Erdafitinib/Cetrelimab Combination Shows Strong Efficacy for Metastatic Urothelial Carcinoma

Erdafitinib plus cetrelimab displayed strong responses for patients with metastatic or locally advanced urothelial carcinoma.

The combination of Erdafitinib (Balversa) plus cetrelimab (JNJ-63723283) showed clinically significant response results among patients with metastatic or locally advanced urothelial carcinoma (mUC) harboring FGFR alterations, according to preliminary data from the phase 2 NORSE trial (NCT03473743) presented by Thomas Powles, MD, during the European Society for Medical Oncology 2021 Virtual Congress.

Erdafitinib plus cetrelimab elicited an overall response rate (ORR) of 68% (95% CI, 43%-87%) in 19 efficacy-evaluable patients, compared with 33% (95% CI, 13%-59%) in 18 patients treated with erdafitinib with pharmacodynamically guided uptitration (UpT). Confirmed complete responses were seen in 4 patients and 1 patient, respectively. The median duration of response (DOR) was 6.9 months (95% CI, 1.6-not evaluable [NE]) in patients treated with erdafitinib plus cetrelimab vs NE (4.4-NE) in the erdafitinib monotherapy group.1

Erdafitinib is an oral pan-FGFR inhibitor and cetrelimab is an immunoglobulin G4 monoclonal antibody specific for PD-1.2

“The standard of care for newly diagnosed mUC is cisplatin-based chemotherapy, however over 50% of patients with mUC are ineligible for cisplatin treatment,” said Powles, director, lead for Solid Tumor Research, and a professor of genitourinary oncology at the Barts Cancer Center in London, England. “Treatment options for patients with newly diagnosed mUC include alternative chemotherapy regimens or anti-PD-(L)1 monotherapy for patients with PD­–L1-positive tumors. There is a significant unmet need for new treatments for patients with mUC who are ineligible for cisplatin.”

Results from the phase 1b portion of the trial established the recommended phase 2 dose (RP2D) as erdafitinib 8-mg UpT plus 240-mg cetrelimab. At the April 2020 data cutoff, the confirmed ORR in 11 evaluable patients treated at the RP2D was 55% and the disease control rate (DCR) was 100%. In the overall patient population (N = 22), treatment-emergent adverse events (TEAEs) occurred in 91% of patients and 32% of patients experienced serious TEAEs.

The phase 2 portion of the NORSE trial enrolled a total of 53 patients and randomized them 1:1 to receive either erdafitinib monotherapy (n = 26) or erdafitinib plus cetrelimab (n = 27). The safety analysis set consisted of 24 patients in each arm and the efficacy-evaluable set was made up of 18 and 19 patients in the monotherapy and combination arms, respectively.

In the monotherapy arm, erdafitinib was administered at a dose of 8 mg with pharmacodynamically UpT up to 9 mg. In the combination group, once-daily erdafitinib was given at a dose of 8 mg in plus 240 mg cetrelimab intravenously every 2-weeks for cycles 1 to 4 and 480 mg every 4 weeks thereafter.

To be eligible for the ongoing trial, patients needed to be at least 18 years old with a confirmed diagnosis of mUC and measurable disease. Patients also needed to have a select FGFR alteration (mutation or fusion), no prior systemic therapy for mUC, and be ineligible for cisplatin.

The primary end points of the trial are ORR and safety. Key secondary end points include DCR, DOR, and time to response. No formal statistical comparisons between arms were prespecified.

The median age of patients treated with erdafitinib alone was 75 (range, 45-92) and 73% of patients were males. In terms of ECOG performance status, most patients registered a 0 or 1 (77%) and 23% scored a 2. Most patients in this arm had an unknown PD-L1 status (54%) and a lower tract primary tumor location (76%). FGFR mutations (88%) were the dominant alteration and no patients had both mutations and fusions.

In the combination group, the median age was 69 (range, 56-91) and 74% of patients were male. Again, ECOG performance status was mostly 0 to 1 (63%) and lower tract was the primary tumor location in 85% of patients. FGFR alterations were more evenly distributed in this arm: 67% of patients had mutations, 26% had fusions, and 1 patient had both.

Both trial arms had impressive DCRs, patients treated with erdafitinib monotherapy experienced a 100% DCR (95% CI, 82%-100%) and the combination arm achieved a DCR of 90% (95% CI, 67%-99%). The median time to response was 2.3 months (range, 1-6) and 1.8 months (range, 1-4), respectively.Responses are ongoing in 28% of the monotherapy cohort and in 53% of the combination cohort.

Patients in both treatment arms experienced durable reductions in the sum of target lesion diameters over time. The median of the maximum reduction in the sum of target lesion diameters was 28% in the erdafitinib group and 51% in the erdafitinib plus cetrelimab cohort.

In general, the safety profile of erdafitinib plus cetrelimab was similar to that of erdafitinib alone. TEAEs of any grade occurred in 96% of the safety populations of both arms. Grade 3/4 TEAEs occurred in 38% of the monotherapy arm and in 50% of the combination arm. There was also 1 death due to respiratory failure in the erdafitinib plus cetrelimab cohort that was determined to be related to cetrelimab.

The most frequent TEAEs of any grade in the monotherapy arm were stomatitis (63%), hyperphosphatemia (58%), diarrhea (50%), and anemia (25%). In the combination arm, hyperphosphatemia and dry mouth were most common (both 58%), followed by stomatitis (54%) and diarrhea (42%).

The incidence of TEAEs of interest was mostly similar between arms, with the exception of immune-related TEAEs. Immune-related TEAEs of any grade occurred at a rate of 50% in the combination arm compared with 4% in the monotherapy group. Common immune-related TEAEs in the erdafitinib plus cetrelimab group consisted of diarrhea and increased lipase (13% each) and stomatitis and anemia (8% each).

“These are the first data on erdafitinib plus cetrelimab in patients with mUC with FGFR alterations who are ineligible for cisplatin-based therapy,” concluded Powles. “Preliminary findings suggest that adding cetrelimab to erdafitinib may improve ORR and depth of response in this population. These data suggest a potential positive interaction between erdafitinib and cetrelimab, possibly mediated by priming the immune environment via neoantigen release in patients with FGFR alterations to increase the response to immune checkpoint blockade.”


  1. Powles TB, Chistyakov V, Beliakouski V, et al. Erdafitinib (ERDA) or ERDA plus cetrelimab (CET) for patients with metastatic or locally advanced urothelial carcinoma (mUC) and fibroblast growth factor receptor alterations (FGFRa): first phase (Ph) 2 results from the NORSE study. Presented at: European Society for Medical Oncologists 2021 Virtual Congress. September 16-21, 2021. Virtual. Abstract LBA27.
  2. Siefker-Radtke AO, Loriot Y, Siena S, et al. 752P Updated data from the NORSE trial of erdafitinib (ERDA) plus cetrelimab (CET) in patients (pts) with metastatic or locally advanced urothelial carcinoma (mUC) and specific fibroblast growth factor receptor (FGFR) alterations. Ann Oncol. 2020;31(suppl 4):S584-S585. doi:10.1016/j.annonc.2020.08.824
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