Findings from a phase II study indicate clinical efficacy with erdafitinib in patients with FGFR-altered inoperable or metastatic urothelial carcinoma. Robust responses were seen with this investigational pan-FGFR inhibitor, including in patients who did not respond to prior immunotherapy.

According to data from a phase II study, erdafitinib (Janssen), an investigational pan-FGFR inhibitor, showed clinical efficacy in patients with FGFR-altered inoperable or metastatic urothelial carcinoma (mUC). The results were presented by Arlene Siefker-Radtke, MD, of The University of Texas MD Anderson Cancer Center in Houston, on June 3 at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL.

Although there are five FDA-approved immune checkpoint inhibitors for mUC, “it has become clear that not all patients benefit from PD-1 blockade,” Siefker-Radtke said. Those harboring FGFR alterations, which occur at a frequency of roughly 20%, are thought to have immunologically “cold” tumors that are less likely to respond to such treatment. Molecularly targeted therapies are needed for these patients, she added, given their lack of options and typically poor outcomes.

The investigators evaluated erdafitinib in 99 patients whose disease had progressed on, or who were ineligible for, platinum chemotherapy. Siefker-Radtke reported that the objective response rate (ORR) to erdafitinib was 40%, including three complete responses. The median time to response was 1.4 months. In one case, she said, “the patient had rapid, systemic disease progression with very large, bulky liver metastases, but his tumor burden was reduced by 53% after just 6 weeks, and by 82% at 12 weeks.” The median progression-free survival was 5.5 months, she added, and the median overall survival was 13.8 months.

Erdafitinib was largely well tolerated, Siefker-Radtke said; common side effects included low-grade hyperphosphatemia and dry skin. Ocular problems—chiefly central serous retinopathy, a known class effect of MAPK pathway inhibitors—were managed by routinely monitoring patients for any visual changes.

In an exploratory subgroup analysis, the investigators found that only one of 22 patients had responded to prior immunotherapy. By contrast, Siefker-Radtke observed, the ORR with erdafitinib in this group was 59%.

Discussing these data during the ASCO meeting, Andrea Apolo, MD, a genitourinary malignancies investigator at the NCI, considered the ORR “pretty impressive, given that the majority of patients had visceral metastases, and this population is generally refractory to treatment.” The quick time to response was also notable, she said.

In addition to erdafitinib, the pan-FGFR inhibitor BGJ398 (Novartis) has shown promising efficacy in a similar population of patients with mUC. According to recently published phase I trial results, among 67 participants, the ORR with BGJ398 was 25.4%, and the drug was also well tolerated.

“I think these two data sets support the role of small-molecule FGFR inhibitors in advanced bladder cancer,” said Sumanta Pal, MD, of City of Hope Comprehensive Cancer Center in Duarte, CA, first author of the BGJ398 article. “Both suggest good response rates that are quite comparable in many respects, with similar toxicity profiles.” One difference with the BGJ398 study, he added, is that “through cell-free DNA analyses, we detected several FGFR resistance mutations that emerged during the course of therapy. This hasn't been reported yet in the context of erdafitinib, but it's something we should be mindful of as this class of drugs is further developed.”

Additional studies in mUC are ongoing with erdafitinib, including the phase III THOR trial: Patients not previously given immunotherapy will be randomly assigned to receive erdafitinib or pembrolizumab (Keytruda; Merck); and those who have received prior PD-1 blockade will be given either the FGFR inhibitor or taxane chemotherapy. –Alissa Poh