For patients with advanced or metastatic bladder cancer whose disease does not respond to standard cisplatin-based chemotherapy, immunotherapy is an attractive treatment option. However, only 15%–20% of bladder cancers respond to immune checkpoint inhibitors, and patients whose disease does not respond to chemotherapy or immunotherapy have few treatment options. Fortunately, some such patients may achieve a response to new agents that target FGFR (fibroblast growth factor receptor).
FGFR genes are mutated in 20%–60% of urothelial carcinomas, the most common bladder cancers. In particular, FGFR3, which appears to be involved in the development of bladder cancer, is mutated in about 15% of patients with metastatic urothelial carcinoma. FGFR3 mutations are believed to contribute to higher rates of cancer cell proliferation in the urothelial lining, allowing the cells to acquire more mutations and transition to higher-grade, more invasive disease.
Bladder tumors with these mutations seem uniquely resistant to immunotherapy. “FGFR3-mutant bladder tumors appear to be associated with the luminal 1 subtype, which is immunologically cold, with low expression of immune markers,” said Arlene Siefker-Radtke, M.D., a professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center. “As we were treating bladder cancer patients with immune checkpoint inhibitors, I started noticing that the FGFR3-mutant tumors were not responding well, and these patients were stopping treatment relatively quickly.”
To address the unmet need of patients whose advanced or metastatic bladder cancer does not respond to chemotherapy or immune checkpoint inhibitors, Dr. Siefker-Radtke is leading clinical trials of the pan-FGFR inhibitor erdafitinib and the FGFR3 inhibitor B-701.
Potential of erdafitinib
Because erdafitinib inhibits all four FGFR isotypes at low concentrations of the drug, this agent may work better than previously studied FGFR-inhibiting compounds in tumors with FGFR mutations. After erdafitinib showed early evidence of activity against FGFR-mutant bladder cancer in a small phase I trial, a phase II trial (No. 2015-0112) was performed to test the tolerability and effectiveness of various dose regimens of the drug in patients with previously treated metastatic or unresectable FGFR2- or FGFR3-mutant urothelial carcinoma of the bladder. The drug was well tolerated at a continuous dose of up to 8 mg orally daily, and the dose could be titrated up to 9 mg daily in patients who did not experience toxic effects or high phosphorus levels.
Better yet, among the 59 patients treated, “The overall response rate at the optimal daily dose of 8–9 mg, depending on the patient, was 42%, and we are seeing evidence of durable responses, with some responses lasting more than 1 year with continued treatment,” Dr. Siefker-Radtke said.
These responses have included partial remissions of urothelial carcinoma liver metastases, which typically have a poor prognosis, even with treatment. Liver metastases from bladder cancers typically do not respond well to treatments that target the immune system, Dr. Siefker-Radtke said. However, some patients in the erdafitinib trial saw their liver metastases shrink dramatically, including one patient who had previously tried immunotherapy and had not had any benefit from it.
The experiences of the patients in the trial supported the theory that FGFR3-mutant tumors are less responsive to immunotherapy. “Twenty-two of the patients had prior immunotherapy, and only one of them had responded to an immune checkpoint inhibitor,” Dr. Siefker-Radtke said. “And that response was not durable.”
Because of these results, presented at the American Society of Clinical Oncology meeting this June, the U.S. Food and Drug Administration has granted erdafitinib a breakthrough therapy designation for the treatment of metastatic urothelial carcinoma.
Current erdafitinib trials
An upcoming phase III trial (No. 2018-0027) will more clearly define the role of both erdafitinib and immune checkpoint inhibitors in the treatment of FGFR-mutant bladder cancers. The trial will enroll patients who have FGFR-mutant metastatic or unresectable urothelial carcinoma of the bladder and have undergone prior systemic therapy. Patients who have previously been treated with a PD-1 (programmed cell death protein 1) inhibitor will be randomly assigned to receive either erdafitinib or chemotherapy with taxanes (the standard of care). And patients who have not undergone prior immunotherapy will be randomly assigned to receive either erdafitinib or the PD-1 inhibitor pembrolizumab.
“This trial will help us determine whether FGFR3-mutant tumors respond better to erdafitinib or immunotherapy,” Dr. Siefker-Radtke said.
Another upcoming trial (No. 2018-0142) will examine how erdafitinib may interact with immune checkpoint inhibitors in combination therapy, possibly by allowing more immune cells to enter the tumor. Patients in the phase II portion of the trial will receive erdafitinib alone or combined with the PD-1 inhibitor JNJ-63723283.
“We will see if the use of erdafitinib will change the tumor environment to one that’s more sensitive to immune checkpoint inhibition and perhaps have synergistic effects,” said Dr. Siefker-Radtke, who will be the principal investigator of both trials.
It is not clear whether a pan-FGFR inhibitor such as erdafitinib or a specific inhibitor of FGFR3 will provide a more effective strategy in patients with FGFR3-mutant bladder cancer because toxic effects may increase as more FGFR isotypes are inhibited. To illuminate the potential of a more selective inhibitor, an ongoing phase IB/II trial (No. 2017-0580) will determine the safety and efficacy of an agent that selectively targets FGFR3. The drug, B-701, is given alone or in combination with pembrolizumab in patients who have locally advanced or metastatic urothelial carcinoma with or without FGFR3 mutations.
The B-701 trial, like the erdafitinib trials, is led by Dr. Siefker-Radtke. “Only by doing these trials will we gain an understanding of whether pan-FGFR inhibition or FGFR3 inhibition is required for a treatment that is both safe and effective,” she said.
Although pan-FGFR inhibitors such as erdafitinib and more specific FGFR3 inhibitors such as B-701 have been developed with advanced bladder cancer in mind, their uses could eventually extend to earlier-stage disease. Dr. Siefker-Radtke said that either drug, if it continues to demonstrate activity against bladder cancer, could present a new option for patients whose early-stage disease may require cystectomy. She added, “Maybe erdafitinib or B-701 will allow patients to keep their bladders longer or keep their tumors from transforming into a more aggressive disease.”
For more information, contact Dr. Arlene Siefker-Radtke at 713-792-2830 or firstname.lastname@example.org. To learn more about clinical trials at MD Anderson, visit www.clinicaltrials.org and search by cancer type, treatment, physician, or trial number.
OncoLog, July 2018, Volume 63, Issue 7