PD-L1 Expression in Metastatic Urothelial Cancer

Shilpa Gupta, MD: Immunotherapy is approved for platinum-refractory patients and their 5 immunotherapy drugs, which are approved, but pembrolizumab was the only drug that has level 1 evidence back by the phase 3 KEYNOTE-045 trial. That is our drug of choice for patients who progressed after platinum-based therapy, although any of the other immunotherapy agents can be used.

As far as first-line immunotherapy use goes, patients who are not eligible for cisplatin and have a high PD-L1 expression in their tumors or do not have high PD-L1 expression are recommended to get single-agent immunotherapy, either pembrolizumab or atezolizumab. These are the only 2 agents recommended. In patients who are not eligible to receive carboplatin either, they can get single-agent immunotherapy too.

We don’t have strict definition for patients who cannot get carboplatin, but our group had done a consensus survey last year and presented at GU ASCO (American Society of Clinical Oncology Genitourinary Cancers Symposium) some guiding factors to which patients cannot be recommended carboplatin. There’s still a lot of work to do in identifying those patients.

Jeanny Aragon-Ching, MD: Currently, there are 5 checkpoint inhibitors that are approved for metastatic urothelial cancers. In this space, most, if not all, of them are approved in the second-line therapy and beyond. This includes pembrolizumab, nivolumab, and durvalumab, which are all PD-1 inhibitors, as well as avelumab and atezolizumab for PD-L1 inhibitors.

In terms of how the PD-L1 expression levels would factor into these FDA approvals, it is important to recognize and remember that these 5 checkpoint inhibitors that are approved for second-line therapy and beyond do not rely on the PD-L1 expression. That means if a patient has failed prior chemotherapy and they are eligible because they have progressed, they can go on to 1 of these 5 checkpoint inhibitors.

On the other hand, there is 1 disease state that is limited by PD-L1 testing, and that is in the first-line metastatic urothelial cancer setting, in terms of the cisplatin-ineligible patients. You may all recall that in 2018, the FDA set a limit for the use of pembrolizumab and atezolizumab, especially for patients who are considered cisplatin-ineligible. The value of PD-L1 testing is limited largely to this population of patients with a cisplatin-ineligible first-line metastatic setting. That is because the key finding from the data safety-monitoring board showed a key finding of the phase 3 trials of IMvigor130 and KEYNOTE-316, which was that the monotherapy arm of the atezolizumab and pembrolizumab showed decreased survival compared with the platinum-based chemotherapy arm. If we are thinking of a patient who is cisplatin-ineligible, PD-L1 testing would be beneficial because if they have high expression of PD-L1, that’s when we can use this over chemotherapy. Obviously, if they are considered platinum-eligible, meaning they cannot receive carboplatin, then that would be the time that you can use these drugs without really testing.

For the longest time in the history of the metastatic urothelial cancer treatment landscape, we’ve had a dearth of drugs. We’ve only had chemotherapy for the longest time. We know the use of checkpoint inhibitors truly revolutionized treatment. The challenge we face in the bladder cancer community is that the actual responses for the use of this drug still have to be improved. It’s in the order of 20%, sometimes as much as 40%, with those who are PD–L1-positive, so there is still a big area of increased, unmet need. One other thing to consider is while most patients do tolerate it without any issues, it is not truly without toxicity either. These have to be factored in when considering patients for these types of treatments with checkpoint inhibitors.

Shilpa Gupta, MD: The drugs are well tolerated compared with chemotherapy. Most patients do very well. Quality of life is maintained on immunotherapy compared with chemotherapy use. However, the risk of immune-related adverse events needs to be explained to the patients because while rare, some of these adverse events can be fatal, so we have to be good teachers and monitor patients very closely. Now that pembrolizumab dosing has been approved for at least 6 weeks, we still do checks every 3 weeks on patients to make sure we’re not missing anything because immunotherapy-related adverse effects can be quite subtle compared with what patients observe with chemotherapy.

Transcript Edited for Clarity