Arlene O. Siefker-Radtke, MD, discusses the promise of erdafitinib in patients with urothelial carcinoma.
Arlene O. Siefker-Radtke, MD
Erdafitinib, a novel pan-FGFR inhibitor, demonstrated promising activity in patients with urothelial cancer who harbor FGFR alterations, according to recent data from a phase II trial.
Urothelial cancer is an aggressive disease that generally leaves a patient with a grim prognosis, said Arlene O. Siefker-Radtke, MD; however, erdafitinib might be the key agent to providing FGFR-mutant patients with the necessary therapy.
More than 40% of patients with metastatic or unresectable urothelial carcinoma responded to treatment with erdafitinib, according to the phase II findings presented by Siefker-Radtke at the 2018 ASCO Annual Meeting. Overall, 40 out of 99 patients responded to treatment with erdafitinib. An additional 39 patients had stable disease. Responses occurred in patients who had no prior exposure to chemotherapy, as well as those who had progressed or relapsed after previous treatment. Response rates were similar in patients with or without visceral metastases.
Patients were orally treated with 8 mg daily with uptitration to 9 mg daily. Enrolled patients had progressed on 1 or more prior lines of therapy or within 12 months of neoadjuvant therapy, or were ineligible for first-line platinum-based chemotherapy. Patients with prior exposure to immunotherapy were also included.
The FDA granted erdafitinib a breakthrough therapy designation in March 2018 for the treatment of patients with metastatic urothelial carcinoma.
FGFR alterations occur in 15% to 20% of metastatic urothelial carcinomas and 40% to 70% of non-muscle invasive bladder cancers. These tumor types tend to be immunologically cold and, therefore, do not respond to immunotherapy, Siefker-Radtke said.
In an interview with OncLive, Siefker-Radtke, associate professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, clinical co-leader, Bladder Spore Executive Committee, discussed the promise of erdafitinib in patients with urothelial carcinoma.Siefker-Radtke: Bladder cancer is really no longer just one disease. We have been treating it that way for several decades now. What we are learning is that there are different types of bladder cancers, some that respond better to chemotherapy, some that respond better to immunotherapy, and some that appear immunologically cold. In fact, the FDA just announced they are no longer accruing patients with low PD-L1 expression to the frontline single-agent immunotherapy trials. Therefore, there is growing evidence that we need more options for our patients with bladder cancer.
FGFR3 tumors may reflect one of those unmet needs. There are some early data that suggest these tumor types may be more immunologically cold. There is a new treatment called erdafitinib that targets FGFR-altered tumors. We saw FGFR3 alterations in approximately 15% to 20% of patients with metastatic urothelial cancer. We saw them at a higher frequency—in the 30% range—for patients with metastatic upper-tract urothelial cancers. In earlier-stage disease, the frequency may be as high as 50% or 60% in patients with low-grade, low-stage urothelial cancers. Finding a treatment that can target these may provide us with better control for our patients.
Erdafitinib is a pan-FGFR inhibitor and it targets FGFR 1, 2, 3, and 4. It is a very good inhibitor to target these alternations. It also has lysosomal uptake, which may enhance sustained intracellular release, impacting the good activity of this treatment. Therefore, the rationale of this trial was to study the use of erdafitinib in a group of patients with metastatic and mostly previously treated urothelial tumors who had need of a new agent. Some of them received prior immunotherapy and some of them had chemotherapy.
The first part of the trial was randomized. We did not know whether continuous dosing was better versus intermittent dosing. As a result of the early part of the trial, continuous dosing was selected, and we were even able to up titration from 8 mg/day to 9 mg/day if patients did not achieve a certain target phosphorous level. The trial data suggest that there is some clinical activity, and the study met its primary endpoint. This was out of 99 patients in the select phase II cohort.
The therapy was very well tolerated and very few patients discontinued treatment because of side effects. The most common reason for discontinuing was due to eventual progression of disease…The [median] progression-free survival was around 5.6 months, and the median overall survival was 13.8 months.
There are currently plans for a large phase III trial, which will explore the question, “Do patients with FGFR-altered tumors respond differently to an FGFR-targeted therapy compared with immunotherapy?” For patients with these tumors, if they had not had prior immunotherapy, they will be randomized to either erdafitinib or immunotherapy.When we looked at patients on this clinical trial, we saw a group of them—about 22 patients— who had prior immune checkpoint inhibition prior to going on treatment with erdafitinib. We do not have the actual images to look at responses, but we did look at the investigator-reported response rates. Out of those 22 patients, there was only 1 response. That was a little interesting. They did not respond to single-agent checkpoint inhibition, but they did have a response to a combination treatment.
At the moment, we see about a 5% objective response rate reported by investigators. There are also data from another group looking at FGF-amplified tumors. They looked at the response to prior therapy with their FGFR inhibitor. They saw 1 patient out of 10 who had stable disease as the best result. We have some data sets suggesting that these types of tumors may not respond well to immunotherapy, but it is not conclusive. The phase III trial for erdafitinib does intend to address that question.We are still learning how this impacts the immune system. One question is, “If these tumors are indeed cold to the immune system, would erdafitinib combined with an immune checkpoint inhibitor make a difference?” There is currently a phase Ib/II trial planned combining erdafitinib with immune checkpoint inhibition. It will determine whether this combination is safe and if there is any improved efficacy.
A second question is, “Could this drug impact earlier-stage disease?” We have seen higher rates of FGFR alterations in superficial bladder tumors. These are patients at risk for ultimate progression of tumor and loss of their bladder. If we had a more effective treatment for those patients, would it help keep them from transforming into a cancer that will take their lives quickly? Would it also help them keep the bladders they were born with?
These are some questions I hope will be addressed in the future.Absolutely. FGFR3 alterations are not just associated with urothelial cancer. We can see them in a host of other tumors, including glioblastoma. There are trials being planned in those settings as well.
I would just encourage everyone to support their local clinical trials. We have a lot of new and exciting therapies that we hope will make a difference for our patients.
Siefker-Radtke AO, Necchi A, Park SH, et al. First results from the primary analysis population of the phase II study of erdafitinib (JNJ-42756493) in patients with metastatic or surgically unresectable urothelial carcinoma and FGFR alterations. J Clin Oncol. 2018;36 (suppl; abstr 4503).