San Diego, CA USA (UroToday.com) In this session, Dr. Vogelzang reminded the audience that advanced UC is uniformly fatal after failure of platinum chemotherapy. Durable response is rarely seen and the Median survival is 9.2 (5.7-11.7) months. To make matters worse, grade 3-4 toxicities are high.
Enter immune checkpoint blockade and the PD-1/PD-L1 pathway. PD-1 is a negative costimulatory receptor expressed primarily on activated T cells. PD-L1 is broadly expressed in human cancer. Specific subgroups harbor high levels of PD-L1. For example, lynch syndrome patients are hypermutated and demonstrate corresponding hypersensitivity to immune checkpoint inhibitors.
Dr. Vogelzang highlighted the IMvigor 210 trial, which includes patients with mUC whose tumors are PD-L1 positive and have progression during/following platinum-based first line chemotherapy. PD-L1 positivity is determined based on 3 scoring levels: IC2/3 (≥5%), IC1 (≥1 but <5), and IC0 <1%). They receive atezolizumab 1200mg IV every 3 weeks until loss of benefit. The co-primary endpoints are overall response rates (ORR) by RECIST v1.1 criteria and ORR per investigator-assessed modified RECIST criteria. Key secondary endpoint are duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
A total of 310 patients were evaluated. Median age was 66 years, 78% of patients were male, 74% had a bladder primary, and 37% had prior cystectomy. PD-L1 status was 32%, 35%, and 33% for IC2/3, IC1, and IC0, respectively. ORR for all comers was 15% (95%CI 11-19%). Though responses were seen in all PD-L1 subgroups, greater ORR was associated with higher PD-L1 IHC status. Complete responses (CR) were seen in 5% of all comers and up to 11% in patients with IC2/3. Responses were durable and the median DOR (range 2-13.7 months) was not reached in any PD-L1 subgroup at median follow-up of 11.7 months (range 0.2-15.2 months). Ongoing responses were seen in 38/45 (84%) responding patients. The disease control rate (defined as CR+partial response+stable disease) was 35%, 21%, and 19% for IC2/3, IC1, and IC0 IHC subgroups, respectively. Median PFS was 2.1 months for all patients and 6-month PFS occurred in 30%, 17%, and 21% of IC2/3, IC1, and IC0 IHC subgroups, respectively. The 12-month OS was 48%, 30%, and 36% for IC2/3, IC1, and IC0 IHC subgroups, respectively. This compares favorably with estimates of 20% 12-month OS for patients in a second line only setting (Agarwal N et al., Clin Genitourin Cancer 2014). The safety profile was acceptable with only 11% of patients reporting serious adverse events (AEs) and no deaths attributable to therapy. The AE profile was similar across IHC groups.
Generally speaking, Dr. Vogelzang highlighted that a higher response was seen in high immune PD-L1 expressing patients and vice versa. However, this was not exclusive and demonstrated the highly dynamic nature of immune checkpoint inhibition. Heavy pre-treatment did not preclude response and the most likely people to respond were lymph node only metastatic sites (relative to hepatic). Responses were durable, but benefit should not be confined to response as many patients experienced disease stabilization. The overall response rate was highest in patients with a high mutational load and also in those the cluster 2 luminal TCGA sub-types. The authors concluded that “Although PDL1 immune cell status is clearly associated with atezolizumab response, incorporation of TCGA gene expression subtype, mutational load, or both of these novel biomarkers…will allow the formal construction of...a next generation of companion diagnostics” (Rosenberg et al. Lancet 2016; 387: 1909).
Dr. Vogelzang concluded that these molecules have the potential to change the trajectory of the natural history of urothelial carcinoma both in localized and metastatic disease. Further, the toxicity of the antibodies is low and can be given to patients with significant renal dysfunction. More study needs to be completed around response prediction, duration of response, and resistance. Finally, studies combining agents with other anti-neoplastic agents is a high priority for urological oncology research.
Presented By: Nicholas Vogelzang, MD
Reported By: Benjamin T. Ristau, MD, at the 2016 AUA Annual Meeting - May 6 - 10, 2016 – San Diego, California, USA Fox Chase Cancer Center, Philadelphia, PA
Follow on Twitter: @benristau