolizumab once every 3 weeks.

Atezolizumab had an overall response rate (ORR) of 15% in patients with locally advanced or mUC, regardless of PD-L1 expression. Among patients with PD-L1 expression ≥5%, ORR was 26%.

It is notable that the drug worked in patients that both did and did not express PD-L1, said O’Donnell.

The therapy was also quite tolerable. There was a 15% rate of grade 3 and 4 adverse events, an acceptable rate compared with other therapies used for metastatic disease, said O’Donnell.

Peter O'Donnell, MD

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