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Key Points

QuestionÌý Can rogaratinib be safely combined with anti–programmed cell death 1 ligand 1 therapy to improve efficacy for patients with advanced/metastatic urothelial carcinoma harboring FGFR3 messenger RNA overexpression?

FindingsÌý In this phase 1b study of 153 patients with untreated locally advanced or metastatic urothelial cancer, the recommended dose of rogaratinib was 600 mg in combination with atezolizumab 1200 mg, which was tolerable and resulted in a high objective response rate despite low programmed cell death 1 ligand 1 expression among most patients.

MeaningÌý This study indicates that combination rogaratinib and atezolizumab is tolerable with relatively high efficacy and that selection of patients by FGFR3 messenger RNA overexpression may expand the fraction of patients who benefit from fibroblast growth factor receptor inhibitor therapy.

ImportanceÌý 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).

ObjectiveÌý 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 ParticipantsÌý 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.

InterventionsÌý Patients received rogaratinib 600 mg or rogaratinib 800 mg twice daily in combination with intravenous atezolizumab 1200 mg every 21 days.

Main Outcomes and MeasuresÌý Primary end points included safety, tolerability, and the recommended phase 2 dose (RP2D) of rogaratinib in combination with atezolizumab.

ResultsÌý 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 RelevanceÌý 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 RegistrationÌý ClinicalTrials.gov Identifier:

Urothelial cancer (UC) is an immunogenic tumor that can respond to programmed cell death 1 ligand 1 (PD-L1) inhibition, but resistance to therapy is common.¹ The PD-L1 antibody atezolizumab has a response rate of 23% in cisplatin-ineligible patients with locally advanced or metastatic UC.² Activation of the fibroblast growth factor receptor 3 (FGFR3) pathway in bladder cancer is associated with a non–T-cell-inflamed tumor microenvironment, which may reduce responsiveness to PD-L1 inhibition.³ Pharmacologic targeting of FGFR3 may modulate the tumor microenvironment and augment immunotherapeutic strategies. Preclinical models have shown enhanced survival and antitumor activity following treatment with FGFR and PD-L1 inhibition, suggesting clinical utility for this combination.⁴

Rogaratinib, a selective, oral, pan-FGFR inhibitor, demonstrated promising safety and efficacy in a phase 1 study of patients with advanced UC selected based on FGFR1/3 messenger RNA (mRNA) expression.⁵ Herein, we report results from the phase 1b portion of the FORT-2 study, which evaluated the safety, pharmacokinetics, and efficacy of rogaratinib combined with atezolizumab in cisplatin-ineligible patients with FGFR1/3 mRNA-positive, locally advanced or metastatic UC.

This phase 1b/2, international, multicenter, open-label, single-arm study was conducted between May 15, 2018, and the primary completion cutoff date of July 16, 2021, across 30 centers in Asia, Europe, and North America in accordance with Good Clinical Practice guidelines, the Declaration of Helsinki, and applicable laws and regulations. An institutional review board or independent ethics committee at all sites approved the protocol (Supplement 1) before the start of the study, and all patients provided written informed consent. Transparent Reporting of Evaluations With Nonrandomized Designs () reporting guidelines for nonrandomized/quasi-experimental study designs were followed.

Patients 18 years or older with untreated locally advanced or metastatic UC (including urinary bladder, renal pelvis, ureter, and urethra) who were cisplatin ineligible were eligible for inclusion (eFigure 1 in Supplement 2). FGFR1/3 mRNA overexpression was required (a score of 3 or 4 by in situ hybridization using the RNAscope platform [Advanced Cell Diagnostics]; eTable 1 in Supplement 2). FGFR3/PI3K/RAS alteration status and PD-L1 expression assessment are outlined in the eMethods in Supplement 2. Based on the previously determined optimal monotherapy dose,⁵ patients received a starting dose of oral rogaratinib 800 mg twice daily continuously and a fixed dose of intravenous atezolizumab 1200 mg on day 1 of 21-day cycles until disease progression, unacceptable adverse effects, or withdrawal. The maximum allowed rogaratinib dose was 800 mg twice daily, but dose reductions to 600 mg and 400 mg twice daily were permitted for clinically significant adverse effects. Based on a lower overall frequency of treatment-emergent adverse events (TEAEs) and improved tolerability of rogaratinib 600 mg in early safety assessments, further enrollment continued at 600 mg, supported by preclinical models demonstrating that efficacious exposure could be reached at this dose.⁶

The primary objectives were to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of rogaratinib in combination with atezolizumab among patients with FGFR mRNA-positive, locally advanced or metastatic UC. The secondary objectives were to assess efficacy and pharmacokinetics. Safety analyses included assessment of AEs up to at least 30 days after the last treatment. Tumor assessments were performed locally using computed tomography or magnetic resonance imaging at screening and every 9 weeks; tumor response was evaluated using Response Evaluation Criteria in Solid Tumors, version 1.1.⁷ Plasma samples for pharmacokinetic assessment were collected at cycle 1, day 1 before dosing, and at 0.5, 1, 2, 3, 4, 6, and 8 hours after dosing. No formal sample-size calculation was performed due to the exploratory nature of this study part; however, approximately 26 to 30 patients were planned for study enrollment, with an additional 20 patients permitted. Dose selection was determined using the modified toxicity probability interval method.⁸

The data analysis was completed from July 2022 to September 2022. Statistical analyses were performed with SAS, version 9.4 (SAS Institute Inc), using noninformative Jeffreys priors. All 95% CIs are to be interpreted as exploratory.

Of the 153 patients who underwent FGFR testing, 73 (48%) were FGFR1/3 mRNA positive, 54 (35%) entered screening, and 37 (69%) were enrolled. Eleven patients (30%) received rogaratinib 800 mg twice daily plus atezolizumab, and 26 (70%) received rogaratinib 600 mg twice daily plus atezolizumab (Figure 1). The overall median (range) age was 75.0 (47.0-85.0) years, and 32 patients (87%) were male (Table). Median (range) duration of treatment was 1.4 (0.3-32.4) months in the rogaratinib 800 mg group and 4.1 (0.4-29.3) months in the rogaratinib 600 mg group.

The safety analysis set included all 37 patients, and 29 patients were included in the maximum tolerated dose (MTD)/RP2D evaluation. Six patients were not included in MTD/RP2D determination due to receiving less than 80% of the planned dose during cycle 1, and 2 patients received treatment after MTD evaluation. Dose-limiting adverse effects occurred in 3 of 29 patients (10%), specifically in 1 of 8 patients (13%) in the rogaratinib 800 mg group (grade 4 hyperlipasemia) and 2 of 21 patients (10%) in the rogaratinib 600 mg group (grade 3 rash and grade 3 hepatitis). The most common rogaratinib-related AEs were diarrhea in 23 patients (62%) and hyperphosphatemia in 19 patients (51%) (eTable 2 in Supplement 2). TEAEs leading to rogaratinib interruption, reduction, and permanent discontinuation were reported in 25 (68%), 15 (41%), and 13 (35%) patients, respectively. There was a lower incidence of TEAEs leading to rogaratinib discontinuation at 600 mg vs 800 mg (7 of 26 patients [27%] vs 6 of 11 patients [55%]). Four grade 5 TEAEs (cardiac arrest, sepsis, craniocerebral injury, and general physical health deterioration) were reported during treatment and within 30 days of discontinuation, though none was considered related to study treatments. Serious AEs were reported in 22 patients (60%), and rogaratinib-related serious AEs were reported in 4 patients (11%) overall; all were grade 3 in severity (increased alanine aminotransferase, increased aspartate aminotransferase, asthenia, dehydration, hemorrhagic diarrhea, and abnormal kidney function test). The MTD and RP2D of rogaratinib were established at 600 mg twice daily in combination with atezolizumab 1200 mg every 21 days.

Of the 37 patients evaluable for efficacy, 16 (43%) achieved an objective response and 24 (65%) achieved disease control (eTable 3 in Supplement 2). Among patients treated at the RP2D, 14 (54%) achieved an objective response, including 4 (15%) complete responses (eTable 3 in Supplement 2). Median time to response was 2.1 (95% CI, 2.0-2.1) months, and the disease control rate was 76.9% (Figure 2A). Median duration of response was not reached at study completion, with some complete responses still ongoing.

Median progression-free survival was 6.1 (95% CI, 3.2-9.8) months overall, with a progression-free survival rate of 27% at 24 months. Median progression-free survival was 7.5 months (95% CI, 4.0 months-not estimable) for rogaratinib 600 mg vs 2.1 (95% CI, 1.0-2.2) months for rogaratinib 800 mg (eFigure 2 in Supplement 2). Median overall survival was 12.0 (95% CI, 8.8-17.0) months, with an overall survival rate of 31% at 24 months. Median overall survival was 16.8 months (95% CI, 12.0 months-not estimable) for rogaratinib 600 mg vs 8.3 (95% CI, 2.2-9.8) months for rogaratinib 800 mg (eFigure 3 in Supplement 2).

Rogaratinib was rapidly absorbed, with a median (range) time to maximum plasma concentration of 1.2 (0.5-3.9) hours and 1.9 (0.5-4.0) hours in the rogaratinib 600 mg and rogaratinib 800 mg groups, respectively (eFigure 4 in Supplement 2). Exploratory analyses found the objective response rate (ORR) to be similar for patients with positive PD-L1 tumors (40.0%) vs negative (44.4%) (Figure 2B and eTable 4 in Supplement 2). PI3K and RAS alterations were identified in 5 patients, none of whom achieved an objective response.

To our knowledge, this is the first study combining FGFR3 inhibition plus anti–PD-L1 therapy in cisplatin-ineligible patients with locally advanced or metastatic UC. The MTD and RP2D of rogaratinib were established at 600 mg twice daily in combination with atezolizumab 1200 mg every 21 days. Observed TEAEs were consistent with reports from these compounds as monotherapies^5,9,10 and align with those reported for erdafitinib plus cetrelimab.¹¹ No new safety signals were observed. Rogaratinib-related grade 3 or higher TEAEs occurred at approximately half the frequency in the rogaratinib 600 mg group vs the rogaratinib 800 mg group (27% vs 55%), suggesting improved tolerability at the lower dose.¹² The rogaratinib plasma concentration profiles following single-dose administration in combination with atezolizumab were consistent with monotherapy data.⁵

The reported ORRs for rogaratinib and atezolizumab are 20.7% and 23%, respectively,^2,5 but herein we demonstrated enhanced activity for the combination with a much higher ORR of 53.8%. In addition, responses were achieved quickly, with a median time to response of 2.1 months. The observed ORR was similar to erdafitinib plus cetrelimab (54.5%),¹¹ but the present study selected patients based on FGFR mRNA positivity, which is much more frequent than FGFR alterations.¹³ Recent data from the EV-302 trial indicated that enfortumab vedotin plus pembrolizumab is superior to platinum-based chemotherapy for first-line treatment.¹⁴ This trial included all patients with UC, irrespective of FGFR3 alteration, cisplatin eligibility, or PD-L1 status. Thus, direct comparisons cannot be made, and the optimal incorporation of FGFR-targeted therapies in the context of EV-302 remains uncertain.

FGFR3 expression is associated with a non–T-cell-inflamed tumor microenvironment,³ suggesting a mechanism of resistance to anti–PD-L1 immunotherapy. The results herein support the hypothesis that inhibition of the FGFR pathway may reverse immunosuppressive effects in the tumor microenvironment and sensitize a broader population of patients with UC to immune checkpoint blockade. Most patients treated had tumors that were negative for PD-L1 expression or FGFR3 gene alteration; despite this fact, these patients achieved a favorable ORR of 52.9%. Thus, efficacy was not dependent on PD-L1 expression or FGFR3 gene alteration. While less than 25% of patients with invasive UC have an FGFR3 alteration or fusion,¹⁵ 48% of patients in this study had FGFR mRNA overexpression. Thus, a greater proportion of patients with UC may receive benefit from an FGFR inhibitor when selected by mRNA overexpression. Finally, the extended duration of response observed in many patients supports an immune-mediated mechanism of efficacy.

Limitations of this study include the small number of patients across biomarker-defined subsets and the exploratory nature of some of the biomarker analyses.

This phase 1b nonrandomized clinical trial demonstrates that rogaratinib can be safely combined with atezolizumab to treat UC with FGFR1/3 overexpression. A favorable ORR of 53.8% was observed, which was not dependent on FGFR3 gene alteration or PD-L1 status, broadening the population of patients who may benefit.

Accepted for Publication: May 14, 2024.

Published Online: September 19, 2024. doi:10.1001/jamaoncol.2024.3900

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2024 Sweis RF et al. JAMA Oncology.

Corresponding Author: Randy F. Sweis, MD, Section of Hematology/Oncology, Department of Medicine, University of Chicago Medicine, 5841 S Maryland Ave, Chicago, IL 60637 (rsweis@uchicago.edu).

Author Contributions: Drs Sweis and Ellinghaus had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Sweis, Ishida, Bao, Zhou, Ellinghaus, Rosenberg.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Sweis, Morales-Barrera, Ishida, Zhou, Ellinghaus, Rosenberg.

Critical review of the manuscript for important intellectual content: Sweis, Gajate, Lee, Necchi, de Braud, Penel, Grünwald, Maruzzo, Meran, Ishida, Bao, Zhou, Ellinghaus, Rosenberg.

Statistical analysis: Ishida, Bao, Ellinghaus.

Administrative, technical, or material support: Ishida, Rosenberg.

Supervision: Sweis, Gajate, Morales-Barrera, Necchi, de Braud, Maruzzo, Ishida, Ellinghaus, Rosenberg.

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.

Funding/Support: The study was funded by Bayer. This work was also supported, in part, by grants from the National Cancer Institute (P30 CA008748, U01 CA243075, and K08 CA234392). Atezolizumab was provided by Roche.

Role of the Funder/Sponsor: Bayer was involved in the design and conduct of the study, but the other funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: FORT-2 data have been presented in poster format at the American Society of Clinical Oncology Virtual Annual Meeting; May 29 to 31, 2020; and the American Society of Clinical Oncology Virtual Annual Meeting; June 4 to 8, 2021.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the patients and their families, coinvestigators, and referring physicians who participated in the study. Laura Lenders-Cousins, PhD, Tamara Sinivassen, BSc (Hons), and Rachel Fairbanks, BA (Hons), on behalf of Complete HealthVizion, IPG Health Medical Communications, provided medical writing and editorial support for this article, based on detailed discussion and feedback from all authors. Named individuals provided medical writing support as contracted agency support funded by Bayer but were not compensated by Bayer directly in salary.