罕见亚型试验的监管考量和终点.pdf

1、REGULATORY CONSIDERATIONS FOR RARE SUBTYPE TRIALS IN RCCCHANA WEINSTOCK,MDGU ONCOLOGY TEAM LEADEROFFICE OF ONCOLOGIC DISEASES,CDER,FDACURRENT TREATMENT LANDSCAPE IN RCCAlmost all approvals in metastatic RCC are histology agnostic;i.e.for treatment of“advanced RCC”Most labels do not break down trial

2、population by histology,although almost all patients enrolled in registrational trials had clear cell componentException 1:Belzutifan in metastatic RCC-Based on mechanism of action inhibiting HIF-2,most relevant to VHL gene inactivation/clear cell RCCApproved for“advanced RCC with a clear cell compo

3、nent following a PD-1 or PD-L1 inhibitor and a VEGF-TKI.”Exception 2:Pembrolizumab/Lenvatinib-Indicated“for the first line treatment of adult patients with advanced RCC”However,information in section 14 for non-clear cell histology,based on single-arm trial KEYNOTE-B61 N=160 patients with advanced n

4、on-clear cell RCC Histologic subtypes:59%papillary,18%chromophobe,4%translocation,1%medullary,13%unclassified,and 6%other.ORR:51%(95%CI:43,59),CR 8%,PR 42%,Median DoR in months 19.5(range 1.5+,23.5+)not broken down by histologyTwo approvals in the adjuvant setting,also histology agnosticIMPLICATIONS

5、 OF BROAD INDICATION STATEMENTSPatients with non-clear cell RCC in the adjuvant and metastatic settings may be treated per product labeling with almost all FDA-approved therapiesPatients with non-clear cell RCC likely have available therapy,especially in the first-line metastatic settingHow to encou

6、rage specific development for non-clear cell histology?Encourage enrollment in dedicated clinical trialsEncourage enrollment of non-clear cell cohorts in broader randomized trialsFDA Guidance-RCC:Developing Drugs and Biologics for Adjuvant Treatment:Discusses broadening enrollment;“Patients with non