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Atezolizumab Approaches FDA Approval in Bladder Cancer, But Biomarkers Remain Unclear

Laura Panjwani
Published: Tuesday, Mar 15, 2016

Dr. Matthew Galsky

Matthew Galsky, MD

The PD-L1 inhibitor atezolizumab showed promising response and durable activity in patients with metastatic urothelial carcinoma, particularly in those with increased levels of PD-L1 expression, according to results of the phase II IMvigor study recently published in The Lancet.

Based on the IMvigor data the FDA has granted atezolizumab priority review as a treatment for patients with locally advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy in the metastatic setting, or whose disease worsened within 12 months of receiving platinum-based chemotherapy before or after surgery.

Study author Matthew Galsky, MD, says the IMvigor findings represent a “watershed moment” for the treatment of metastatic urothelial carcinoma.

“We really have not had a lot of good treatments for patients in this disease state, ever,” says Galsky, who is an associate professor of Medicine, Hematology and Medical Oncology and assistant professor of Urology at Mount Sinai Hospital. “Once patients progress on standard first-line chemotherapy, we really have very little to offer them. Atezolizumab could potentially be the first drug approved in this space.”

In the study, IMvigor 310 patients received atezolizumab. PD-L1 expression was determined by infiltrating immune cells (ICs) in the tumor microenvironment and was defined by the percentage of PD-L1–positive immune cells. Patients were identified as IC0 (<1%), IC1 (≥1% but <5%), and IC2/3 (≥5%).

The primary analysis showed that, compared with a historical control, overall response rate (ORR) of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective ORR for each immune cell group, with a 27% ORR in the IC2/3 group (95% CI, 19-37; P <.0001), 18% ORR in the IC 1/2/3 group (95% CI, 13-24; P = .0004) and 15% ORR in all patients (95% CI, 11-20; P = .0058).

With longer follow-up data by independent review, objective response rates were 26% (95% CI, 18-36) in the IC2/3 group, 18% (95% CI, 13-24) in the IC1/2/3 group, and 15% (95% CI, 11-19) overall in all 310 patients. At a median follow-up of 11.7 months (95% CI, 11.4-12.2), ongoing responses were recorded in 38 (84%) of 45 responders.

Regarding grade 3/4 treatment-related adverse events, fatigue was the most common, occurring in 50 (16%) of 310 treated patients. Grade 3/4 immune-mediated adverse events occurred in 15 (5%) of patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnea being the most common. No treatment-related deaths occurred during the study.

In addition to PD-L1 expression being linked to response, an exploratory analysis also showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. This study was the first to investigate TCGA subtypes with response to immune checkpoint in metastatic urothelial carcinoma.

However, the role of both PD-L1 and TCGA subtyping remains unclear in this patient population, says Galsky.

In an interview with OncLive, Galsky explains the challenges of utilizing molecular subtyping and PD-L1 as biomarkers. He also discusses the impact a potential approval of atezolizumab could have in metastatic bladder cancer, possible combinations that could increase ORR, and next steps in understanding the IMvigor study.

OncLive: What are the most significant findings from the IMvigor study that oncologists should be aware of?

Galsky: For patients with metastatic urothelial cancer that has progressed, despite first-line chemotherapy, we really haven’t had any standard therapies for the past several decades. In this study, a subset of patients responded to PD-L1 blockade, and those patients tended to have durable responses. That is the major take-home message of this trial.

However, there is an ORR of 15% in this study, which means that, unfortunately, the majority of patients will not respond to this treatment, so there is much more work to be done. But this is still very significant because of the lack of really anything working well in this patient population.

What role could subtyping have in predicting response to atezolizumab?

In the past few years, it has been recognized that bladder cancer, at the transcriptome level and at the molecular level, is not one disease but several different diseases. A few independent groups developed classification schemes based on gene expression profiling of bladder cancer specimens, and those overlap somewhat with what TCGA has found.

We have these different subtypes, and there have been some recent efforts to unify these subtypes so that everyone is talking about a standard classification system. These subtypes we know differ in terms of expression of some genes that are important in the pathogenesis of cancer.

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