SAN FRANCISCO — The investigational cancer immunotherapy atezolizumab (also known as MPDL3280A, Roche) significantly improves overall response rates (ORRs) in metastatic urothelial cancers, according to findings presented here at the Genitourinary Cancers Symposium 2016.
The updated results from the IMvigor 210 study also showed that these responses are durable.
In addition, a higher level of expression of programmed death-ligand 1 (PD-L1) was associated with better response rates, although low levels of expression did not preclude responses; complete responses were observed regardless of the level of PD-L1 expression, even in those with poor prognostic factors.
"Given the current landscape of chemotherapy options for our patients with urothelial cancer who progress following platinum chemotherapy, this primary analysis of IMvigor 210 demonstrates that atezolizumab has the potential to become the standard of care for metastatic urothelial cancers," said lead researcher Jean H. Hoffman-Censits, MD, director of the Multidisciplinary Genitourinary Oncology Center at Jefferson University Hospitals in Philadelphia.
The ORRs and survival of patients with metastatic urothelial cancer who progress after platinum-based chemotherapy are generally quite poor, and treatment options are limited.
"Daily, we are challenged to treat these patients with chemotherapies that are toxic and have no survival benefit in this frail population," said Dr Hoffman-Censits. "Effective and tolerable treatments for metastatic urothelial carcinoma are desperately needed."
Atezolizumab, an investigational monoclonal antibody designed to target and bind to PD-L1, was granted breakthrough therapy designation last year by the US Food and Drug Administration for patients whose metastatic bladder cancer expresses PD-L1. Signaling mediated by PD-L1 (expressed in metastatic urothelial cancer) can inhibit antitumor immune responses, Dr Hoffman-Censits explained. Through the inhibition of PD-L1, atezolizumab can enhance T-cell priming and reinvigorate suppressed immune cells.
In the open-label, multicenter, single-group, phase 2 IMvigor 210 study, Dr Hoffman-Censits and her colleagues evaluated the safety and efficacy of atezolizumab in 310 patients with locally advanced or metastatic urothelial cancer, regardless of PD-L1 expression. Patients who had progressed on initial therapy (second-line or later) were treated with intravenous atezolizumab 1200 mg on day 1 of 21-day cycles until the loss of clinical benefit.
Last year, the manufacturer announced that early results from IMvigor 210 were successful, and that the primary end point of objective response rate was met.
Primary End Point Met
Patients in the IMvigor 210 study were divided into two cohorts. The first cohort comprised those who had received no previous therapies for locally advanced or metastatic urothelial cancers, but who were ineligible for first-line cisplatin-based therapy. "The results for this cohort are not yet mature," Dr Hoffman-Censits reported. "Those data will be presented at a later date."
But she presented results from the second cohort, which comprised patients who experienced disease progression during or after treatment with a platinum-based chemotherapy regimen. Overall, 41% had received two or more treatments in the metastatic setting.
An investigational immunohistochemistry test was used to select patients by histology, previous lines of therapy, and PD-L1 expression on tumor-infiltrating immune cells (IC). PD-L1 positivity was stratified into three subgroups: IC2/3 (at least 5%), IC1 (between 1% and 5%), and IC0 (below 1%).
All prespecifed subgroups met the primary end point of a 10% objective response, compared with historic control subjects. Although a better response rate was associated with a higher level of PD-LI expression, responses were seen in the seen in IC0 and IC1 subgroups. "This included complete responses," said Dr Hoffman-Censits.
The ORR was 26% for the IC2/3 subgroup, 18% for the IC0/1 subgroup, and 15% for all patients. Complete responses were seen in up to 11% of patients in the IC2/3 subgroup and in 5% of all patients. These responses were durable, and the median duration of response (range, 2.0 - 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).
"Impressively, 84% were experiencing a response at the time of data cutoff," Dr Hoffman-Censits pointed out.
Data Truly Exciting
Responses were also observed in patients with poor prognostic factors, such as the 243 patients with visceral metastases (ORR, 10%), the 97 with liver metastases (ORR, 6%), the 193 with an ECOG performance status of 1 (ORR, 10%), and the 68 with a hemoglobin level below 10 g/dL (ORR, 9%).
Median progression-free survival was 2.1 months for all patients. At 6 months, median progression-free survival was 30% in the IC2/3 subgroup, 17% in the IC1 subgroup, and 21% in the IC0 subgroup.
Median overall survival was 11.4 months in the IC2/3 subgroup, 6.7 months in the IC0/1 subgroup, and 7.9 months for all patients. Twelve-month overall survival was 48% in the IC2/3 subgroup, 30% in the IC0/1 subgroup, and 36% for all patients.
These data compare favorably with the 12-month overall survival estimate of 20% in a second-line only cohort, she said.
"These data are truly exciting," Dr Hoffman-Censits said enthusiastically.
The overall reduction in tumor burden was associated with PD-L1 status. It was 61% in the IC2/3 subgroup, 45% in the IC1 subgroup, and 30% in the IC0 subgroup.
The safety profile was acceptable and, overall, the drug was well tolerated, with 65% of patients experiencing an adverse event but only 11% reporting a serious adverse event. There were no deaths attributable to therapy, and the discontinuation rate was 4%.
The most common grade 3/4 adverse events were fatigue, anemia, pneumonitis, and hypertension/hypotension, and about 5% experienced a grade 3/4 immune-related event.
First Cohort Data Needed
This "may change the landscape of the treatment of the disease," said William Y. Kim, MD, from the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, during a discussion of the study.
This study has built on data from previous phase 1 trials that examined PD-L1 blockade in this setting. One of its strengths is the number of patients enrolled. "I don't know when was the last time I saw a study in the metastatic bladder cancer setting with 310 patients," Dr Kim pointed out.
"It's also important to note that there was not enrichment or screening for PD-L1 positivity in this trial, compared with the phase 1 trials," he said. "This may account for the small differences in response rates and overall survival seen."
Results from the first cohort of IMvigor 210 patients are anxiously awaited, and Dr Kim noted that "follow-up regarding the durability of these responses is needed as well."
Roche has an ongoing randomized phase 3 study, IMvigor 211, comparing atezolizumab with standard-of-care chemotherapy in patients with metastatic urothelial cancer that has progressed after initial treatment.
The study was funded by Roche/Genentech. Dr Hoffman-Censits reports relationships with Roche and Sanofi. Several coauthors report relationships with industry, including Roche/Genentech.
Genitourinary Cancers Symposium (GUCS) 2016: Abstract 355. Presented January 8, 2016.
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