FDA granted full approval for erdafitinib in 2L mUC

On January 19, 2024, Janssen announced that the FDA granted full US approval for erdafitinib (Balversa; pan-FGFRi) for 2L+ FGFR3alt la/mUC, converting the US accelerated approval ~6 weeks ahead of the target action date. The Balversa USPI has been updated to reflect the new indication.

This approval was expected and provides momentum to erdafitinib but does not change overall assessment of the limited direct threat posed by erdafitinib in the 2L+ setting given its niched use in an FGFRalt mUC population (~15-20%).

Key Highlights and Potential Implications:

• Full US approval was based on Cohort 1 results from the confirmatory P3 THOR trial in which erdafitinib demonstrated benefit versus standard of care chemotherapy (docetaxel or vinflunine) in 2L/3L (incl. prior PD-[L]1i) FGFRalt mUC
  • EU approval is also expected later this year (~Q3’24) following MAA submission in Sept’23
• The full approval indication features several updates versus the accelerated approval indication, reflecting P3 THOR’s enrolled population and totality of results. These changes are not expected to meaningfully change erdafitinib’s market opportunity
  • Notably, the updated indication specifies disease progression following at least one line of prior “systemic therapy” (vs. “platinum-containing chemotherapy”) while also now recommending against its use in patients not previously treated with PD-(L)1i
  • Although these updates could technically position Erda ahead in the treatment paradigm (i.e., as a 2L option to EV + Pembro) based on current label, global insights suggest physician willingness to sequence Trodelvy after EV+Pembro and that US physicians don’t anticipate label limiting Trodelvy usage
• Overall, erdafitinib remains a minor competitor in the 2L+ setting as it is targeted to an FGFRalt mUC population (estimated at up to ~15-20%)
  • However, increasing fragmentation of the 2L+ market could delay use of Trodelvy
  • While strong efficacy results and oral administration may be differentiators for erdafitinib, challenges of AE management and FGFR testing bottleneck/delay will remain key limitations 

Additional Information

• Based on P2 data, erdafitinib received US accelerated approval in 2019 for la/mUC with susceptible FGFR3 or FGFR2 alterations that has progressed during or following platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy
• Key updates to full approval vs US AA indication (updated USPI vs prior USPI)
  • New limitation of use: “not recommended for treatment of patients who are eligible for but have not received prior PD-1 or PD-L1 inhibitor therapy”, likely due to negative Cohort 2 data (OS HR 1.18)
    • Less material given evolving treatment paradigm with PD-(L)1i as backbone of 1L SOCs (including as 1L maintenance); Trodelvy label also specifies prior PD-(L)1i
  • Broader 2L positioning language of disease progression following at least one line of prior “systemic therapy” versus “platinum-containing chemotherapy”, in line with THOR inclusion criteria and allowing for positioning post-EV+P in 1L
  • Key Data – P3 THOR Cohort 1 (per USPI)
    • Efficacy (Balversa vs SOC chemo [docetaxel or vinflunine])
      • mOS (mos): 12.1  vs 7.8 (HR 0.64)
      • mPFS (mos): 5.6 vs 2.7 (HR 0.58)
      • cORR: 35% vs 9%
        • CR: 5% vs 1%
      • Safety
        • Median DOT: 4.8 months (range 0.2-38 mo)
        • Key selected Gr 3-4 AEs (Balversa vs chemo):
          • Nail disorders: 12% vs 0%
          • PPE syndrome: 10% vs 0%
          • Stomatitis: 10% vs 2%
          • Central serous retinopathy: 2% vs 0%
        • Fatal AEs: 4%
          • Sudden death 1.5%, pneumonia 1.5%, renal failure 0.7%, cardiorespiratory arrest 0.7%
        • AEs leading to Balversa discontinuation: 14%, including due to nail disorders (3%) and eye disorders (2%)
        • AEs leading to Balversa dose interruption: 72%, mainly due to nail disorders (22%), stomatitis (19%), eye disorders (16%), PPE syndrome (15%), diarrhea (10%), and others
        • AEs leading to Balversa dose reduction: 69%, mainly due to nail disorders (27%), stomatitis (19%), eye disorders (17%), PPE syndrome (12%), diarrhea (7%), and others
      • Key Data - P3 THOR Cohort 2
        • Population: Erdafitinib monotherapy vs pembrolizumab in 2L FGFRalt mUC naïve to anti-PD-(L)1 treatment
        • Efficacy (Balversa vs SOC chemo [docetaxel or vinflunine])
          • mOS (mos): 9 vs 11.1 (HR 1.18) – OS HR from Cohort 2 noted in USPI
          • mPFS (mos): 4.4 vs 2.7 (HR 0.88)
          • ORR: 40% vs 22%
          • DOR (mos): 4.3 vs 14.4
        • Safety (erda vs pembro)
          • Gr 3-4 TRAEs: 43% vs. 12%
          • Most common Gr3+ TRAEs:
            • Palmar-plantar erythrodysesthesia syndrome: 9.2%
            • Stomatitis: 8.7%
            • Onycholysis: 5.8%
            • Hyponatremia: 5.2%
            • Diarrhea: 3.5%
          • Discontinuation due to TRAEs: 15%
            • Most commonly due to GI disorders (N=9), eye disorders (N=9) and skin and subcutaneous disorders (N=6)