Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer

BACKGROUND: The randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone (hazard ratio [HR]=0.75, 95% confidence interval [CI] 0.61-0.93). We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety. RESULTS: Of the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR=0.79, 95% CI 0.59-1.06), combined second- and third-line PFS (HR=0.85, 95% CI 0.68-1.05) or OS (HR=0.96, 95% CI 0.76-1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected. CONCLUSION: In this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS but no improvement in longer-term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life. CLINICALTRIALSGOV: NCT01250379

Safety and Efficacy of Atezolizumab in Understudied Populations with Pretreated Urinary Tract Carcinoma: Subgroup Analyses of the SAUL Study in Real-World Practice

PURPOSE: Atezolizumab is an established treatment option for pretreated urothelial carcinoma, demonstrating efficacy in phase II/III trials. The SAUL study enrolled a broader patient population to determine safety and efficacy in underrepresented subgroups. MATERIALS AND METHODS: Patients with metastatic urinary tract carcinoma received atezolizumab 1,200 mg every 3 weeks until disease progression, unacceptable toxicity, loss of clinical benefit, or patient/physician decision. The primary endpoint was safety. Efficacy was a secondary endpoint. Analyses by programmed cell death ligand-1 (PD-L1) status, age, Eastern Cooperative Oncology Group performance status (ECOG PS) and renal impairment were prespecified; post hoc analyses explored outcomes by tumor location. RESULTS: A total of 1,004 patients were enrolled. Subgroup analyses in patients with older age, renal impairment, or upper tract urothelial carcinoma showed safety and efficacy similar to those in patients without these characteristics. Patients with ECOG PS 2 had clinical features typically associated with aggressive disease; median overall survival was 2.3 months versus 10.0 months in patients with ECOG PS0/1. Patients with PD-L1 expression on ≥5% of tumor-infiltrating immune cells tended to have better outcomes than those with <5% PD-L1 expression, although conclusions on the relative efficacy of atezolizumab cannot be drawn from this single-arm study. CONCLUSIONS: The understudied populations included in the SAUL study had similar outcomes to those in more selected populations included in phase II/III trials of atezolizumab, except for those with ECOG PS 2. Age ≥80 years and/or creatinine clearance <30 ml/minute does not preclude administration of atezolizumab; however, treatment risk versus benefit must be carefully assessed in patients with ECOG PS 2

Zhodnocení účinnosti prevence proti PUP v porubech na Dole Paskov v OKR

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Primary Results from SAUL, a Multinational Single-arm Safety Study of Atezolizumab Therapy for Locally Advanced or Metastatic Urothelial or Nonurothelial Carcinoma of the Urinary Tract

Background: Atezolizumab, a humanised monoclonal antibody targeting PD-L1, is approved for locally advanced/metastatic urothelial carcinoma. SAUL evaluated atezolizumab in a broader, pretreated population, including patients ineligible for the pivotal IMvigor211 phase 3 trial of atezolizumab. Objective: To determine the safety and efficacy of atezolizumab in an international real-world setting. Design, setting, and participants: Between November 2016 and March 2018 (median follow-up 12.7 mo), 1004 patients with locally advanced or metastatic urothelial or nonurothelial urinary tract carcinoma who experienced progression during or after one to three prior therapies for inoperable, locally advanced, or metastatic disease were enrolled. Patients with renal impairment, treated central nervous system metastases, or stable controlled autoimmune disease were eligible; 10% had Eastern Cooperative Oncology Group performance status (ECOG PS)2 and 98% were platinum pretreated (Clinicaltrials.gov: NCT02928406). Intervention: Atezolizumab 1200 mg every 3 wk until progression or unacceptable toxicity. Outcome measurements and statistical analysis: The primary endpoint was safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Results and limitations: The median treatment duration was 2.8 mo (range 0–19); 22% remained on treatment and 8% discontinued because of toxicity. Grade ≥3 adverse events occurred in 45% of patients. The most common grade ≥3 treatment-related adverse events were fatigue, asthenia, colitis, and hypertension (each in 1%). Median OS was 8.7 mo (95% confidence interval [CI]7.8–9.9). The 6-mo OS rate was 60% (95% CI 57–63%), median PFS was 2.2 mo (95% CI 2.1–2.4), and the ORR was 13% (95% CI 11–16%; 3% complete responses). Among IMvigor211-like patients (excluding ECOG PS 2 and other IMvigor211 exclusion criteria), median OS was 10.0 mo (95% CI 8.8–11.9)and 6-mo OS was 65% (95% CI 61–69%). Conclusions: SAUL confirms the tolerability of atezolizumab in a real-world pretreated population with urinary tract carcinoma. Efficacy overall and in the IMvigor211-like subgroup is consistent with previous pivotal anti-PD-L1/PD-1 urothelial carcinoma trials. These results support the use of atezolizumab in urinary tract carcinoma, including patients with limited treatment options. Patient summary: In this international study we investigated the efficacy and safety of atezolizumab treatment for advanced urinary tract cancer in a large population of pretreated patients, including those who would not normally be candidates for clinical trials. Patients tolerated the treatment well, even if they had autoimmune disease, were being treated with corticosteroids, or had disease that had spread to their brain. Life expectancy in this study for patients typical of everyday clinical practice was similar to that seen in trials that enrolled only selected fitter patients. © 2019 The Author(s) SAUL confirms the tolerability of atezolizumab in real-world patients with urinary tract carcinoma. Efficacy in the IMvigor211-like subgroup and the broader unselected population was consistent with previous anti-PD-L1/PD-1 pivotal trials, supporting the use of atezolizumab in these patients. © 2019 The Author(s

Partial Response and Stable Disease Correlate with Positive Outcomes in Atezolizumab-treated Patients with Advanced Urinary Tract Carcinoma

Background: The value of a complete response to immune checkpoint inhibitor treatment for urothelial cancer is well recognised, but less is known about long-term outcomes in patients with a partial response or the benefit of achieving disease stabilisation. Objective: To determine clinical outcomes in patients with a partial response or stable disease on atezolizumab therapy for advanced urinary tract carcinoma (UTC). Design, setting, and participants: Data were extracted from three prospective trials (IMvigor210 cohort 2, SAUL, and IMvigor211) evaluating single-agent atezolizumab therapy for platinum-pretreated advanced UTC. The analysis population included 604 atezolizumab-treated and 208 chemotherapy-treated patients (229 achieving a partial response and 583 achieving stable disease). Intervention: Atezolizumab 1200 mg every 3 wk until progression or unacceptable toxicity or single-agent chemotherapy for patients in the control arm of IMvigor211. Outcome measurements and statistical analysis: Baseline characteristics, treatment exposure, overall survival, duration of disease control. Partial response and stable disease populations were analysed separately. Results and limitations: The population of patients with a partial response included more patients with programmed cell death ligand 1 (PD-L1) expression on ≥5% of tumour-infiltrating immune cells than the stable disease population. The median time to best response was 2.1 mo across trials and treatments, regardless of the type of response. Atezolizumab-treated patients with a partial response had sustained disease control (median overall survival not reached); durations of disease control and overall survival were longer with atezolizumab than with chemotherapy. In patients with stable disease, median overall survival was numerically longer with atezolizumab (exceeding 1 yr) than with chemotherapy. Irrespective of treatment, durations of disease control and survival were shorter in patients with stable disease than in those achieving a partial response. These analyses are limited by their post hoc exploratory nature and relatively short follow-up. Conclusions: Stable disease and partial response are meaningful clinical outcomes in atezolizumab-treated patients with advanced UTC. Patient summary: In this report, we looked at the outcomes in patients whose tumours responded to treatment to some extent, but the tumour did not disappear completely. We aimed to understand whether a modest response to treatment was associated with meaningful long-term outcomes for patients. We found that on average, life expectancy was >1 yr in patients whose disease was stabilised and even longer in those whose tumours showed some shrinkage in response to treatment