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Atezolizumab in patients with renal insufficiency and mixed variant histology: analyses from an expanded access program in platinum-treated locally advanced or metastatic urothelial carcinoma.

ABSTRACT: BACKGROUND:Atezolizumab is a treatment for locally advanced/metastatic urothelial carcinoma (mUC). However, its use in patients with renal insufficiency or UC with mixed variant histology (MVH) is not well characterized. OBJECTIVE:To report efficacy and safety of atezolizumab in these special subpopulations from an expanded access program (EAP). DESIGN, SETTING, AND PARTICIPANTS:A total of 218 patients were enrolled at 36 US study sites (November 2015-August 2016), and the trial ended following the approval of atezolizumab by the US Food and Drug Administration. This post hoc analysis investigated outcomes in specific study subgroups. INTERVENTION:Atezolizumab 1200 mg was administered intravenously every 3 weeks until loss of clinical benefit, unacceptable toxicity, death, consent withdrawal, decision to discontinue, commercial availability, or study closure. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Response Evaluation Criteria in Solid Tumors V.1.1 responses and safety were evaluated by baseline renal function and histology. RESULTS AND LIMITATIONS:Objective responses occurred in 0/6 (0%), 4/19 (21%), 1/27 (3.7%), and 12/62 (19%) of evaluable patients with creatinine clearance (CrCl) <30, 30-45, 45-60, and ?60 mL/min, respectively, and stable disease was seen in three patients with CrCl <30 mL/min. Objective responses were seen in 13/102 patients (13%) with urothelial carcinoma (UC) histology only and in 4/12 patients (33%) with UC with MVH. Treatment-related adverse event frequencies ranged from 35% to 54% across the earlier indicated CrCl subgroups and they were also similar in patients with pure UC or UC with MVH (46%). CONCLUSIONS:In this EAP mUC subgroup analysis, clinical benefit of atezolizumab occurred in patients with compromised renal function or MVH UC tumors. Safety was comparable across subgroups. PATIENT SUMMARY:We examined the efficacy and safety of atezolizumab for UC in certain patients participating in an EAP. We found that responses to atezolizumab occurred, and safety was similar, in most patient subgroups with varying levels of kidney functioning or less common types of tumor tissue histology.

SUBMITTER: Hoffman-Censits J

PROVIDER: S-EPMC7342864 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Atezolizumab in patients with renal insufficiency and mixed variant histology: analyses from an expanded access program in platinum-treated locally advanced or metastatic urothelial carcinoma.

Hoffman-Censits Jean J Pal Sumanta S Kaiser Constanze C Ding Beiying B Bellmunt Joaquim J

Journal for immunotherapy of cancer 20200701 2

<h4>Background</h4>Atezolizumab is a treatment for locally advanced/metastatic urothelial carcinoma (mUC). However, its use in patients with renal insufficiency or UC with mixed variant histology (MVH) is not well characterized.<h4>Objective</h4>To report efficacy and safety of atezolizumab in these special subpopulations from an expanded access program (EAP).<h4>Design, setting, and participants</h4>A total of 218 patients were enrolled at 36 US study sites (November 2015-August 2016), and the ...[more]

PMID: 32641319

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Project description:BackgroundPatients with metastatic urothelial carcinoma (mUC) who progress after platinum-based chemotherapy have had few treatment options and uniformly poor outcomes. Atezolizumab (anti-programmed death-ligand 1) was approved in the USA for cisplatin-ineligible and platinum-treated mUC based on IMvigor210, a phase 2, single-arm, two-cohort study.ObjectiveTo evaluate the efficacy and safety of atezolizumab by the number of prior lines of systemic therapy in patients with pretreated mUC.Design, setting, and participantsIMvigor210 enrolled 315 patients with mUC with progression during or following platinum-based therapy at 70 international sites between May 2014 and November 2014. Key inclusion criteria included age ≥18 yr, creatinine clearance ≥30ml/min, and Eastern Cooperative Oncology Group performance status 0-1, with no limit on prior lines of treatment.InterventionPatients in this cohort received atezolizumab 1200mg intravenously every 3 wk until loss of clinical benefit.Outcome measurements and statistical analysisCentrally assessed Response Evaluation Criteria In Solid Tumors v1.1 objective response rate (ORR), median duration of response, overall survival (OS), and adverse events were evaluated by prior treatment. Potential differences between subgroups were evaluated using log-rank (for OS) and chi-square (for ORR and adverse events frequencies) testing.Results and limitationsThree hundred and ten patients were efficacy and safety evaluable (median follow-up, 21 mo). Objective responses and prolonged OS occurred across all prespecified subgroups; median duration of response was not reached in most subgroups. In patients without prior systemic mUC therapy (first-line subgroup), ORR was 25% (95% confidence interval: 14-38), and median OS was 9.6 mo (95% confidence interval: 5.9-15.8). No significant differences in efficacy or toxicity by therapy line were observed.ConclusionsAtezolizumab demonstrated comparable efficacy and safety in previously treated patients with mUC across all lines of therapy evaluated.Patient summaryWe investigated effects of previous treatment in patients with metastatic urothelial carcinoma that progressed after platinum-based therapy. Atezolizumab was active and tolerable no matter how many treatment regimens patients had received. ClinicalTrials.gov, NCT02108652.

Project description:Background:Conventional criteria for tumor progression may not fully reflect the clinical benefit of immunotherapy or appropriately guide treatment decisions. The phase II IMvigor210 study demonstrated the efficacy and safety of atezolizumab, a programmed death-ligand 1-directed antibody, in patients with platinum-treated locally advanced or metastatic urothelial carcinoma. Patients could continue atezolizumab beyond Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 progression at the investigator's discretion: this analysis assessed post-progression outcomes in these patients. Patients and methods:Patients were treated with atezolizumab 1200?mg i.v. every 3?weeks until loss of clinical benefit. Efficacy and safety outcomes in patients who experienced RECIST v1.1 progression and did, or did not, continue atezolizumab were analyzed descriptively. Results:In total, 220 patients who experienced progression from the overall cohort (n?=?310) were analyzed: 137 continued atezolizumab for ??1 dose after progression, 19 received other systemic therapy, and 64 received no further systemic therapy. Compared with those who discontinued, patients continuing atezolizumab beyond progression were more likely to have had a baseline Eastern Cooperative Oncology Group performance status of 0 (43.1% versus 31.3%), less likely to have had baseline liver metastases (27.0% versus 41.0%), and more likely to have had an initial response to atezolizumab (responses in 11.7% versus 1.2%). Five patients (3.6%) continuing atezolizumab after progression had subsequent responses compared with baseline measurements. Median post-progression overall survival was 8.6?months in patients continuing atezolizumab, 6.8?months in those receiving another treatment, and 1.2?months in those receiving no further treatment. Atezolizumab exposure-adjusted adverse event frequencies were generally similar before and following progression. Conclusion:In this single-arm study, patients who continued atezolizumab beyond RECIST v1.1 progression derived prolonged clinical benefit without additional safety signals. Identification of patients most likely to benefit from atezolizumab beyond progression remains an important challenge in the management of metastatic urothelial carcinoma. ClinicalTrials.gov ID:NCT02108652.

Project description:Until recently in the United States, no products were approved for second-line treatment of advanced urothelial carcinoma. On May 18, 2016, the U.S. Food and Drug Administration approved atezolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking antibody and represents the first approved product directed against PD-L1. This accelerated approval was based on results of a single-arm trial in 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression after prior platinum-containing chemotherapy. Patients received atezolizumab 1,200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity. Key efficacy measures were objective response rate (ORR), as assessed by Independent Review per RECIST 1.1, and duration of response (DoR). With a median follow-up of 14.4 months, confirmed ORR was 14.8% (95% CI: 11.1, 19.3) in all treated patients. Median DoR was not reached and response durations ranged from 2.1+ to 13.8+ months. Of the 46 responders, 37 patients had an ongoing response for ≥ 6 months. The most common adverse reactions (≥20%) were fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, and constipation. Infection and immune-related adverse events also occurred, including pneumonitis, hepatitis, colitis, endocrine disorders, and rashes. Overall, the benefit-risk assessment was favorable to support accelerated approval. The observed clinical benefits need to be verified in confirmatory trial(s).Implications for practiceThis accelerated approval of atezolizumab for second-line use in advanced urothelial carcinoma provides patients with an effective, novel treatment option for the management of their disease. This represents the first immunotherapy approved in this disease setting.

Project description:Standard-of-care first-line treatment for metastatic urothelial carcinoma (mUC) is platinum-based chemotherapy (CTx). Maintenance immunotherapy is a treatment option for patients without progressive disease (PD) after induction CTx. IMvigor130 was a randomised, phase 3 study evaluating atezolizumab plus platinum-based CTx (arm A), atezolizumab monotherapy (arm B), or placebo plus platinum-based CTx (arm C) as first-line treatment for mUC. The primary progression-free survival (PFS) analysis showed a statistically significant PFS benefit favouring arm A versus arm C, which did not translate into overall survival (OS) benefit at the final OS analysis. We report exploratory analyses based on response to combination induction treatment (arm A vs arm C) using final OS data. Post-induction OS was analysed for patients without PD during induction (4-6 CTx cycles) who received at least one dose of single-agent atezolizumab/placebo maintenance treatment. Post-progression OS was analysed for patients with PD during induction CTx. Addition of atezolizumab to CTx did not impact OS outcomes, regardless of response to induction CTx, with hazard ratios of 0.84 (95% confidence interval [CI] 0.63-1.10) for patients without PD and 0.75 (95% CI 0.54-1.05) for those with PD during induction CTx. Treatment effects appeared to be greatest for patients treated with cisplatin and for those with PD-L1-high tumours.Patient summaryThe IMvigor130 trial showed that addition of atezolizumab to chemotherapy (CTx) did not improve survival over CTx alone in patients with bladder cancer. Overall, patients whose cancer did not progress during initial treatment tended to live longer than patients whose cancer did progress, but addition of atezolizumab to CTx did not help either group live longer in comparison to CTx alone. However, the results suggest that patients who received a certain CTx drug (cisplatin) or who had high levels of a marker called PD-L1 in their tumour may get the most improvement from addition of atezolizumab to CTx.The IMvigor130 trial is registered on ClinicalTrials.gov as NCT02807636.

Project description:BackgroundFirst-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients.MethodsFor this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652.FindingsBetween June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients.InterpretationAtezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer.FundingF Hoffmann-La Roche, Genentech.

Dataset Information

Atezolizumab in patients with renal insufficiency and mixed variant histology: analyses from an expanded access program in platinum-treated locally advanced or metastatic urothelial carcinoma.

Publications

Atezolizumab in patients with renal insufficiency and mixed variant histology: analyses from an expanded access program in platinum-treated locally advanced or metastatic urothelial carcinoma.

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