Checkpoint inhibitors in the treatment for metastatic urothelial cancer
Frontier in Urology 2016
Jingsong Zhang, M.D., Ph.D.
Disclosures:
• Research grants from Bayer, Astellas and Medivation Inc.
• Consulting fees: Bayer & Sanofi
Evolution of Systemic Therapy for Metastatic Urothelial Carcinoma (mUC)
Rationale for anti-PD1 or anti-PDL1 in mUC
Over-expression of PDL1 in mUC gene expression analysis
IMvigor 210: response to Atezolizumab based on PDL1 IHC on tumor infiltrating immune cells (IC)
Ventana Anti-PDL1 (sp142) PDL1 expression on IC IC2/3: 5% or more positivity; IC1: 1-4%; IC0 <1% IHC positivity
Responses were seen in all IC groups with higher ORR & CR rates in IC2/3 46% of evaluable patients 9118/259) had a decrease in target lesions
IMvigor 210: time to response
IMvigor 210: duration of response
ImVigor 210: Overall Survival
Baseline clinical features and their associations with overall survival after Atezolizumab
Anti-PD1 or Anti-PDL1 in mUC: Response Rate
Anti-PD1 or Anti-PDL1 in mUC: 1 yr survival rate
Adverse events observed with Anti-PD1 or Anti-PDL1 therapy in mUC
PD-L1 expression as a potential predicative biomarker for anti-PDL1 or anti-PD1 therapy in mUC
Other potential predicative biomarkers
N Engl J Med.
Mutations a/w acquired resistance to PD-1 blockade
Whole-exome sequencing of biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma
resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells
A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) , which led to loss of surface expression of major histocompatibility complex class I
Trials Beyond check point blockade
A phase I study combining enzalutamide with gemcitabine-cisplatin as a frontline therapy for mUC. A Phase 1 Study of the Safety and Pharmacokinetics of Escalating Doses of ASG-22CE is at the dose expansion cohort for mUC. • ASG-22CE is a drug antibody conjugate that delivers
MMAE with anti-Nectin4, a marker that is over expressed in >80% of bladder cancer.
• No limitaiton on prior lines of therapy, Cr up to 2 is allowed.
• Anti-tumor activities were noted in the post checkpoint inhibitor setting as well as liver metastasis