Immunotherapy's Role in Advanced Bladder Cancer Continues to Evolve

Immunotherapy has been a buzzworthy topic in the field of bladder cancer over the last couple of years. However, according to a Food and Drug Administration (FDA) safety warning, patients with metastatic disease may need to have their treatment altered.

After analysis of two clinical trials, the FDA warned against the frontline use of single-agent Keytruda (pembrolizumab) or Tecentriq (atezolizumab) in patients with advanced urothelial carcinoma who are platinum-eligible and whose tumors test low for PD-L1 status.

“We’re trying to solve how to integrate immunotherapy in terms of where we use it and at what sequence we use it along with chemotherapy, which has been our standard for many years,” said Peter O’Donnell, M.D., an associate professor of medicine at the University of Chicago Medicine, in an interview with OncLive, a sister publication of CURE.

About a year ago, O’Donnell mentioned that he was using frontline immunotherapy to treat his patients; however, that has since changed.

“It’s changed dramatically just in the last couple of months, with the FDA announcements, that (oncologists are) restricted in our use of frontline immunotherapies if the patient hasn’t received platinum (chemotherapy) yet,” he said. “Certainly, cisplatin-based therapy is still the gold standard in that frontline setting. If (a) patient is cisplatin-ineligible, (an oncologist is) going to be offering them a cisplatin-based combination.”

For patients who are not eligible to receive cisplatin-based therapy, O’Donnell said that these patients should be receiving gemcitabine or carboplatin instead of immunotherapy, unless it is known that they are positive for PD-L1 — the protein that checkpoint inhibitors target – which is now being tested for in the frontline setting.

However, patients who are not eligible for any kind of chemotherapy are able to receive immunotherapy rather than no treatment at all, per FDA guidance, O’Donnell said.

These treatment nuances outline the importance of testing patients for PD-L1, which is required for cisplatin-ineligible patients or chemotherapy-eligible patients who may still wind up on an immunotherapy.

“If I’m concerned about my patient’s chemotherapy fitness, then the label would suggest I could just give that patient immunotherapy. I find myself wanting to test the PD-L1 status in those patients who are on the border,” O’Donnell said. “I might be able to give them gemcitabine/carboplatin, but they might do better with immunotherapy.”

O’Donnell also mentioned that treatment protocol is likely to continue to change for this population, especially as two targeted agents potentially move into the space: erdafitinib and enfortumab vedotin.

Erdafitinib is an oral pan-FGFR inhibitor that was granted FDA breakthrough therapy designation in March 2018. “We’re all interested to see where that fits in the armamentarium if it’s approved,” O’Donnell said.

Enfortumab vedotin is an anti-body drug conjugate that has shown clinical benefit among patients in an early-phase study. “It has a very interesting signal in patients with liver metastases,” he added. “Traditionally, that is a terrible prognostic factor, but this drug is showing impressive response rates in this population.”

As the field continues to advance, it is going to become even more important to test patients’ tumors to narrow down the best possible treatment for that individual — and that may mean a clinical trial. For example, patients with HER2 or ERBB family alterations could be eligible for clinical trials, O’Donnell explained. Other trials are also investigating the efficacy of PARP inhibitors in this space.

“We can’t stop here. The future is in molecular subsets of metastatic urothelial carcinoma,” O’Donnell said.

This was adapted from an article that appeared on OncLive under the title, “Immunotherapy Continues to Be Integrated in Metastatic Bladder Cancer”