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