Systemic treatment for advanced urothelial cancer is quickly evolving. On this week's podcast, Arjun Balar, MD, director of the genitourinary medical oncology program at New York University discusses his approach amid changing times with guest host Alan Lyss, MD, a community-based medical oncologist and clinical researcher in the St. Louis area before his recent retirement.

Chemotherapy or immunotherapy first line?

With the negative phase 3 results for chemotherapy in combination with either pembrolizumab or atezolizumab, "if I use immunotherapy, I use it alone," Dr. Balar said.
Patients who need "a response right away" for aggressive disease get chemotherapy. In general, first-line chemotherapy "probably is the better route for a lot of people," he said.
There is a role for immunotherapy in the first line when chemotherapy can't be tolerated because of age or other reasons, and in the second line, immunotherapy is standard of care.
PD-1/PD-LI expression is too inconsistent to help guide the decision. It's based instead on clinical judgement, given patient and disease characteristics.

Antibody-drug conjugates

The class includes enfortumab vedotin and sacituzumab govitecan, both approved for third-line treatment after chemo and immunotherapy.
Essentially, they are homing molecules targeting cancer-specific antigens coupled with a potent cytotoxic payload.
They have strong potential in combination with immunotherapy. "I think, in the next 3-5 years, we're going to find ADCs plus immunotherapy become the new standard of care," Dr. Balar said.
New enfortumab vedotin data show activity in the second line among medically frail patients ineligible for chemotherapy who were treated instead with immunotherapy for metastatic disease. "This drug can potentially rescue those patients as an option after immunotherapy," said Dr. Balar, an enfortumab vedotin investigator.

Next-generation sequencing

There's no role yet for sequencing in the first line, but it's necessary in later lines to check eligibility for drugs aimed at specific mutations, such as the tyrosine kinase inhibitor erdafitinib for patients with susceptible FGFR3 or FGFR2 genetic alterations.
Assays are available commercially from Foundation and other companies.
Results can take up to 6 weeks, so "I do it early on. I know that information is potentially going to be useful in making treatment decisions," Dr. Balar said.

Enfortumabe vedotin adverse events

Side effects can include hyperglycemia within the first one or two cycles. Sometimes it's asymptomatic, sometimes it's accompanied by acid-base disturbances, and in very rare cases, it's fatal. The problem is possibly linked to higher baseline body mass index.
At least half of patients develop a sunburn-like rash, also within the first one or two cycles, that spares the face and can be pruritic. It's manageable by topical steroids, oral antihistamines, dose reductions, or dose interruptions.
"If anything severe is going to happen, it's going to happen within the first one or two cycles. I see [patients at] every visit" in the first two cycles "primarily to catch anything untoward," Dr. Balar said.
Neuropathy is the "most significant dose-limiting toxicity, and tends to develop about 4 months into treatment," he said.

Show notes written by M. Alexander Otto.

Dr. Balar disclosed research, advisory, and/or speaker relationships with Genentech, Incyte, Bristol-Myers Squibb, Janssen, Merck, Pfizer, AstraZeneca, and other companies. Dr. Lyss writes a column for MDedge Hematology/Oncology called "Clinical Insights" and had no other conflicts of interest.