FGFRalt are seen in ∼20% of pts with mUC. Erda is an oral pan-FGFR tyrosine kinase inhibitor for pts with locally advanced or mUC with susceptible FGFR3/2alt who have progressed after platinum-containing chemo. THOR (NCT03390504), a randomized phase 3 study, assessed whether erda provided an overall survival (OS) advantage vs chemo in pts with mUC who progressed after 1-2 prior therapies (tx), including anti-PD-(L)1.
Pts (≥18 y) with unresectable advanced/mUC and select FGFR3/2alt (mutations/fusions), ECOG PS 0-2, adequate organ function, progression on/after 1-2 prior lines of systemic tx that included anti-PD-(L)1 were randomized 1:1 to erda (8 mg with pharmacodynamically guided uptitration to 9 mg) QD or investigator’s choice of chemo (docetaxel or vinflunine) Q3W until disease progression or intolerable toxicity. Primary end point was OS. Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.
266 pts were randomized (median [m] age 67 y, follow-up 16 mo) to erda (N=136) or chemo (N=130). Primary end point was met: mOS 12.1 vs 7.8 mo in erda vs chemo (HR=0.64; 95% CI, 0.47-0.88). OS benefit was seen across subgroups (Table). Erda improved mPFS (6 vs 3 mo) and ORR (46% vs 12%) vs chemo. Most frequent tx-related adverse events (TRAEs): hyperphosphatemia (79%), diarrhea (55%), and stomatitis (46%) with erda; anemia (28%), alopecia (21%), and nausea (20%) with chemo. 46% in each arm had Gr 3/4 TRAEs. 1 and 6 pts had TRAEs leading to death with erda and chemo, respectively. Table: 2362MO
| Subgroup | Erda (n=136) | Chemo (n=130) | HR (95% CI) | |||
| n | mOS, mo | n | mOS, mo | |||
| Age | <65 y | 59 | 14 | 45 | 9 | 0.46 (0.27-0.79) |
| ≥65 y | 77 | 11 | 85 | 8 | 0.71 (0.47-1.07) | |
| Baseline ECOG PS | 0-1 | 125 | 12 | 119 | 9 | 0.65 (0.46-0.90) |
| 2 | 11 | 6 | 11 | 3 | 0.47 (0.16-1.35) | |
| FGFRalt | Fusion | 25 | 16 | 19 | 8 | 0.49 (0.23-1.03) |
| Mutation | 108 | 11 | 107 | 8 | 0.67 (0.47-0.95) | |
| Prior lines of tx | 1 | 45 | 14 | 33 | 8 | 0.61 (0.35-1.09) |
| 2 | 90 | 12 | 97 | 8 | 0.67 (0.45-0.98) | |
| Visceral metastasis | Y | 103 | 12 | 101 | 8 | 0.65 (0.45-0.93) |
| N | 33 | 11 | 29 | 9 | 0.61 (0.32-1.14) | |
| Primary tumor | Upper tract | 41 | 23 | 48 | 7 | 0.34 (0.18-0.64) |
| Lower tract | 95 | 11 | 82 | 10 | 0.82 (0.56-1.18) | |
| Chemo | Docetaxela | 136 | 12 | 69 | 11 | 0.76 (0.52-1.11) |
| Vinfluninea | 136 | 12 | 43 | 8 | 0.60 (0.39-0.92) | |
| PD-L1 status | CPS ≥10 | 7 | 10 | 11 | 20 | 1.98 (0.57-6.91) |
| CPS <10 | 89 | 12 | 68 | 9 | 0.58 (0.38-0.89) |
aChemo group tx.
Conclusions
In pts with FGFRalt advanced/mUC after prior anti-PD-(L)1 tx, erda significantly improved OS vs chemo. Clinically relevant subgroups showed a consistent OS benefit for erda. No new safety signals were observed. These results support the role of erda to treat pts with FGFRalt mUC after anti-PD-(L)1 tx.