(UroToday.com) The 2023 ESMO annual meeting included a session on urothelial carcinoma, featuring a discussant presentation by Dr. Michiel Van der Heijden. For this presentation, Dr. Van der Heijden discussed the abstract “Phase 3 THOR Study: Results of Erdafitinib vs Pembrolizumab in Pretreated Patients with Advanced or Metastatic Urothelial Cancer with Select FGFR Alterations” by Dr. Arlene Siefker-Radtke and the abstract “THOR-2 cohort 1: Results of erdafitinib vs intravesical chemotherapy in patients with high-risk NMIBC with select FGFR alterations who received prior BCG treatment” by Dr. James Catto. FGFR3 mutations are present in all aspects of urothelial carcinoma, with the following figure highlighting the impact across the disease spectrum:
Previously in THOR cohort 1 presented at ASCO, we saw activity of erdafitinib versus docetaxel or vinflunine. Patients with unresectable advanced/metastatic urothelial cancer and select FGFR3/2alt (mutations/fusions), 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 up-titration to 9 mg on day 14) QD or investigator’s choice of chemotherapy (docetaxel or vinflunine) Q3W until disease progression or intolerable toxicity. 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:
Dr. Van der Heijden notes that based on work from the TCGA on molecular subtypes we have information with regards to FGFR3 mutations in each subtype, specifically 32% in the luminal/papillary subtype:
As such, luminal-papillary tumors have historically been deemed an immunologically “cold” tumor. Because erdafitinib is pro-immunogenic in vivo, there is a physiological rationale for combining pembrolizumab with erdafitinib in an attempt to “heat” the immunogenicity of the tumor and improve responsiveness. In THOR cohort 2, patients with unresectable advanced/metastatic urothelial cancer with select FGFR3/2 alterations, 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 uptitration to 9 mg or pembrolizumab 200 mg every 3 weeks. The primary endpoint was OS, and secondary endpoints included PFS, objective response rate (ORR), and safety. The trial design for THOR cohort 2 trial is as follows:
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 primary endpoint 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):
Dr. Van der Heijden does not feel like this is the end for erdafitinib + IO, given that at ASCO 2023 the NORSE trial showed a PFS and OS benefit of erdafitinib + cetrelimab versus erdafitinib alone among patients with FGFR alterations in the first line setting:
Dr. Van der Heijden’s conclusions from the THOR Cohort 2 trial are as follows:
- This was a well conducted phase 3 study, unfortunately, it was negative for the primary endpoint
- Erdafitinib remains best positioned in the chemotherapy/IO refractory setting
- Erdafitinib + IO combination therapy is intriguing, but may not be sufficiently active to compete against new front line therapies
Dr. Dr. Van der Heijden then discussed THOR-2 cohort 1, looking at the utilization of erdafitinib in patients with BCG-experienced NMIBC. The likely benchmark in this disease setting is pembrolizumab from the KEYNOTE-057 trial,1 which showed a 43.5% 12 months disease free survival rate:
Adult patients with recurrent, BCG-treated, papillary-only high risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing/ineligible for radical cystectomy were randomized 2:1 to 6 mg oral erdafitinib or investigator’s choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint for this trial was recurrence-free survival (RFS), and secondary endpoints included RFS rate at 6 and 12 months and safety. Notably, 882 patients had to be screened in order to identify 336 patients (38%) with FGFR mutations. The trial design for THOR-2 cohort 1 is as follows:
Dr. Van der Heijden noted that THOR-2 used a novel definition for BCG-experienced high risk NMIBC to address the BCG shortages:
The median follow-up was 13.4 months for both groups, and median RFS was not reached for erdafitinib and was 11.6 months for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.10-0.60):
The following table highlights how oral erdafitinib fits with other agents in the post-BCG high-risk NMIBC treatment landscape:
Dr. Van der Heijden concluded his discussant presentation of THOR-2 with the following take-home points:
- This was a well conducted study, despite early closure
- There is strong evidence for proof of concept for FGFR inhibition in NMIBC
- Systemic erdafitinib in his view is too toxic for this setting
- Intravesical erdafitinib may be an interesting alternative
Presented by: Michiel S. Van der Heijden, MD, PhD, Netherlands Cancer Institute, Amsterdam, Netherlands
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.
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Related Content:ESMO 2023: Phase 3 THOR Study: Results of Erdafitinib vs Pembrolizumab in Pretreated Patients with Advanced or Metastatic Urothelial Cancer with Select FGFR Alterations
ESMO 2023: THOR-2: Results of Erdafitinib vs Intravesical Chemotherapy for High-Risk Non Muscle Invasive Bladder Cancer with Select FGFR Alterations Who Received Prior BCG Treatment