ETCTN 10483: Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR3/2 genetic alterations (GAs).
Bibliographic record
Abstract
808 Background: Erdafitinib (E) is an approved treatment in patients with mUCwith FGFR 3 GAs after progression on platinum-based chemotherapy (PBC). Enfortumab Vedotin (EV) is approved to treat patients with mUC following prior PBC and PD1/L1 inhibitors or as First-line therapy in combination with pembrolizumab. Retrospective studies suggest that the activity of EV is not compromised by FGFR 3/2 GAs. EV and erdafitinib have different mechanisms of activity and toxicities are mostly non-overlapping. Hence, there is rationale to evaluate the feasibility of combination EV and E, to overcome the difficulties of resistance and sequencing agents in mUC patients with FGFR 3/2 GAs. Methods: This is an ongoing, single arm, multicenter, Phase I, 3+3 design dose-escalation and expansion study of E+ EV combination evaluating the safety, tolerability, PK, and antitumor activity in patients with mUC harboring FGFR3/2 GAs who have progressed after platinum and/or PD1/L1 inhibitor therapies. Dose escalation phase aims to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of EV in combination with fixed dose of E at 8 mg/day (table). Results: As of data cutoff, 9 patients were enrolled and completed dose limiting toxicity (DLT) period (1 st cycle) in the dose-escalation phase. Six patients were enrolled at DL1 with 1 DLT (skin rash) and 3 at DL2 (no DLT). The most common all grade treatment-related adverse events (TRAEs) included hyperphosphatemia (88%), mucositis (88%), high AST (88%), hypercalcemia (75%), palmar plantar erythrodysesthesia (75%), peripheral neuropathy (75%), alopecia (63%), diarrhea (63%), hypoalbuminemia (63%) and hypomagnesemia (63%). Grade 3 TRAEs included palmar plantar erythrodysesthesia (50%), anemia (17%), rash (17%), anorexia (17%) and paronychia (17%). One patient developed grade 4 Stevens-Johnson syndrome related to EV which subsequently improved. PK data are available for all 6 patients in DL1. The average steady-state Cmin of E and MMAE was 1430 ± 639 ng/mL and 1.4 ± 0.9 ng/ml, respectively, and the average Cmax of MMAE was 3.9 ± 0.9 ng/mL at DL1. All 9 patients are evaluable with 100% best objective rate, including 8 partial responses (PRs) and 1 complete response (CR). The mOS was NR (95% 17.1 months-NR), mPFS was 7.52 months (95% CT 5.55-NR) with median follow up of 22.7 months. The mDOR is 5.49 months. The RP2D of EV is 1.25 mg/kg in combination with E at 8 mg/day. Conclusions: E+EV combination is feasible and preliminarily exhibits promising antitumor activity. Dose expansion is ongoing at RP2D dose of EV with E. Clinical trial information: NCT04963153 . Dose Level (DL) Dose Cycle Length E EV Level -1 8 mg PO QD 0.75 mg/kg IV (maximum dose 75 mg) D1,8,15 28 days Level 1 8 mg PO QD 1 mg/kg IV (maximum dose 100 mg) D1,8,15 Level 2 8 mg PO QD 1.25 mg/kg IV (maximum dose 125 mg) D1,8,15
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".