Atezolizumab Effective for Pretreated Metastatic Urothelial Carcinoma

The Lancet.

The phase II multicenter, single-arm, two-cohort study showed a correlation between PD-L1 expression on immune cells (IC) and increased response in patients with metastatic urothelial carcinoma. In patients with the highest level of PD-L1 expression, the objective response rate (ORR) with atezolizumab was 27%.

The FDA granted atezolizumab a breakthrough therapy designation in 2014 for patients with metastatic urothelial carcinoma whose tumor expresses PD-L1. Data from the IMvigor 210 study serve as the basis for a Biologics License Application for atezolizumab, according to the developer of the immunotherapy, Genentech.

“Since the development of combination treatment with methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy 30 years ago, no major improvements have been made in treatment outcomes for patients with urothelial carcinoma,” wrote lead author Jonathan Rosenberg, MD, medical oncologist, Memorial Sloan-Kettering Cancer Institute, in the publication. “The results of this large single-arm phase II study show that atezolizumab induced durable antitumor responses in patients with advanced urothelial carcinoma whose tumors have progressed during or after treatment with platinum-based chemotherapy.”

According to the study, this is the first set of data that shows a definitive correlation between subtypes listed in The Cancer Genome Atlas (TCGA) and a positive response to immune checkpoint inhibition. Additionally, the study stressed the importance of mutation load as a biomarker of response to immune checkpoint inhibitors in metastatic urothelial carcinoma.

The study enrolled 315 pretreated patients, out of an initial accrual of 486 patients, between May 13, 2014, and November 19, 2014. Patients enrolled were above the age of 18 and spanned 70 academic medical centers across Europe and the United States.

Of the 315 patients, 127 had received two or more previous systemic regimens for metastatic disease. Of the enrolled patients, 310 received atezolizumab, with 5 patients ultimately dropping off the study due to ineligibility. PD-L1 expression on infiltrating ICs was classified as IC0 (<1% PD-L1 expression), IC1 (&ge;1% but <5%), and IC2/3 (&ge;5%).

In the primary analysis, which was conducted on May 5, 2015, the ORR by RECIST was 27% in patients classified as either IC2 or IC3 (95% CI, 19-37;P<.0001). The ORR was 18% in patients classified as IC1, IC2, and IC3 (95% CI, 13-24,P= .0004). The ORR across the full study was 15% (CI, 11-20;P= .0058). These ORRs compared favorably to the historical control of 10%.

At the time of data cutoff on September 14, 2015, 202 of the 310 patients had exited the study. Of these 202 patients, 193 had died, 8 had discontinued treatment, and 1 additional patients discontinued participation for undisclosed reasons.

An independent review showed a 26% ORR in patients classified as either IC2 or IC3 (95% CI, 18-36). In patients classified as IC1, IC2, and IC3 The ORRs were 18% and 15% in patients classified as IC1,2, and 3 and in the overall population. Responses were ongoing for 84% of patients at a median follow-up of 11.7 months (95% CI, 11.4-12.2). Patients were allowed to continue their treatment beyond the September 2015 cutoff date to account for pseudoprogression.

Of the 310 patients who received treatment, the most frequently observed grade 3 and 4 treatment-related adverse event was fatigue (16%). Grade 3 and 4 immune-mediated adverse events were also reported in 5% of patients. The most common immune-related events were pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnea. There were no treatment-related deaths throughout the study.

Gene expression analysis was used to parse 195 patients participating in the study into either luminal (n=73) or basal (n=122) subtypes. These subtypes are as classified by he Cancer Genome Atlas (TCGA). The basal disease subtype had markedly higher PD-L1 immune cell presence over the luminal subtype (60% vs 23%,P<0.0001). Boosted PD-L1 tumor cell expression was nearly exclusive to the basal subtype as well (39% in basal vs 4% in luminal,P<0.0001)

Mutation load was also examined in 150 patients by way of 315 cancer-related gene panel. The load was exceptionally higher in those who responded to atezolizumab (12.4 per megabase [Mb]) versus non-responders (6.4 per Mb,P<0.0001). There was no association between mutation load and TCGA subtype or immune cell group.

&ldquo;In conclusion, we report that targeting PD-L1 with atezolizumab is effective in heavily pretreated patients with locally advanced or metastatic urothelial carcinoma, and that responses are more common in patients with higher levels of PD-L1 expression on immune cells than in those with lower expression,&rdquo; Rosenberg wrote. &ldquo;The efficacy seems to be driven by underlying genomic, molecular, and immunological factors.&rdquo;

The FDA granted atezolizumab a breakthrough therapy designation in 2014 for patients with metastatic urothelial carcinoma whose tumor expresses PD-L1. Data from the IMvigor 210 study are currently being review by the FDA as part of a Biologics License Application.

References

1. Rosenberg J, Hoffman-Censits J, Powles T et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. The Lancet. 2016. doi:10.1016/s0140-6736(16)00561-4.