A recently approved treatment for urothelial carcinoma provides durable responses when used as first-line treatment in patients who are ineligible for cisplatin-based therapy, according to a recent study.
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In addition, a separate analysis examined immune and genetic predictors of response to atezolizumab (Tecentriq) in the IMvigor 210 cohort of patients treated with atezolizumab as second-line therapy.
In May 2016, atezolizumab became the first PD-L1 inhibitor approved for the treatment of urothelial carcinoma. The indication was for use as second-line therapy in patients with locally advanced or metastatic disease that had progressed during or following platinum-based chemotherapy or that worsened within 12 months of receiving platinum-based neoadjuvant or adjuvant chemotherapy, and it was based on outcomes achieved in a cohort of 310 patients enrolled in the phase II IMvigor 210 trial (“Cohort 2”).
Dr. BalarAt the American Society of Clinical Oncology annual meeting in Chicago, Arjun V. Balar, MD, presented findings from a cohort of 119 patients in the same study (“Cohort 1”) on behalf of the IMvigor 210 investigators. He described the responses as “unprecedented.”
The objective response rate (ORR) was 24%, including 7% complete responses and 17% partial responses. At a median follow-up of 14.4 months (data cut-off, March 2016), 75% of the responses were ongoing, and the estimated median survival was 14.8 months, although the data were still immature (event rate was 47%). The estimated 12-month overall survival rate was 57%.
Subgroup analyses showed that the response rates, tumor regression rates, and estimated median survival were similar regardless of the level of PD-L1 expression on tumor-infiltrating immune cells (IC) and in patients with poor prognostic factors.
Next: “The data are immature and longer follow-up is needed, but I think they make a compelling argument for atezolizumab to be a potential new standard of care for cisplatin-ineligible patients with metastatic or locally advanced urothelial carcinoma."
“The data are immature and longer follow-up is needed, but I think they make a compelling argument for atezolizumab to be a potential new standard of care for cisplatin-ineligible patients with metastatic or locally advanced urothelial carcinoma. Moreover, it could also represent the beginning of a seismic shift in our treatment approach for all patients with metastatic disease, irrespective of their eligibility for cisplatin,” said Dr. Balar, assistant professor of medicine at New York University Langone Medical Center, New York.
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Patients were eligible for enrollment in the IMvigor 210 Cohort 1 arm investigating atezolizumab as first-line therapy if they had received no chemotherapy for their metastatic disease and had developed disease recurrence at least 12 months since completion of perioperative chemotherapy. They received intravenous atezolizumab, 1,200 mg once every 3 weeks until RECIST v1.1-defined progression by the treating investigator.
The patients had a median age of 73 years with 21% age 80 years or older, and two-thirds had visceral metastatic disease, which is a poor prognostic feature. PD-L1 IC status was categorized as IC2/3 (≥5% staining) in 32 patients, IC1 (≥1% to <5%) in 48 patients, and IC0 (<1%) in 39 patients. In general, the baseline characteristics were similar across the PD-L1 IC subgroups.
Dr. Balar also reported that the response to atezolizumab occurred quickly, at a median of about 2 months in all PD-L1 IC subgroups. The ORR was 28% among patients older than age 80, 42% for patients whose primary tumor site was in the upper tract, and 17% for those with a primary tumor in the bladder or urethra. Patients having only lymph node metastases had a relatively higher ORR than those with visceral metastases: 32% versus 15%. The ORR was similar—25% to 27%—whether patients were ineligible for cisplatin because of impaired renal function and/or poor performance status.
Dr. Balar reported that only 6% of patients discontinued treatment due to an adverse event. The overall incidence of grade 3-4 adverse events was 15%, which was similar to that observed in the cohort of patients receiving atezolizumab after platinum-based therapy, and the overall rate of immune-related grade 3-4 adverse events was 6%. There was one death that was judged by a treating investigator to be treatment related.
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The only adverse events that occurred at an incidence >10% were fatigue (30%), diarrhea (11%), and pruritus (11%). Fatigue (3%) and increased alanine aminotransferase (3%) were the most frequent grade 3-4 adverse events.
“Interestingly, no decline in kidney function was observed in patients with preexisting renal impairment,” Dr. Balar said.
Next: Immune, genetic predictors explored
Immune, genetic predictors explored
Dr. RosenbergIn a separate study, findings from exploratory analyses of immune and genetic predictors of response to atezolizumab in the IMvigor 210 cohort of patients treated with atezolizumab as second-line therapy were presented by Jonathan E. Rosenberg, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, New York.
Although all PD-L1 IC subgroups showed some response to atezolizumab, patients with IC2/3 PD-L1 status had better outcomes than those with IC0/1 status for both ORR (28% vs. 10%) and median survival (11.9 vs 6.7 months).
Dr. Rosenberg reported that Tumor Cancer Genome Atlas (TCGA) subtype and mutation load were also significant independent predictors of atezolizumab response and that high mutation load was validated as a predictor of response in patients treated in Cohort 1. In addition, the combination of PD-L1 IC status and TCGA subtype improved response prediction for Cohort 2, while adding mutation load to the model added further value.
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“These data highlight the importance of the interaction between the tumor and its microenvironment in understanding response to atezolizumab,” Dr. Rosenberg said.
“The data suggest atezolizumab efficacy is driven by genomic, molecular, and immunologic factors related to adaptive immunity and point to the possibility that simultaneous assessment of these characteristics may define drivers of immune responsiveness and inform potential combination strategies as well as mechanism of resistance.”
Dr. Balar is a consultant/adviser to Roche/Genentech, Merck, Cerulean Pharma, Dendreon, and Pfizer, and receives research funding from Genentech and Merck. Dr. Rosenberg is a consultant/adviser for Boehringer Ingelheim, Bristol-Myers Squibb, Dendreon, Janssen Oncology, Johnson & Johnson, Lilly, Merck, Oncogenex, and Onyx. Several of Dr. Balar’s and Dr. Rosenberg’s co-authors have a financial or other relationship with Roche/Genentech; for a full list of disclosures, see bit.ly/IMvigordisclosures.
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