Arlene Siefker-Radtke, MD, MD Anderson Cancer Center at The University of Texas, Houston, Texas, shares results from the phase 3 THOR study which compared erdafitinib with pembrolizumab among pretreated patients with advanced or metastatic urothelial cancer with certain FGFR alterations.

This study found similar overall survival between erdafitinib and pembrolizumab, though erdafitinib showed a numerically longer progression-free survival and numerically higher objective response rate.

Dr Siefker-Radtke added, “As we think about positioning these agents, I do think it appears that the majority of patients, at least based on population-based studies, should receive chemotherapy and an immune checkpoint inhibitor first. However, we're still dealing with patients at the individual level. And there could be patients in a visceral crisis who are having significant symptoms…and perhaps giving erdafitinib earlier will work.”

Transcript:

I am at ESMO 2023 discussing the results of the THOR clinical trial. I am Arlene Siefker-Radtke, a professor of genitourinary medical oncology at the University of Texas MD Anderson Cancer Center, where I do all bladder cancer, all the time. We've seen a very big ESMO this year talking about the field of urothelial cancer with multiple trials reading out.

The THOR clinical trial was based on the biology of FGFR3 alterations, which are present in 15% to 20% of urothelial tumors of the bladder and up to 35% of urothelial tumors of the upper tract, including the renal, pelvis and ureter, as these are potentially targetable mutations. We developed a clinical trial studying a novel treatment, erdafitinib, a pan-FGFR inhibitor, which inhibits all 4 FGFRs 1 through 4. And the goal was to see, is there clinical activity in patients with urothelial cancer?

If we look at early evidence with erdafitinib, erdafitinib was previously granted accelerated approval in the United States on the basis of a phase 2 clinical trial showing an objective response rate of 40% and a median survival of nearly 1 year. The THOR phase 3 clinical trial was designed to try to determine whether erdafitinib would be better than the typical standards of care chemotherapy. We saw the results of the earlier cohort presented at ASCO proving that there's a significant improvement in overall survival when comparing erdafitinib with a single-agent taxane. And as a result, we saw objective response rates of around 40% and again, a median survival that was definitely better than what was observed with chemotherapy alone.

But our story didn't end there. If we look at the impact of FGFR3 alterations, they appeared to associate with immunologically cold tumors. And these immunologically cold tumors with low PD-L1 expression, at least based on early clinical trial data in urothelial cancer, they were predicted to have a lesser degree of benefit from an immune checkpoint inhibitor. As a result, we wanted to study the impact of erdafitinib in patients who had these alterations, but compare it to pembrolizumab to determine, is there an optimal sequence to therapy? This is one of the first trials looking at sequencing: should we give a treatment earlier or should we allow the current standards of care to be driving patient care?

This clinical trial randomized over 175 patients in each arm, and unfortunately, it was a negative clinical trial. We did not see an improvement in survival. The survival rates were similar between the erdafitinib and the pembrolizumab groups. This is despite an objective response rate of 40% with erdafitinib compared to a 21% objective response rate observed with pembrolizumab. When we looked at the survival curve, the impact of erdafitinib was seen early, which I think reflects its cytoreductive capacity. We see very good responses, patients with symptoms which would improve dramatically within 2 weeks of starting therapy. But immune checkpoint inhibitors have a durability of response that has not been achieved with cytoreductive strategies. And as a result, even though the response rate was lower with pembrolizumab, those who did respond had more durable outcomes compared to the response or the durability of response with erdafitinib alone.

As we think about positioning these agents, I do think it appears that the majority of patients, at least based on population-based studies, should receive chemotherapy and an immune checkpoint inhibitor first. However, we're still dealing with patients at the individual level. And there could be patients in a visceral crisis who are having significant symptoms, gross hematuria, that's been challenging to control, worsening dyspnea due to rapidly progressive lung metastases. These are patients where cytoreduction may be indicated, and perhaps giving erdafitinib earlier will work.

Source:

Siefker-Radtke AO, Matsubara N, Park SH, et al. Phase III THOR study: Results of erdafitinib (erda) vs pembrolizumab (pembro) in pretreated patients (pts) with advanced or metastatic urothelial cancer (muc) with select fibroblast growth factor receptor alterations (FGFRalt). Presented at ESMO Annual Congress; October 20-24, 2023; Madrid, Spain. Abstract 2359O