Success Shown With Biomarker-Informed Treatment in Upper Tract Urothelial Cancer

Infigratinib (Truseltiq) demonstrated substantial activity in patients with localized upper tract urothelial cancer (UTUC) who harbor FGFR3 mutations, according to interim results from a biomarker-informed preoperative study of the oral inhibitor.¹

Findings from the phase 1b trial(NCT04228042) were consistent with previous data reported in patients who were treated in the metastatic setting.

In the study, investigators examined the use of infigratinib prior to surgery in patients with UTUC. The trial enrolled a total of 12 patients with FGFR3 mutations, and 11 patients were deemed evaluable. Participants enrolled are required to have low-grade or localized cisplatin-ineligible high-grade UTUC, currently undergoing either ureteroscopic (URS) management or nephroureterectomy/urethrectomy (NU/U). Further inclusion requirements for patients consist of having a glomerular filtration rate of 30 or greater, sufficient biopsy tissue for mutational analysis, and a tumor map of all residual tumors after endoscopic biopsy and any ablation.

Patients were given 2 cycles of infigratinib at a dose of 125 mg orally for 21 days within a 28-day cycle. After completion of the second cycle, patients underwent tumor mapping based on URS or NU/U. The primary end point of the trial was tolerability with secondary end points including objective response based on tumor mapping, circulating cell-free DNA analysis, expression of markers, and FGFR3 alteration type.

Of the 11 evaluable patients enrolled in the trial, 9 completed therapy and 2 continued on treatment. Among the 9 patients completing therapy, 2 reported having toxicities which prevented them from receiving the full duration of treatment, and 4 (44%) patients had a response with tumor reduction (range 25%-83%). All patients who responded had FGFR3 mutations. Among non-responders, a majority had a prior history of bladder cancer and 1 had FGFR3-TACC3 fusion.

Overall, infigratinib showed substantial activity and tolerability in patients with localized UTUC with FGFR3 mutations. Enrollment is currently underway for the phase 2 expansion of the trial evaluating additional cycles, based on these promising initial results.

In an interview with Targeted Oncology^TM, Matthew T. Campbell, MD, assistant professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, examined the positive phase 1 study results of infigratinib for the treatment of patients with localized UTCU.

Targeted Oncology: Can you explain the phase 1b trial of evaluating the tolerability and activity of FGFR inhibition in localized UTCU?

Campbell: This is a phase 1B clinical trial for patients with upper tract urothelial cancer. These patients have to have either low-grade upper tract urothelial cancer, or high-grade and not be considered cisplatin chemotherapy candidates. In this study, they are provided with 2 cycles of infigratinib, which is a pill-based therapy that targets FGFR3 mutations. After that point, patients undergo either laser therapy for residual cancer with the goal of trying to preserve the kidney, or they can undergo a nephroureterectomy depending on Dr. Surena Matin, or Dr. Mehrad Adibi or other urologists at MD Anderson's opinion for best care for these patients.

We reported the early patients treated in the study. It's still ongoing and still accruing. We found that 4 out of 9 patients had significant tumor aggression on the infigratinib. Several of these patients were able to undergo surgery that spared them the need to surgically remove their kidney. The patients that seemed to benefit the most, as we anticipated, are those that harbor FGFR3 mutations.

So far, the 2-month therapy has been reasonably well tolerated. These drugs have well known side effect profiles, and the 2 months seems to be reasonable for the majority of patients to make it through. Side effects are managed with treatment holds and treatment breaks.

With the trial still ongoing, what results are you looking to further unveil?

We're really interested in trying to figure out, can we do therapies for patients with this cancer and spare them as often as possible the need to lose their ureter in their kidney. Unfortunately, oftentimes with these patients, they have limited kidney function to begin with, or they have at times multifocal disease, which means that they can have cancer in both ureters, or renal pelvis, and sometimes in the bladder as well. That can create a major problem for these patients.

We're trying to figure out how we can best maximize the therapy. We're interested in exploring either stretching out the therapy or looking at potential combinations to see if we can maximize the impact of these treatments. We're planning to specifically reserve these treatments for patients that have the FGFR3 mutation.

How have previous studies examined infigratinib? Are there any ongoing trials evaluating the oral inhibitor?

Infigratinib has been explored in metastatic urothelial cancer and there is a nice signal of activity. It is being explored and being tested right now for patients that have an FGFRI-3 mutation as an adjuvant therapy, and for urothelial cancer for upper tract disease. It is being looked at in other cancer types as well.

What unmet needs remain in this patient population?

We continually need better treatments for patients with low grade disease, as well as high grade disease. We need to have the best treatment strategies that we can for patients with reduced kidney function. There have been some important studies that have been published recently in upper tract urothelial cancer, and it's exciting that a number of groups are really exploring this area, but we still have a long way to go.

Much of the focus has been urothelial cancer of the bladder. While there are a lot of similarities, there are some nuances to upper tract urothelial cancer that really require us to study it in isolation.

What are the key points from this research you hope community oncologists take away?

Right now, the takeaway is that it is very feasible to do studies. In this patient population you can accrue to them. We've seen that recently with a nice study from Memorial Sloan Kettering which is showing that we can do studies in this patient group.

The takeaway for community urologists and oncologists is that we still need additional information before this would become something to consider for patients, but it is a promising strategy that warrants further investigation.

What do you believe are the next steps in this research?

In the future, we are looking forward to reporting the final results and looking forward to also expanding it and doing a phase 2 study. We anticipate that the study will be fully accrued by the end of this year. We would hope around this time next year that we can report the conclusions of this study. The next phase of this study is currently under discussion, but we would hope to be able to open the next phase in the near future as well.

REFERENCE:

Matin S, Adibi M, Shah A, et al. LBA01-10 Interim results from a phase 1b clinical trial evaluating tolerability and activity of fgfr inhibition in localized upper tract urothelial carcinoma (utuc). J Urol. 2022;207(5):e1039. doi: 10.1097/JU.0000000000002669.10