Petros Grivas, MD, PhD, director, University of Washington Medicine’s Genitourinary Cancers Program, associate professor, Oncology, University of Washington, Seattle Cancer Care Alliance, discusses the IMvigor211 trial in metastatic urothelial carcinoma.

The IMvigor211 trial with atezolizumab (Tecentriq) versus chemotherapy did not meet its primary endpoint of overall survival (OS) benefit. However, Grivas explains that the primary endpoint was OS in the subset of patients with high PD-L1 expression.

The trial was designed in a hierarchal fashion. Therefore, the primary endpoint of OS had to be met before investigators examined the combination in all-comers. However, Grivas explains that the investigators used a different assay to evaluate PD-L1 expression compared with other trials.

In this study, the assay showed that patients who had a higher PD-L1 expression lived longer and had better outcomes. However, Grivas explains that it is more difficult to see a difference between the 2 arms if people live longer in this subset. That may be why the primary endpoint of the trial was negative.

In all-comers, there was a statistically significant difference with atezolizumab versus chemotherapy in platinum-refractory advanced urothelial cancer. Therefore, if the study was not designed in a hierarchal fashion, the trial would have been positive by statistical criteria, states Grivas.

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Dr. Grivas on the IMvigor211 Trial in Metastatic Urothelial Carcinoma

Petros Grivas, MD, PhD, director, University of Washington Medicine’s Genitourinary Cancers Program, associate professor, Oncology, University of Washington, Seattle Cancer Care Alliance, discusses ongoing trials in advanced bladder cancer.

Right now, there are ongoing trials that are evaluating whether targeted therapies, such as FGFR inhibitors, may have activity in this disease. Early data from phase I trials in well-selected patients look very promising, says Grivas. Moreover, there are other agents that target the 

There are also data with antibody-drug conjugates. These are toxins that are linked to an antibody that can target a particular protein in urothelial cancer cells. This can lead to the internalization of the toxin, which can potentially kill the cancer cells, explains Grivas. Two antibody-drug conjugates have shown interesting results that are being moved to larger phase II and III trials.

Antiangiogenic agents are also being evaluated, says Grivas. There is a pending trial looking at the combination of gemcitabine and cisplatin with or without the anti-VEGF agent bevacizumab (Avastin). The combination will be evaluated in the first-line setting in cisplatin-eligible patients. The trial has been going on for a while but has still not read out yet, which Grivas believes may be a result of patients’ improved survival outcomes.

Dr. Grivas on Ongoing Trials in Advanced Bladder Cancer

Petros Grivas, MD, PhD, director, University of Washington Medicine’s Genitourinary Cancers Program, associate professor, Oncology, University of Washington, Seattle Cancer Care Alliance, discusses the use of immunotherapy in patients with advanced urothelial cancer.

There is much excitement surrounding the advent of immune checkpoint inhibitors, says Grivas. Many of the approvals in urothelial cancer were based on single-arm phase II trials. There have been 2 randomized phase III trials trying to evaluate the role of immune checkpoint inhibitors, such as pembrolizumab (Keytruda) versus single-agent taxane—docetaxel or paclitaxel&mdash;in the United States.

The trial met the primary endpoint of overall survival (OS) benefit with pembrolizumab as a salvage therapy versus chemotherapy in patients with platinum-refractory advanced urothelial cancer, says Grivas. The median OS difference was about 3 months, favoring pembrolizumab in all-comers.

Based on the assay that was used, patients with higher PD-L1 expression still showed benefit with pembrolizumab. This provided level 1 evidence for the use of pembrolizumab in patients with platinum-refractory advanced urothelial cancer. That agent has the highest level of evidence in the salvage setting in patients who progress on or after platinum-based chemotherapy, Grivas says.

Dr. Grivas on Immunotherapy in Advanced Urothelial Cancer

Petros Grivas MD, PhD, director, University of Washington Medicine’s Genitourinary Cancers Program, associate professor, Oncology, University of Washington, Seattle Cancer Care Alliance, discusses emerging biomarkers in advanced urothelial cancer.

Physicians have developing data regarding emerging biomarkers in advanced urothelial cancer. In May 2018, the FDA released a statement commenting on the potential role of PD-L1 immunohistochemistry testing to predict whether patients would respond better or worse to immune checkpoint inhibitors. Predicting response to therapy based on PD-L1 expression is not part of clinical practice, says Grivas.

It may become another debate whether physicians consider that biomarker expression further. For the time being, Grivas says it is not a companion diagnostic. It is, however, something to look for alongside tumor mutational burden, gene expression profiling and subtypes, DNA damage response to mutations, and circulating tumor DNA. These will be examined in prospective clinical trials to evaluate their clinical utility, says Grivas.

Petros Grivas MD, PhD, director, University of Washington Medicine’s Genitourinary Cancers Program , associate professor, Oncology, University of Washington, Seattle Cancer Care Alliance, discusses emerging biomarkers in advanced urothelial cancer.

Dr. Grivas on Emerging Biomarkers in Urothelial Cancer

Petros Grivas, MD, PhD, medical oncologist, Cleveland Clinic, discusses next steps for immunotherapy for the treatment of patients with bladder cancer.

According to Grivas, this is a great environment because there are many ongoing clinical trials. There are close to 1000 clinical trials across tumor types evaluating different combinations of immunotherapy

Dr. Grivas on the Next Steps for Immunotherapy in Bladder Cancer

Petros Grivas, MD, PhD, medical oncologist, Cleveland Clinic, discusses combining chemotherapy and immunotherapy as a treatment approach for patients with bladder cancer.

Chemotherapy alone has the potential to induce changes in a tumor microenvironment. Cleveland Clinic data indicated there was variability in PD-L1 and PD-L2 expression after neoadjuvant chemotherapy in patients. Some patients had a lower PD-L1/PD-L2 expression at the cystectomy specimens compared with the transurethral resection of bladder tumor specimens. Those who experienced increased or stable PD-L1 expression had earlier recurrence.

The combination of chemotherapy with immunotherapy may have synergistic results, says Grivas. There is also the theoretical concept of immunogenic cell death that needs to be further evaluated in clinical practice, explains Grivas.

Petros Grivas MD, PhD

Articles

Dr. Grivas on the IMvigor211 Trial in Metastatic Urothelial Carcinoma

Dr. Grivas on Ongoing Trials in Advanced Bladder Cancer

Dr. Grivas on Immunotherapy in Advanced Urothelial Cancer

Dr. Grivas on Emerging Biomarkers in Urothelial Cancer

Dr. Grivas on the Next Steps for Immunotherapy in Bladder Cancer

Dr. Grivas on Combining Chemotherapy and Immunotherapy in Bladder Cancer