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Janssen Plans Year-End Erdafitinib Filing Based on Phase II Data in FGFR-Mutated Bladder Cancer

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NEW YORK (GenomeWeb) – Janssen will pursue US marketing approval for the FGFR inhibitor erdafitinib after a Phase II study showed the drug shrunk tumors in 40 percent of patients with advanced urothelial cancer and FGFR mutations.

The Phase II trial, presented earlier this month at the American Society of Clinical Oncology annual meeting, enrolled 99 patients with metastatic or surgically unresectable, locally advanced urothelial cancer. All patients had FGFR fusions or mutations determined by central lab testing and received erdafitinib.

Up to 20 percent of metastatic urothelial cancers, which commonly affect the bladder and ureter, harbor FGFR alterations. Arlene Siefker-Radtke from MD Anderson Cancer Center, who presented the Phase II data at the ASCO meeting, noted that FGFR alterations are seen in around 30 percent of upper tract tumors and at even higher rates in earlier development stages of the disease, particularly in patients with non-muscle invasive bladder cancer.

In the trial, 40 patients saw their tumors shrink — three had complete responses, and 37 had partial responses. An additional 39 had stable disease, with a median response duration of 5.6 months. Overall, three-fourths of the study participants saw some shrinkage of target lesions.

Siefker-Radtke and colleagues also looked at whether response to erdafitinib differed between patients who had FGFR mutations and FGFR fusions and found that it didn't. "When we first started out, we were trying to determine what types of FGFR alterations would predict sensitivity to erdafitinib, and it turns out that both types … respond well," Craig Tendler, vice president of late-stage development, global medical affairs for oncology/hematology at Janssen Research & Development, told GenomeWeb.

Separately at ASCO, researchers reported the first data from the National Cancer Institute's basket study, MATCH, which is evaluating the activity of targeted drugs across tumor types that only have a biomarker in common. One of the first arms to report data involved patients with FGFR alterations — fusions, single nucleotide variants, or amplifications — who were treated with AstraZeneca's investigational FGFR inhibitor AZD4547. In this arm, patients with FGFR fusions fared best and researchers recommended further investigation of AZD4547 in this subset of patients. 

Although erdafitinib's development program involves the use of a companion diagnostic to identify patients with FGFR alterations, Janssen is not disclosing the test development partner. "The companion diagnostic has been an integral part of the development program from the beginning," Tendler said. "We are working with a vendor who has a lot of experience developing these types of companion diagnostics."

Janssen plans to submit a premarket approval application for the in vitro diagnostic kit to the US Food and Drug Administration alongside the regulatory filing for the drug. It has inked companion diagnostic partnerships with a number of firms for its portfolio of drugs, including Illumina to develop a universal next-generation sequencing-based assay that can guide treatment based on multiple tumor markers associated with response to a range of drugs. 

The FDA granted erdafitinib breakthrough therapy designation in March. In her presentation, Siefker-Radtke recounted the experience of one patient in the trial who had "very large, bulky liver metastases" and was progressing quickly before starting erdafitinib. "When we enrolled him, he told me, 'Doctor, I feel like I'm dying,'" she said.

The patient had indicated that he would leave the study if he wasn't feeling better in two weeks, because he wanted to spend his last days with his children. "Two weeks later, his symptoms had significantly improved," Siefker-Radtke said. "He achieved an 82 percent reduction in the size of the tumor by his second restaging."

The median progression-free survival in the study was around 6 months, and median overall survival was more than a year. Patients in the trial mostly had grade 1 or grade 2 toxicities in the trial, though seven patients discontinued due to treatment-related toxicities, including three patients who developed an eye disease, central serous retinopathy, that causes visual impairment.

This year, more than 81,000 patients will be newly diagnosed with bladder cancer in the US and more than 17,000 will die from the disease. Patients with advanced urothelial cancers tend to have poor outcomes, with objective response rates around 10 percent or less and median survival of seven to nine months on standard chemotherapy.

Newly diagnosed urothelial cancer patients are usually treated with a combination of chemotherapy agents gemcitabine and cisplatin. Those with advanced disease who cannot receive or don't respond to cisplatin, and whose tumors express PD-L1, can receive the immunotherapy Keytruda (pembrolizumab).

"The recent development of immunotherapy has yielded much excitement in the field, with improved clinical outcomes," said Siefker-Radtke, but she noted that only around 20 percent of patients respond to such treatment and the median overall survival is approximately 10 months. "It has become clear that not all patients benefit from this therapy."

In this Phase II study, researchers also tried to explore the impact of immunotherapy treatment in urothelial cancer patients with FGFR alterations. Specifically, they considered how a subset of 22 patients who had previously been treated with immunotherapy responded to erdafitinib, and found that the objective response rate was 59 percent.

"The response that we're seeing in patients that have been previously exposed to checkpoint inhibitors, progressed, and went on our trial, was very comparable to what we saw in the overall study population," Tendler said. He added that the data from this Phase II trial suggest that erdafitinib is efficacious in patients with FGFR-mutated urothelial cancer before or after they receive checkpoint inhibitors.

However, of the 22 patients who had immunotherapy, only 1 responded. This seems to suggest that patients with FGFR mutations may be poor responders to checkpoint inhibitors. "This is an observation coming out of the Phase II study, and it's something we're continuing to investigate," Tendler said.

Janssen is now investigating erdafitinib in a Phase III trial, comparing it against chemotherapy or the immunotherapy Keytruda. In another Phase Ib/II study, Janssen is studying erdafitinib in combination with JNJ-63723283, a PD-1 inhibitor.

In the Phase III study, erdafitinib will be evaluated in a second-line setting. "The hypothesis is that the FGFR alteration will predict good response to erdafitinib and suboptimal response to the checkpoint inhibitor," Tendler said. Patients in this study will have to have FGFR alterations, but will not need to have PD-L1 expressing tumors because they'll be receiving second-line treatment.

The Phase Ib/II study is combining erdafitinib and a PD-1 inhibitor in a frontline setting. According to Tendler, Janssen has reason to believe from prior research that in an earlier stage disease, the two mechanisms of actions, an immune-activating agent along with a targeted therapy, may complement each other. The efficacy assessment in this study will be done in patients who have both PD-L1-positive tumors and FGFR alterations.

Janssen is pursuing FDA approval for erdafitinib based on the Phase II data presented at the ASCO meeting, and is hoping to complete the regulatory submission for erdafitinib in this indication by the second half of 2018.

The drugmaker is also exploring the activity of erdafitinib in other tumor types characterized by FGFR alterations, such as in cholangiocarcinoma, lung cancer, and multiple myeloma.