(UroToday.com) The 2023 ASCO annual meeting included a late-breaking abstract session, featuring a presentation by Dr. Yohann Loriot discussing results of the phase 3 THOR study assessing erdafitinib versus chemotherapy in patients with advanced or metastatic urothelial cancer with select fibroblast growth factor receptor alterations. Dr. Loriot notes that there is an unmet need for post-checkpoint inhibitor therapies in the metastatic urothelial carcinoma population:
FGFRalt are observed in ~20% of patients with metastatic urothelial cancer and may function as an oncogenic driver. Erdafitinib is an oral selective pan-FGFR tyrosine kinase inhibitor granted accelerated approval in the United States and 17 other countries to treat locally advanced or metastatic urothelial cancer in adults with susceptible FGFR3/2alt who have progressed after platinum-containing chemotherapy. THOR (NCT03390504) is a confirmatory, randomized phase 3 study, with cohort 1 assessing whether erdafitinib provided a survival advantage vs investigator’s choice of chemotherapy in patients with metastatic urothelial cancer who progressed after 1 or 2 prior treatments, including an anti-PD-(L)1 agent.
In cohort 1 of THOR, patients ≥18 years of age with unresectable advanced/metastatic urothelial cancer and select FGFR3/2alt (mutations/fusions), ECOG performance status 0-2, adequate organ function, progression on/after prior systemic therapy that included an anti-PD-(L)1 agent, and ≤2 prior lines of therapy were randomized 1:1 to receive erdafitinib (8 mg with pharmacodynamically guided uptitration to 9 mg on day 14) QD or investigator’s choice of chemotherapy (docetaxel or vinflunine) Q3W until disease progression or intolerable toxicity. The primary end point was overall survival, and secondary end points included progression-free survival, objective response rate, and safety. The trial design for cohort 1 is as follows:
The study was designed assuming a 53% improvement in median overall survival of the erdafitinib arm over the chemotherapy arm (ie. HR 0.65). With a planned enrollment of ~280 patients followed until ~208 deaths have occurred, the study had at least 85% power at a significance level of 0.05 (2-sided), with one interim analysis when about 65% (136 deaths) of the 208 deaths have occurred. The interim analysis was planned to assess both the efficacy and futility with stopping thresholds derived based on the O’Brien-Fleming alpha-spending function. At the data cutoff for this interim analysis (January 15, 2023), 155 deaths had occurred corresponding to ~75% information fraction. The significance level of stopping for efficacy was p = 0.019, corresponding to a hazard ratio of 0.69.
There were 266 patients randomized, including 136 patients to erdafitinib and 130 to chemotherapy. In all patients, the median age was 67 years, 30% had 1 prior line of therapy, 70% had 2 prior lines, 74% had visceral metastases, and 90% were PD-L1 low (CPS <10). The full demographics and disease characteristics are as follows:
All patients enrolled in the study had received anti-PD1 in the first- or second-line setting:
The median follow-up was 15.9 months over which the primary endpoint of the study was met, with erdafitinib significantly increasing overall survival and reducing the risk of death versus chemotherapy: median overall survival 12.1 months vs 7.8 months, HR 0.64, 95% CI 0.47-0.88:
These data met the predefined stopping criteria for superiority recommended by the IDMC. Additionally, the overall survival benefit with erdafitinib versus chemotherapy was consistently observed across subgroups:
Erdafitinib also significantly improved median progression-free survival (5.6 vs 2.7 months) with a HR of 0.58, 95% CI 0.44-0.78:
Furthermore, objective response rate was significantly higher for erdafitinib vs chemotherapy (45.6% vs 11.5%; relative risk 3.94, 95% CI 2.37-6.57, p < 0.001):
The safety profiles were consistent with the known profiles of erdafitinib and chemotherapy. Serious treatment-related adverse events were observed in 13.3% and 24.1% of patients with erdafitinib and chemotherapy, respectively, and grade 3/4 treatment-related adverse events were observed in 45.9% and 46.4% of patients with erdafitinib and chemotherapy, respectively:
Treatment-related adverse events leading to death were reported in 1 and 6 patients with erdafitinib and chemotherapy, respectively. More treatment-related adverse events leading to dose reduction were observed with erdafitinib (66%) vs chemotherapy (21%), and 8% and 13% of patients had treatment-related adverse events leading to discontinuation of erdafitinib and chemotherapy, respectively. Central serous retinopathy occurred in 23 patients (17%) with erdafitinib (grade 1-2, 20 patients).
Dr. Loriot concluded his presentation discussing results of the phase 3 THOR study assessing erdafitinib versus chemotherapy in patients with advanced or metastatic urothelial cancer with select fibroblast growth factor receptor alterations with the following take-home points:
- Erdafitinib significantly extended overall survival in patients with FGFRalt advanced/metastatic urothelial cancer after prior treatment with PD-(L)1, with a median overall survival of 1 year
- Erdafitinib provided a 36% reduction in risk of death compared to chemotherapy
- The overall survival benefit of erdafitinib was consistent across clinically relevant subgroups
- Erdafitinib provided significantly longer progression free survival and greater objective response rate versus chemotherapy
- The erdafitinib safety profile was consistent with the BLC2001 study1
- These results support the role of erdafitinib as standard of care for treatment of patients with FGFRalt metastatic urothelial cancer after PD-(L)1 therapy
- The overall survival benefit of erdafitinib in patients with metastatic urothelial carcinoma with FGFRalt supports molecular testing for FGFRalt in all patients with metastatic urothelial carcinoma
Presented by: Yohann Loriot, MD, PhD, Department of Cancer Medicine, Gustave Roussy Institute, University Paris-Saclay, Paris, France
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.
Reference:
- 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.