(UroToday.com) The 2024 GU ASCO annual meeting featured a urothelial carcinoma session and a presentation by Dr. Rohit Jain discussing the phase Ib trial of erdafitinib combined with enfortumab vedotin following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma with FGFR2/3 genetic alterations. Erdafitinib, a FGFR inhibitor, is a treatment option in metastatic urothelial carcinoma patients with somatic FGFR2/3 genetic alterations after progression on platinum-based chemotherapy.1,2 Enfortumab vedotin, a human antibody-drug conjugate targeting nectin-4, is approved as a single agent to treat metastatic urothelial carcinoma patients following prior platinum-based chemotherapy and PD1/L1 inhibitors or as second-line therapy for cisplatin-ineligible patients.3,4 Retrospective studies suggest that the activity of enfortumab vedotin is not compromised by FGFR2/3 genetic alterations. Erdafitinib and enfortumab vedotin have different mechanisms of activity, and toxicities are mostly non-overlapping. Tubulin antagonists are cytotoxic and induce a G2-M cell cycle block, while FGFR inhibitors are cytostatic and cause a G1 block, with preclinical studies suggesting that the combination may be synergistic. Hence, there is rationale to evaluate the feasibility of combination erdafitinib + enfortumab vedotin, to overcome the difficulties of resistance and sequencing agents in metastatic urothelial carcinoma patients with FGFR2/3 genetic alterations.
This is an ongoing, single arm, multicenter, dose-escalation and expansion study of combination erdafitinib + enfortumab vedotin evaluating the safety, tolerability, pharmacokinetics, and antitumor activity in patients with metastatic urothelial carcinoma harboring somatic FGFR2/3 genetic alterations who have progressed after platinum-based chemotherapy and/or PD1/L1 inhibitor therapies:
The dose escalation phase aims to identify the maximum tolerable dose and recommended phase 2 dose of enfortumab vedotin at dose levels of 1 mg/kg and 1.25 mg/kg in combination with erdafitinib at 8 mg/day. Preliminary safety, pharmacokinetics, and efficacy data for dose levels 1 and 2 are presented at GU ASCO 2024.
As of the data cutoff, based on 3+3 design, a total of 9 patients are enrolled and finished dose limiting toxicity period (1st cycle). The baseline characteristics are as follows:
Six patients were enrolled in dose level 1 with 1 dose limiting toxicity (skin rash) and three patients in dose level 2 with no dose limiting toxicities. The most common treatment-related adverse events included hyperphosphatemia (100%), mucositis (100%), hypercalcemia (89%), high AST (89%), hand foot syndrome (67%), peripheral neuropathy (67%), alopecia (56%), diarrhea (78%), hypoalbuminemia (67%) and hypomagnesemia (67%). Grade 3 treatment-related adverse events included hand foot syndrome (33%), anemia (11%), rash (11%), anorexia (11%), and paronychia (11%). One patient developed grade 4 Stevens-Johnson syndrome related to enfortumab vedotin which subsequently improved:
Pharmacokinetic data are available for all 6 subjects in dose level 1. The average steady-state Cmin of erdafitinib and monomethyl auristatin erdafitinib (MMAE) was 1,430 ± 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 dose level 1.
The best objective response rate is 100%, with one patient achieving a complete response, and 8 patients having a partial response. The median progression free survival is not reached (95% CI 7.4 to not reached) and all nine patients are alive at the data cutoff date. Four patients are still actively being treated on the trial.
Dr. Jain concluded his presentation by discussing the phase Ib trial of erdafitinib combined with enfortumab vedotin following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma with FGFR2/3 genetic alterations with the following take-home points:
- In the dose-escalation phase of this trial, combination of enfortumab vedotin + erdafitinib is deemed to be safe and tolerable in metastatic urothelial carcinoma patients with FGFR3/2 alterations post chemotherapy and immunotherapy
- The RP2D was determined to be enfortumab vedotin 1.25 mg/kg day 1, 8, 15, every 28 days with erdafitinib 8 mg daily
- Early signs of promising activity were observed (9/9 responses)
- Dose expansion (n = 12) is ongoing coupled with exploratory biomarker studies
- Given the feasibility and activity of erdafitinib + PD1 inhibition (NORSE trial), the combination of enfortumab vedotin + pembrolizumab + erdafitinib in this selected population may be warranted
Presented by: Rohit K. Jain, MD, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25th – January 27th, 2024
References:
- Loriot Y, Necchi A, Park SH, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2019 Jul 25;381(4):338-348.
- Loriot Y, Matsubara N, Park SH, et al. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971.
- Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal trial of Enfortumab Vedotin in Urothelial Carcinoma after Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10;37(29):2592-2600.
- Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med 2021 Mar 25;384(12):1125-1135.