(UroToday.com) The 2023 ESMO annual meeting included a session on urothelial carcinoma, featuring a presentation by Dr. Arlene Siefker-Radtke discussing results of the THOR study, a phase 3 trial of erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select fibroblast growth factor receptor (FGFR) alterations.
There is currently an unmet need in patients with metastatic urothelial carcinoma in the post-platinum-based chemotherapy setting. FGFR alterations are observed in ~20% of advanced or metastatic urothelial carcinoma of the bladder and ~35% of high grade upper tract urothelial carcinoma, and may function as oncogenic drivers. Additionally, FGFR alteration tumors are enriched in luminal 1 subtype and may have limited clinical benefit from anti–PD-(L)1 treatment. Erdafitinib is an oral pan-FGFR tyrosine kinase inhibitor approved to treat locally advanced or metastatic urothelial cancer in patients with susceptible FGFR3/2 alterations who have progressed after platinum-containing chemotherapy. In the single-arm phase 2 BLC2001 trial, erdafitinib showed a benefit in patients with FGFR-altered advanced urothelial carcinoma:1
THOR is a phase 3, randomized, open-label study, enrolling two independent cohorts analyzed separately:
- Cohort 1: assessed erdafitinib versus chemotherapy in patients with FGFR-altered metastatic urothelial cancer who progressed on or after >=1 prior treatment that included anti-PD-(L)1
- Cohort 2: assessed erdafitinib versus pembrolizumab in patients with metastatic urothelial cancer who had progressed after 1 prior treatment not containing an anti-PD-(L)1 agent
In cohort 1 of THOR, erdafitinib improved survival versus chemotherapy in patients with FGFR-altered metastatic urothelial cancer:
The results of cohort 2 from THOR were presented at the ESMO 2023 annual congress.
Patients ≥18 years with unresectable advanced/metastatic urothelial cancer with select FGFR3/2 alterations, ECOG PS 0-2, disease progression on 1 prior treatment, and naive to anti–PD-(L)1 were randomized 1:1 to receive erdafitinib 8 mg daily with pharmacodynamically guided up-titration to 9 mg or pembrolizumab 200 mg every 3 weeks. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS), objective response rate (ORR), safety. The trial design for THOR cohort 2 trial are as follows:
The study design assumed a 46% improvement in median OS of the erdafitinib group over the pembrolizumab group, with an HR of 0.69 for the erdafitinib relative to the pembrolizumab group under the exponential distribution assumption. For sample size calculation purposes, median OS for pembrolizumab was estimated to be 7.24 months, while the median OS for erdafitinib was estimated to be 10.5 months based on statistical modeling and preliminary data from the BLC2001 study. The study had at least 85% power, given that planned number of events, to detect a HR of 0.69 at a statistical significance level of 5% (2-sided). A 2-sided significance level of 0.046 was used for this final analysis after adjusting for the interim analysis at which the efficacy boundary was not crossed.
At the January 15, 2023 data cutoff, the intent-to-treat set comprised 175 patients in erdafitinib and 176 in pembrolizumab arm (median follow-up 33.2 months). The baseline demographics and disease characteristics are as follows:
The primary end point was not met, with no statistically significant difference in OS between treatment arms: median OS was 10.9 months (95% CI 9.2-12.6) for erdafitinib and 11.1 months (95% CI 9.7-13.6) for pembrolizumab (HR 1.18, 95% CI 0.90-1.50):
The hazard ratio for OS was similar across subgroups:
Erdafitinib had numerically longer PFS with a median PFS of 4.4 months (95% CI 4.1-5.5) for erdafitinib and 2.7 months (95% CI 1.6-3.0) for pembrolizumab (HR 0.88, 95% CI 0.70-1.10):
The objective response rate for erdafitinib was 40.0% compared to 21.6% with pembrolizumab leading to a relative risk of 1.85 (95% CI 1.32-2.39, p < 0.001):
The median duration of response was 4.3 months (95% CI 3.7-6.9) for erdafitinib and 14.4 months (95% CI 7.4-27.8) for pembrolizumab.
The most common treatment-related adverse events of any grade were hyperphosphatemia (72.8%), stomatitis (45.1%), diarrhea (44.5%), and dry mouth (35.3%) with erdafitinib, and pruritus (12.1%), asthenia (10.4%), hypothyroidism (10.4%), and fatigue (9.8%) with pembrolizumab. Grade 3-4 treatment related adverse events and serious treatment related adverse events occurred in 43.4% and 13.3% in erdafitinib and 12.1% and 10.4% in pembrolizumab arm, respectively. Treatment related adverse events leading to death occurred in 0 patients in erdafitinib and 3 (2%) in pembrolizumab arm, whereas 15.0% of patients discontinued erdafitinib and 4.6% discontinued pembrolizumab due to treatment related adverse events. There was a specific interest in central serous retinopathy events in the erdafitinib group, with 22.5% any grade adverse events, and 1.2% grade 3-4 events. These serious events were managed with dose interruptions and resolved by the clinical cutoff date.
Dr. Siefker-Radtke concluded her presentation discussing results of the THOR study, a phase 3 trial of erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select fibroblast growth factor receptor alterations with the following take-home points:
- The primary endpoint of superior OS with erdafitinib was not met, with similar survival observed with erdafitinib and pembrolizumab in this anti-PD(L)1-naïve metastatic urothelial carcinoma population with FGFR alterations
- Erdafitinib had a numerically better median PFS and ORR compared with pembrolizumab
- Pembrolizumab is active in patients with FGFR alterations and outcomes with pembrolizumab were in line with those previously reported for non-FGFR-altered selected populations
- The safety results were consistent with the known safety profiles for erdafitinib and pembrolizumab in this patient population
- Erdafitinib toxicities were manageable with dose modifications
Dr. Siefker-Radtke noted that this trial was concomitantly published in Annals of Oncology.2
Presented by: Arlene O. Siefker-Radtke, MD, MD Anderson Cancer Center, Houston, TX
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.
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.
- Siefker-Radtke AO, Matsubara N, Park SH, et al. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: Cohort 2 of the randomized phase III THOR trial. Ann Oncol. 2023 Oct 21 [Epub ahead of print].