Applying Recent Developments in Targeted Molecular Therapeutics for Advanced Bladder Cancer

Bladder cancer is one of the most common cancers, estimated to be the 10^th most common cancer worldwide, but molecular therapeutics for patients with advanced bladder cancer have evolved greatly in recent years.

Shilpa Gupta, MD, Director of Genitourinary Medical Oncology at the Cleveland Clinic Taussig Cancer Institute and Co-Leader of the Cleveland Clinic Genitourinary Oncology Program, discussed recent developments in targeted molecular therapeutics for advanced bladder cancer.

GU Oncology Now: How have targeted molecular therapeutics for advanced bladder cancer changed the treatment landscape?

Shilpa Gupta, MD: I’m Dr. Shilpa Gupta, I’m a genitourinary medical oncologist at the Cleveland Clinic Taussig Cancer Institute in Cleveland, Ohio. Today, we are talking about molecular therapeutics for advanced bladder cancer.

We really made a lot of progress in the last four or five years with these novel drugs for patients who have had prior chemotherapy and immunotherapy, or either/or. Especially notable are the advances with the first targeted therapy, which targets a mutation in bladder cancer, called FGFR. Erdafitinib was approved a few years ago for patients who harbor this mutation in their tumors, and it led to remarkable responses and clinical outcomes. Especially since after patients have had immunotherapy, we really did not have a whole lot of choices, and immunotherapy doesn’t work in everybody. In fact, it only works in about 20% patients.

The other class of drugs, is the antibody-drug conjugates, which are really unique agents, they have an antibody and the linker, which makes them a very effective therapy. The two antibody-drug conjugates that we now have approved are enfortumab vedotin and sacituzumab govitecan, which have been used in patients who have had prior therapies, including chemotherapy and immunotherapy. Enfortumab vedotin has full FDA approval for patients with progression on any one prior line of therapy. Sacituzumab govitecan has accelerated FDA approval in patients who had prior platinum chemo and immunotherapy.

GU Oncology Now: How do targeted molecular therapeutics for advanced bladder cancer compare with immune checkpoint inhibitors and more traditional chemotherapy regimens?

Shilpa Gupta, MD: Immune checkpoint inhibitors, we’ve seen in bladder cancer, for example, that we really don’t have a good biomarker to select which patients may benefit from that therapy. Although, in the past, there was a thought that high PD-L1 expression makes patients respond better. We are seeing more and more that PD-L1 has not panned out to be a great biomarker. So, at this point, anybody with advanced bladder cancer who progresses on platinum chemotherapy can get checkpoint inhibitors.

We have shown in some work that high tumor mutational burden can potentially serve as a complement to clinical decision making for patients who are not candidates for cisplatin-containing chemotherapy in the frontline setting and can help where the immunotherapy or carboplatin-based chemotherapy is the better option. In terms of how the molecular therapeutics are different from immunotherapy, I think the highlight is that these agents are effective, even after patients have had immunotherapy and progressed. For example, the FGFR inhibitor, if patients harbor the mutation, they could have had one prior line of therapy, and can be treated with this agent. And many times, patients are not fit enough to receive chemotherapy, and if we are able to give these targeted agents, that really creates an additional option. Same goes for the antibody-drug conjugates, which can be given to patients who may not be candidates for chemotherapy.

GU Oncology Now: Are there certain types of patients who are ideal candidates for molecular therapeutics?

Shilpa Gupta, MD: So at this point, for the FGFR inhibitor erdafitinib, the key criteria that we need is the presence of the alteration or mutation of fusion in the tumor for the patient—that’s one of the features that is needed for the drug to work—and besides that, patients who are able to swallow the pills and don’t have any other issues. I think those are the key factors. Those agents have a different set of toxicity profiles, which is very different from chemotherapy, but it still requires monitoring, especially their phosphorus levels. Sometimes patients can get ocular toxicity, so we need to team up with ophthalmologists. It’s a whole team effort for those agents, even though it is not traditional chemotherapy.

For antibody-drug conjugates, I think the key criteria is progression, or prior immunotherapy, or chemotherapy. However, these drugs can also have a lot of side effects, even though they may be different from traditional chemotherapy. For example, enfortumab vedotin has side effects of rash, which can be very severe, and peripheral neuropathy, which can be severe. So, in patients who already have grade two neuropathy, we would be cautious about using it, or adjusting the dose, or giving them a treatment break. As far as the other antibody-drug conjugate, sacituzumab govitecan, goes the side effect profile is different. It can cause life-threatening neutropenia, neutropenic fever, or diarrhea. We have to be very proactive with the use of growth factors and anti-diarrheal agents and close monitoring.

I think the patient’s comorbidities do determine this. The presence of uncontrolled diabetes, for example. We see instances of diabetic ketoacidosis with EV, so we have to just be cautious, and monitor these things closely. I would say that, based on the patient’s comorbidities, and the toxicity profile of these individual agents, we would select what to use first. Ideally, we would want to use all these agents in some sequence.