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Importance: The oral pan-fibroblast growth factor receptor inhibitor rogaratinib previously demonstrated encouraging safety and efficacy in a phase 1 study of patients with urothelial cancer (UC) overexpressing FGFR messenger RNA (mRNA)., Objective: To evaluate the safety, pharmacokinetics, and preliminary efficacy of rogaratinib in combination with the programmed cell death 1 ligand 1 (PD-L1) inhibitor atezolizumab in cisplatin-ineligible patients with FGFR mRNA-positive, locally advanced/metastatic UC., Design Setting and Participants: The FORT-2 nonrandomized clinical trial was an open-label, single-arm, multicenter study conducted between May 15, 2018, and July 16, 2021, in 30 centers across Asia, Europe, and North America. Eligible patients had locally advanced/metastatic UC with FGFR1 / 3 mRNA overexpression and were ineligible for cisplatin-based chemotherapy. The data analysis was completed from July 2022 to September 2022., Interventions: Patients received rogaratinib 600 mg or rogaratinib 800 mg twice daily in combination with intravenous atezolizumab 1200 mg every 21 days., Main Outcomes and Measures: Primary end points included safety, tolerability, and the recommended phase 2 dose (RP2D) of rogaratinib in combination with atezolizumab., Results: Among 153 patients screened, 73 (48%) had tumors with FGFR1/3 mRNA overexpression, and 37 patients were enrolled and treated (median [range] age, 75.0 [47.0-85.0] years; 32 [87%] male). The most common treatment-emergent adverse events (TEAEs) included diarrhea in 23 patients (62%), hyperphosphatemia in 19 (51%), and fatigue in 15 (41%). Grade 3 or higher TEAEs were reported in 27 patients (73%), and 4 grade 5 TEAEs were reported, though unrelated to treatment. The RP2D was rogaratinib 600 mg in combination with atezolizumab 1200 mg. At the RP2D, the overall response rate was 53.8% in the rogaratinib 600 mg group, including 4 patients (15%) with complete responses; 12 responders (86%) did not have an FGFR3 gene alteration, and 11 (79%) had low PD-L1 expression., Conclusions and Relevance: In this phase 1b nonrandomized clinical trial, rogaratinib plus atezolizumab demonstrated a manageable safety profile, with no unexpected safety signals. Efficacy for this combination at the RP2D was observed in tumors with low PD-L1 and was not dependent on FGFR3 gene alterations, suggesting broad potential benefit for patients with locally advanced/metastatic UC and FGFR mRNA overexpression., Trial Registration: ClinicalTrials.gov Identifier: NCT03473756., Competing Interests: Conflict of Interest Disclosures: Dr Sweis reported grants paid to institution from Ascendis, AstraZeneca, Astellas, ALX Oncology, Bayer, BMS, CytomX, Eisai, Genentech/Roche, Gilead, Immunocore, Jounce, Loxo Oncology, Lilly, Merck, Moderna, Mirati, Novartis, Pfizer, Pionyr, Pyxis, QED, Regeneron, and Scholar Rock outside the submitted work; personal fees from AbbVie, Aveo, Eisai, Exelixis, Gilead, Janssen, and Lilly outside the submitted work; and a patent pending for Neoantigens in Cancer (PCT/US2020/031357). Dr Gajate reported personal fees from BMS, Merck, Roche, Pfizer, Astellas, Janssen, and MSD outside the submitted work. Dr Morales-Barrera reported serving in an advisory role for MSD, Pfizer, Merck, Janssen, and Astellas, as well as receiving honoraria or travel expenses from Roche, Sanofi Aventis, Astellas, Janssen, MSD, Bayer, Merck, and Pfizer. Dr de Braud reported personal fees from Pierre Fabre, Mattioli 1885, MSD, IQVIA, BMS, Indena, Incyte, Taiho, Menarini, Novartis, Roche, Sanofi, AccMed, Itanet, ESO, Dephaforum, Nadirex, Events, Fare Comunicazione, Motore Sanità, Effetti, Ambrosetti, Dynamicom Education, and AstraZeneca outside the submitted work. Dr Grünwald reported personal fees from Bristol Myers Squibb, Merck Serono, MSD, AstraZeneca, and Astellas during the conduct of the study; personal fees from AstraZeneca, Gilead, Pfizer, Novartis/AAA, Janssen-Cilag, Amgen, Ipsen, Eisai, Debiopharm, Apogepha, PCI Biotech, Synthekine, and Oncorena outside the submitted work. Dr Rosenberg reported personal fees from Bayer during the conduct of the study; personal fees from Janssen, AstraZeneca, Chugai, Merck, Seagen, Pfizer, Astellas, Genentech/Roche, EMD-Serono, Boehringer Ingelheim, Lilly/Loxo Oncology, Tyra Biosciences, QED Therapeutics, Gilead, Hengrui, Century Therapeutics, and Aktis Consultant outside the submitted work. No other disclosures were reported., (Copyright 2024 Sweis RF et al. JAMA Oncology.)

Objective: To harmonize eligibility criteria and radiographic disease assessments in clinical trials of adjuvant therapy for muscle-invasive bladder cancer (MIBC)., Methods: National experts in bladder cancer clinical trial research, including medical and urologic oncologists, radiologists, biostatisticians, and patient advocates, convened at a public workshop on November 28, 2017, to discuss eligibility, radiographic entry criteria, and assessment of disease recurrence in adjuvant clinical trials in patients with MIBC., Results: The key workshop conclusions for adjuvant MIBC clinical trials included the following points: (1) patients with urothelial carcinoma with divergent histologic differentiation should be allowed to enroll; (2) neoadjuvant chemotherapy is defined as at least 3 cycles of neoadjuvant cisplatin-based combination chemotherapy; (3) patients with muscle-invasive, upper-tract urothelial carcinoma should be included in adjuvant trials of MIBC; (4) patients with severe renal insufficiency can enroll into trials using agents that are not renally excreted; (5) patients with microscopic surgical margins can be included; (6) patients should undergo a standard bilateral lymph node dissection prior to enrollment; (7) computed tomographic (CT) imaging should be performed within 4 weeks prior to enrollment. For patients with renal insufficiency who cannot undergo CT imaging with contrast, noncontrast chest CT and magnetic resonance imaging of the abdomen and pelvis with gadolinium should be done; (8) biopsy of indeterminate lesions to evaluate for malignant disease should be done when feasible; (9) a uniform approach to evaluate indeterminate radiographic lesions when biopsy is not feasible should be included in any trial design; (10) a uniform approach to determining the date of recurrence is important in interpreting adjuvant trial results; and (11) new high-grade, upper-tract primary tumors and new MIBC tumors should be considered recurrence events., Conclusions and Relevance: A uniform approach to eligibility criteria, definitions of no evidence of disease, and definitions of disease recurrence may lead to more consistent interpretations of adjuvant trial results in MIBC.