First-line treatment of patients (pts) with advanced or metastatic UC consists of platinum-based chemotherapy (CT), and currently, there is no well-established therapy following CT failure. Recently, checkpoint inhibitors have shown clinical benefit in this setting, and are likely to become a future standard of care. However, to date, no other targeted therapies have shown significant clinical activity. Given that ∼20% of UCs harbour ERBB receptor alterations or abnormalities, the blockade of the ERBB pathway may be an effective therapeutic strategy. Indeed, afatinib, an irreversible ERBB family blocker, demonstrated activity in a Phase II trial in a subgroup of pts with UC harbouring ERBB2/ERBB3 aberrations. These data provide rationale for the current Phase II trial assessing afatinib in pts with UC, molecularly selected for ERBB receptor alterations (LUX-Bladder 1; NCT02780687).
The Phase II, single-arm LUX-Bladder 1 trial evaluates the efficacy and safety of afatinib in pts with UC and ERBB2/ERBB3 mutations or ERBB2 amplification (Cohort A), or EGFR amplification (Cohort B). Eligible pts are ≥18 years of age, with histologically confirmed advanced/metastatic UC of the urinary tract not amenable to surgery and progression during or after platinum-based CT (previous immunotherapy allowed), ECOG PS 0–1, with archival tissue samples available for pre-screening biomarker analysis. Pts will receive oral afatinib 40 mg/day until disease progression or discontinuation for other reasons. Cohort A will enrol in two stages, with Stage (S) 2 enrolment depending on afatinib anti-tumour activity in S1. The primary endpoint and key secondary endpoint in Cohort A are PFS rate at 6 months and ORR; other secondary endpoints include PFS, OS, disease control rate, duration of response and tumour shrinkage. These endpoints will also be explored in Cohort B. Safety and biomarkers will be assessed in both cohorts. The trial commenced in June 2016. Recruitment is ongoing in Spain and planned in two additional European countries; planned enrolment: Cohort A, ∼70 pts (S1, n=∼25; S2, n=∼45); Cohort B, ∼10 pts.
Clinical trial identification
Legal entity responsible for the study
J. Puente: Consulting/advisory role: Pfizer, Roche, Janssen, Lilly Speakers bureau: Pfizer, BI, Astellas Research funding: Astellas, Pfizer. F.J. Vazquez Mazon: Honoraria: Janssen/Astellas/Sanofi/Bayer/Novartis Consulting/ad board/Expert testimony: Janssen Astellas/Sanofi/Bayer/Novartis; Speaker: Novartis; Travel, accommodations, expenses: Astellas/Pfizer/Janssen. N. Sala: Consulting/advisory role: Astellas, Janssen, Pfizer, Bristol-Myers Squib; Speakers bureau: Astellas, Janssen, Pfizer, Bristol-Myers Squib; Travel, accommodations, expenses: Astellas, Pfizer, Janssen. E. Grande Pulido: Research funding: Astellas, Pfizer, AstraZeneca. D. Castellano: Honoraria: Pfizer, Astellas, Janssen; Consulting/advisory role: Roche, Epsen; Speakers bureau: Amgen, Novartis, Bristol-Myers Squib. M.A. Climent: Honoraria: Roche, Bristol-Myers Squib, Bayer, Astellas, Sanofi, Janssen, Pfizer, Novartis; Consulting/advisory role: Janssen, Pfizer, Roche, Sanofi, Astellas, Bayer; Travel, accommodation, expenses: Astellas, Janssen, Pfizer. P. Jares: Patents, royalities, other intellectual property: Barcelona University. I. Aldecoa: Travel, accommodation, expenses: Sysplex Espana S.L. N. Gibson, J. Serra, E.R. Imedio, E. Ehrnrooth: Employment: BI. All other authors have declared no conflicts of interest.