Atezolizumab Promising in Cisplatin-Ineligible Metastatic Bladder Cancer


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Atezolizumab (Tecentriq), an anti–programmed cell death ligand 1 (PD-L1) inhibitor, achieved durable responses as first-line treatment in cisplatin-ineligible patients with metastatic urothelial carcinoma in a primary analysis of a phase II trial. These data represent an unmet need, because cisplatin-ineligible patients have poor performance status, impaired renal function, or multiple comorbidities and few treatment options.

Overall response rate in the study was 24%, and responses were seen at all levels of PD-L1 expression. At the time of data cutoff, 21 (75%) of 28 responses remained ongoing. At a median follow-up of 14.4 months, median overall survival was 14.8 months, and the 12-month overall survival rate was 57%.


The ultimate question is whether [atezolizumab] should be used as first-line therapy. We are headed in the direction for first-line use, but we need the data to demonstrate this.
— Arjun V. Balar, MD

Survival data are still immature but compare well with historical controls, according to lead author Arjun V. Balar, MD, of Perlmutter Cancer Center, NYU Langone Medical Center, New York. Dr. Balar presented primary results from cohort 1 (cisplatin-ineligible patients) of the IMvigor210 trial at the 2016 ASCO Annual Meeting.1

“Patients with metastatic urothelial cancer are often too sick to receive aggressive chemotherapy with cisplatin, which is the only therapy shown to improve survival in this disease,” Dr. Balar said. “These data make a compelling argument for atezolizumab as a new standard of care in cisplatin-ineligible metastatic urothelial cancer, but further studies are needed.”

Atezolizumab is currently approved as second-line therapy in metastatic urothelial cancer. There are no therapies proven to prolong survival in metastatic urothelial cancer in cisplatin-ineligible patients.

“Regimens used in this setting are heterogeneous and are associated with short response durations; many patients are managed with best supportive care only,” Dr. Balar told listeners.

Study Details

IMvigor210 is a multinational single-arm, phase II trial. Cohort 1 comprised 119 cisplatin-ineligible patients treated with first-line atezolizumab at 1,200 mg IV every 3 weeks until ­RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 disease progression, assessed by the treating investigator. All patients had never received chemotherapy for metastatic disease and developed disease recurrence at least 12 months from any perioperative chemotherapy, if they received it. Patients were deemed cisplatin-ineligible if they had an Eastern Cooperative Oncology Group performance status of 2, impaired kidney function, or grade 2 or worse peripheral neuropathy or hearing loss.

At a median follow-up of 14.4 months, the overall response rate was 24%, including 7% complete responses and 17% partial responses. PD-L1 expression on tumor-infiltrating immune cells was assessed by immunohistochemistry and scored as immune cell (IC)0, IC1, or IC2/3. Responses were seen at all levels of PD-L1 expression: 21% who were PD-L1–negative, 23% for those with IC1 expression, and 28% for IC2/3 expression.

The median duration of response had not yet been reached at the time of the March 2016 data cut-off. Only 15% of patients experienced a grade 3 or 4 treatment-related adverse event, and only 6% withdrew from treatment due to a treatment-related adverse event. Most adverse events were grade 1 or 2. One patient had a grade 5 event (sepsis).

“Atezolizumab was efficacious and very well tolerated. Atezolizumab compares favorably with historic data from cisplatin-ineligible patients,” Dr. Balar said.

PD-L1 as Biomarker?

Dr. Balar discussed the usefulness of PD-L1 as a biomarker for response. “The issue of PD-L1 continues to be hotly contested. The immune system is dynamic, but testing of archival tumor tissue is done in a static setting,” he noted.

Role of Atezolizumab Explored

  • Preliminary data from an ongoing phase II trial showed that first-line treatment with atezolizumab achieves durable responses and encouraging survival in platinum-ineligible patients with metastatic urothelial cancer.
  • Further study is needed to validate the role of atezolizumab as first-line treatment in this patient population.

“There are differences between companies’ diagnostic methods of testing for PD-L1. In the phase I study of ­atezolizumab in pretreated patients, we saw significant separation of response by PD-L1 expression. When you look at other cohorts, such as cohort 2 and in particular cohort 1 of IMvigor210, this biomarker appears to be less relevant,” Dr. Balar noted.

“That being said, other factors in bladder cancer such as site of disease, performance status, and mutational burden seem to have a more significant impact on defining who is most likely to respond to atezolizumab,” he continued.

“My hunch is that PD-L1 is not the right biomarker. Other biomarkers are being tested,” he told the audience.

An application had been submitted to the U.S. Food and Drug Administration for Fast Track approval of atezolizumab. “Atezolizumab was approved as second-line therapy for patients [whose disease progresses] on prior platinum. The ultimate question is whether it should be used as first-line therapy,” he continued. “I am confident we are headed in the direction for first-line use, but we need the data to demonstrate this.” ■

Disclosure: IMvigor210 was sponsored by Hoffmann-La Roche. Dr. Balar has had a consulting or advisory role with Cerulean Pharma, Dendreon, Pfizer, and Roche/Genentech.

Reference

1. Balar AV, Galsky MD, Loriot Y, et al: Atezolizumab as first-line therapy in cisplatin-ineligible locally advanced/metastatic urothelial carcinoma: Primary analysis of IMvigor210 cohort 1. 2016 ASCO Annual Meeting. Abstract LBA4500. Presented June 5, 2016.


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Expert Point of View: Charles Ryan, MD

Charles Ryan, MD

Charles Ryan, MD

“These are important data. It is safe to envision a future where atezolizumab [Tecentriq] can be used first-line. These were cisplatin-ineligible patients, and many patients fall into this category, especially the elderly. Platinum-ineligibility is a big problem due to...


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