Erdafitinib prevails in bladder cancer with select FGFRalt

The oral selective pan-FGFR tyrosine kinase inhibitor (TKI) erdafitinib demonstrated a survival advantage over chemotherapy, extending multiple efficacy endpoints in individuals with advanced or metastatic urothelial carcinoma (mUC) with FGFR alterations (FGFRalt) after previous anti-PD-(L)1 treatment, findings from the confirmatory phase III THOR trial have shown.

“In our study, erdafitinib significantly extended overall survival (OS) and progression-free survival (PFS), as well as objective response rate (ORR),” said Dr Yohann Loriot from Gustave Roussy, Université Paris-Saclay, Villejuif, France, at ASCO 2023.

Erdafitinib was superior to chemo in terms of OS after a median follow-up of 15.9 months (median 12.1 vs 7.8 months), cutting the risk of death by 36 percent (hazard ratio [HR], 0.64; p=0.005). “Based on these interim analysis results, the IDMC* recommended to stop the study, unblind the data, and cross the patients over from chemo to erdafitinib,” Loriot said.

The OS benefit was consistent across clinically relevant subgroups**, including FGFRalt type. HRs ranged from 0.34 (upper tract disease) to 0.82 (lower tract disease). [ASCO 2023, abstract LBA4619]

Median PFS was twice as long with erdafitinib than with chemo (5.6 vs 2.7 months), cutting the risk of progression or death by 42 percent (HR, 0.58; p=0.0002).

ORR was substantially higher with erdafitinib vs chemo (45.6 percent vs 11.5 percent; relative risk, 3.94; p<0.001). With erdafitinib, 53 patients were able to achieve a partial response (PR), while nine had a complete response (CR). Whereas with chemo, the corresponding numbers were lower (n=14 and 1 for PR and CR, respectively).

The safety profile seen in the study aligned with the know safety profiles of erdafitinib and chemo. The most frequent grade ≥3 treatment-related adverse events (TRAEs) with erdafitinib were PPE*** syndrome, stomatitis, and hyperphosphataemia (10, 8, and 5 percent, respectively).

Erdafitinib was associated with more grade 3/4 AEs of special interest, including nail, skin, and eye disorders (11, 12, and 2 percent, respectively), as well as central serous retinopathy (2 percent). None were reported with chemo.

Only one treatment-related death was reported with erdafitinib. With chemo, there were six.

Eight percent of erdafitinib recipients discontinued treatment owing to TRAEs. “Of these, the most frequent were eye and skin disorders. [Nonetheless,] AEs with erdafitinib were mostly manageable with dose modification and supportive care,” noted Loriot.

Molecular testing important

“After progression on PD-(L)1 inhibitors, treatment options for mUC patients are limited,” said Loriot. “So far, no large randomized studies have demonstrated survival benefit in biomarker-selected populations after anti-PD-(L)1 treatment, thus demonstrating the unmet need for these patients.”

Loriot and colleagues sought to evaluate whether erdafitinib improved survival compared with chemo in this subset of mUC patients who have progressed on or after ≥1 prior treatment including immune checkpoint inhibitors (ICIs). A total of 266 individuals (median age 68 years, 72 percent male) were randomized 1:1 to receive erdafitinib 8 mg QD (with pharmacodynamically guided uptitration to 9 mg) or chemo (docetaxel or vinflunine) Q3W. About 90 percent of participants had PD-L1 low status.

“Overall, our study supports the clinical efficacy of erdafitinib as the standard-of-care option for patients with mUC and FGFRalt after ICI treatment,” concluded Loriot. The OS benefit of erdafitinib also supports molecular testing for FGFRalt in all mUC patients, he added.

Professor Daniel Petrylak from the Yale School of Medicine, New Haven, Connecticut, US, resonated Loriot’s sentiments. “This is the most important take-home message. All patients with mUC need to be tested for FGFR3 or FGFR2 alterations, preferably at first diagnosis.”

“Future studies are needed to develop rational sequencing of erdafitinib … Understanding the resistance pathways to erdafitinib is essential to developing effective combination therapies, either with ICIs, TKIs, or HDAC inhibitors,” added Petrylak.