799TiP PROOF 302: A randomized, double-blind, placebo-controlled, phase III trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring susceptible FGFR3 alterations

TPS600 Background: Radical surgery ± cisplatin‐based (neo)adjuvant therapy (NAT) is the mainstay of treatment for invasive urothelial carcinoma of the upper urinary tract (UTUC) or bladder (UBC), but recurrence rates are high. Furthermore, many patients (pts) are unable to receive NAT because of cisplatin ineligibility. Fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in up to 70% of UTUC and up to 20% of UBC, and may constitute a potential candidate for targeted therapy. Infigratinib (BGJ398), a selective FGFR1–3 inhibitor, has shown promising clinical activity and tolerability in pts with advanced urothelial carcinoma having FGFR3 alterations [Pal et al. Cancer Discov 2018]. PROOF 302 has been designed to investigate the efficacy and safety of infigratinib versus placebo as adjuvant therapy in pts with high-risk invasive urothelial carcinoma and FGFR3 alterations. Methods: PROOF 302 is a randomized, double-blind, placebo-controlled, phase III study of approx. 218 pts. Adults with high-risk invasive UTUC or UBC with FGFR3 genetic alterations (i.e. mutations, gene fusions or translocations) who are ≤120 days following surgical resection and ineligible for cisplatin-based adjuvant chemotherapy or with residual disease after cisplatin- based NAT are eligible. Those who received non cisplatin-based NAT are eligible if they have residual disease and are ineligible for adjuvant cisplatin. Pts receive oral infigratinib 125 mg or placebo (1:1 ratio) once daily on days 1–21 every 28 days for up to 52 weeks or until disease recurrence, unacceptable toxicity or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: DFS including intraluminal low-risk recurrence; metastasis-free survival; overall survival; DFS (per investigator); safety and tolerability. Exploratory endpoints include: quality of life; pharmacokinetics; cell-free DNA (cfDNA) and/or RNA for resistance mechanisms. The study will involve approximately 120 centers worldwide. Enrollment is expected to begin in January 2020. Trial registration: EudraCT 2019-003248-63. Clinical trial information: EudraCT 2019-003248-63.

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PROOF 302: A randomized, double-blind, placebo-controlled, phase III trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring susceptible FGFR3 alterations.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps5095 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS5095-TPS5095

Author(s):

Siamak Daneshmand ◽

Petros Grivas ◽

Srikala S. Sridhar ◽

Shilpa Gupta ◽

Joaquim Bellmunt ◽

...

Keyword(s):

High Risk ◽

Adjuvant Chemotherapy ◽

Adjuvant Therapy ◽

Urothelial Carcinoma ◽

Residual Disease ◽

Genetic Alterations ◽

Phase Iii ◽

Double Blind ◽

Free Survival ◽

Double Blind Placebo

TPS5095 Background: Radical surgery ± cisplatin‐based (neo)adjuvant chemotherapy (NAC) is the mainstay of treatment for invasive urothelial carcinoma of the upper urinary tract (UTUC) or bladder (UBC), but recurrence rates are high. Furthermore, many patients are unable to receive NAC due to cisplatin ineligibility. Fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in up to 70% of UTUC and up to 20% of UBC and may constitute a potential candidate for targeted therapy. Infigratinib (BGJ398), a FGFR1–3 selective oral tyrosine kinase inhibitor, has shown promising clinical activity and tolerability in patients with advanced urothelial carcinoma having FGFR3 alterations [Pal et al. Cancer Discov 2018]. PROOF 302 has been designed to investigate the efficacy and safety of infigratinib versus placebo as adjuvant therapy in patients with high-risk invasive urothelial carcinoma and susceptible FGFR3 alterations. Methods: PROOF 302 is a randomized, double-blind, placebo-controlled, phase III study of approx. 218 patients. Adults with high-risk invasive UTUC or UBC with susceptible FGFR3 genetic alterations (i.e. activating mutations, gene fusions or translocations) who are ≤120 days following surgical resection and ineligible for or refusing cisplatin-based adjuvant chemotherapy or with residual disease after cisplatin-based NAC are eligible. Those who received non cisplatin-based NAC are eligible if they have residual disease and are ineligible for adjuvant cisplatin. Patients receive oral infigratinib 125 mg or placebo (1:1 ratio) once daily on days 1–21 every 28 days for up to 52 weeks or until disease recurrence, unacceptable toxicity or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: DFS including intraluminal low-risk recurrence; metastasis-free survival; overall survival; DFS (per investigator); safety and tolerability. Exploratory endpoints include quality of life, pharmacokinetics, cell-free DNA (cfDNA) and/or RNA for resistance mechanisms. The study will involve approximately 120 centers worldwide. The study was initiated in late 2019 and is expected to end in 2024. Clinical trial information: NCT04197986 .

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