Targeting FGFR Mutations in Metastatic Urothelial Cancer - Episode 8

Frontline Therapy for Metastatic Urothelial Cancer


Factors that impact the selection of immunotherapy vs chemotherapy for frontline metastatic urothelial cancer.

Arlene O. Siefker-Radtke, MD: I hear that you’re reaching for cisplatin whenever possible. This patient is bit borderline with a GFR [glomerular filtration rate] of 54 mL/min/1.73 m2. We don’t know if their kidney is obstructed or not. If it were obstructed, you would try to place a nephrostomy tube or a stent to see if you could improve the kidney function, correct? Even in the metastatic setting and if the patient were willing?

Scott T. Tagawa, MD, MS, FACP: Yes.

Arlene O. Siefker-Radtke, MD: That’s an important thing to note. All the studies have suggested that cisplatin is better than carboplatin. Whenever you can give it safely, it can help extend a patient’s life. As you point out, there’s that tail of the curve of long-term survivors from cisplatin. Although arguably, those were probably more than node-only disease who then underwent surgical consolidation rather than this unfortunate gentleman with the extensive liver metastases. Is there anything about this case that’s leading you away from that frontline immune checkpoint inhibitor?

Scott T. Tagawa, MD, MS, FACP: The answer is yes, but I’ll come back to that. In the setting of whatever testing, whatever drug, PD-L1 high, let’s say, and not a cisplatin candidate, but is a carboplatin candidate, there is a choice in terms of front-line PD-1 or PD-L1 vs carboplatin-based therapy. In my mind, with the introduction of phase 3 overall survival data for maintenance PD-L1—not that I have randomized data to say that it’s better—I’ve mostly shifted in carboplatin candidates, regardless of the PD-L1 results, to gemcitabine-carboplatin followed by avelumab. I recognize that remains a factor. I recognize that some patients that are not great chemotherapy candidates or refuse chemotherapy.

The other part that you may have been hinting at was the FGFR. We don’t know what it was. It said, “Activating FGFR3 mutation.” There’s a bit of conflicting data. But many of the data sets point toward a lower chance of response to at least single-agent immune checkpoint inhibition. That would be in the back of my mind in terms of starting off with chemotherapy, as well as the liver metastasis.

Arlene O. Siefker-Radtke, MD: Those are great points. The liver metastases have historically had very low response rates to an immune checkpoint inhibitor. There’s a sense that immunotherapy can’t debulk these tumors once they’ve spread to the liver. Giving something cytoreductive may be most helpful. I like the idea of giving cisplatin if at all possible, which is what I would typically do, with split-dose cisplatin. I’m still a believer in split-dose—giving the cisplatin over 2 days, which we’ll do in a GFR as low as 40 mL/min/1.73 m2. But we also would make sure, if we were giving cisplatin, that the kidney is not obstructed; otherwise, the patient will suffer from further kidney damage if their kidney is obstructed by the tumor.

I also want to make a point that there are clinical trials in the frontline setting. If any colleagues in the community have a patient like this, please consider referring them. There are several trials looking at FGF inhibition with or without an immune checkpoint inhibitor. The goal is to potentially overcome any immuno-resistance that has been reported, at least in some data sets, in patients treated with FGF-targeted agents where they didn’t see as good a response with immunotherapy. And we have several trials where early data—the NORSE trial of erdafitinib with or without cetrelimab in the frontline setting, poor GFR—suggest a response rate of around 65% in patients who have received erdafitinib with cetrelimab, which is an immune checkpoint inhibitor. There are lots of clinical trials to consider. But outside a clinical trial, I’d recommend that standard cytoreducing with chemotherapy and then, as Scott mentioned, that maintenance strategy with maintenance avelumab, given the benefit that has been seen with survival.

Transcript edited for clarity.