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.

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.

Safety and efficacy of atezolizumab in patients with autoimmune disease: Subgroup analysis of the SAUL study in locally advanced/metastatic urinary tract carcinoma.

AIM: Patients with pre-existing autoimmune disease (AID) are typically excluded from clinical trials of immune checkpoint inhibitors, and there are limited data on outcomes in this population. The single-arm international SAUL study of atezolizumab enrolled a broader 'real-world' patient population. We present outcomes in patients with a history of AID. METHODS: Patients with locally advanced/metastatic urinary tract carcinoma received atezolizumab 1200 mg every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary end-point was safety. Overall survival (OS) was a secondary end-point. Subgroup analyses of AID patients were prespecified. RESULTS: Thirty-five of 997 treated patients had AID at baseline, most commonly psoriasis (n = 15). Compared with non-AID patients, AID patients experienced numerically more adverse events (AEs) of special interest (46% versus 30%; grade ≥3 14% versus 6%) and treatment-related grade 3/4 AEs (26% versus 12%), but without relevant increases in treatment-related deaths (0% versus 1%) or AEs necessitating treatment discontinuation (9% versus 6%). Pre-existing AID worsened in four patients (11%; two flares in two patients); three of the six flares resolved, one was resolving, and two were unresolved. Efficacy was similar in AID and non-AID patients (median OS, 8.2 versus 8.8 months, respectively; median progression-free survival, 4.4 versus 2.2 months; disease control rate, 51% versus 39%). CONCLUSIONS: In 35 atezolizumab-treated patients with pre-existing AID, incidences of special- interest and treatment-related AEs appeared acceptable. AEs were manageable, rarely requiring atezolizumab discontinuation. Treating these patients requires caution, but pre-existing AID does not preclude atezolizumab therapy. TRIAL REGISTRATION: NCT02928406.

Comparative Effectiveness of Non-cisplatin First-line Therapies for Metastatic Urothelial Carcinoma: Phase 2 IMvigor210 Study Versus US Patients Treated in the Veterans Health Administration.

BACKGROUND: First-line treatments for cisplatin-ineligible patients with metastatic urothelial carcinoma (mUC) include carboplatin-based chemotherapy and checkpoint inhibitors such as atezolizumab (anti-PD-L1). OBJECTIVE: To compare overall survival (OS) among patients with mUC treated in the first-line setting with atezolizumab versus carboplatin-based chemotherapies (any carboplatin-based regimens or carboplatin-gemcitabine). DESIGN, SETTING, AND PARTICIPANTS: Cisplatin-ineligible patients with mUC from the phase 2 trial IMvigor210 (ClinicalTrials.gov NCT02951767) treated with atezolizumab and patients from the Veterans Health Administration (VHA) health care system (2006-2017, with IMvigor210 eligibility criteria applied using proxy measurements) treated according to normal clinical practice. INTERVENTIONS: IMvigor210 cohort 1 patients were treated with atezolizumab, and real-world VHA cohorts were treated with carboplatin-based regimens. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Entropy-balance weighting was applied to balance prespecified baseline patient characteristics. OS was analyzed using weighted Kaplan-Meier and Cox methods. RESULTS AND LIMITATIONS: The median OS was 15.0 mo with atezolizumab (n = 110), 12.1 mo with any carboplatin-based chemotherapy (n = 282), and 8.7 mo with carboplatin-gemcitabine (n = 120). An OS benefit occurred with atezolizumab versus carboplatin-based regimens after 9 mo (hazard ratio [HR] 0.43; p = 0.004) and with atezolizumab versus carboplatin-gemcitabine after 5 mo (HR 0.52; p = 0.005). Study limitations include a predominantly male VHA cohort and ≤24-mo follow-up. Adjustment for confounding, a potential limitation of nonrandomized studies, was limited by the availability of clinical measurements in the VHA data, which allowed for replication of IMvigor210 exclusions in the VHA cohorts. CONCLUSIONS: First-line atezolizumab for cisplatin-ineligible mUC may provide an OS benefit over carboplatin-based treatments after 5-9 mo, depending on the regimen. PATIENT SUMMARY: Many patients with metastatic urothelial carcinoma are ineligible for cisplatin-based chemotherapy. This study compared patients from a clinical trial receiving the immunotherapeutic agent atezolizumab with those in Veterans Health Administration clinical practice receiving carboplatin-based chemotherapy. Atezolizumab provided a survival benefit over chemotherapy after 5-9 mo.

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 12.7mo), 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 1200mg every 3wk 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 2.8mo (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 8.7mo (95% confidence interval [CI] 7.8-9.9). The 6-mo OS rate was 60% (95% CI 57-63%), median PFS was 2.2mo (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 10.0mo (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.

Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial.

BACKGROUND: Combining bevacizumab with first-line or second-line chemotherapy improves progression-free survival in HER2-negative locally recurrent or metastatic breast cancer. We assessed the efficacy and safety of further bevacizumab therapy in patients with locally recurrent or metastatic breast cancer whose disease had progressed after treatment with bevacizumab plus chemotherapy. METHODS: In this open-label, randomised, phase 3 trial, we recruited patients who had HER2-negative locally recurrent or metastatic breast cancer that had progressed after receiving 12 weeks or more of first-line bevacizumab plus chemotherapy from 118 centres in 12 countries. Patients were randomly assigned (1:1) by use of a central interactive voice response system using a block randomisation schedule (block size four) stratified by hormone receptor status, first-line progression-free survival, selected chemotherapy, and lactate dehydrogenase concentration, to receive second-line single-agent chemotherapy either alone or with bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks). Second-line therapy was continued until disease progression, unacceptable toxicity, or consent withdrawal. At progression, patients randomly assigned to chemotherapy alone received third-line chemotherapy without bevacizumab; those randomly assigned to bevacizumab continued bevacizumab with third-line chemotherapy. The primary endpoint was progression-free survival from randomisation to second-line progression or death in the intention-to-treat population. This trial is ongoing, and registered with ClinicalTrials.gov, number NCT01250379. FINDINGS: Between Feb 17, 2011, and April 3, 2013, 494 patients were randomly assigned to treatment (247 in each group). The median duration of follow-up at the time of this prespecified primary progression-free survival analysis was 15·9 months (IQR 9·1-21·7) in the chemotherapy-alone group and 16·1 months (10·6-22·7) in the combination group. Progression-free survival was significantly longer for those patients treated with bevacizumab plus chemotherapy than for those with chemotherapy alone (median: 6·3 months [95% CI 5·4-7·2] vs 4·2 months [3·9-4·7], respectively, stratified hazard ratio [HR] 0·75 [95% CI 0·61-0·93], two-sided stratified log-rank p=0·0068). The most common grade 3 or more adverse events were hypertension (33 [13%] of 245 patients receiving bevacizumab plus chemotherapy vs 17 [7%] of 238 patients receiving chemotherapy alone), neutropenia (29 [12%] vs 20 [8%]), and hand-foot syndrome (27 [11%] vs 25 [11%]). Grade 3 proteinuria occurred in 17 (7%) of 245 patients receiving combination therapy and one (<1%) of 238 patients receiving chemotherapy alone. Serious adverse events were reported in 61 (25%) of 245 patients receiving bevacizumab plus chemotherapy versus 44 (18%) of 238 patients receiving chemotherapy alone. INTERPRETATION: These results suggest that continued VEGF inhibition with further bevacizumab is a valid treatment option for patients with locally recurrent or metastatic HER2-negative breast cancer whose disease was stabilised or responded to first-line bevacizumab with chemotherapy. FUNDING: F Hoffmann-La Roche.

Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial.

BACKGROUND: Longer duration of first-line chemotherapy for patients with metastatic breast cancer is associated with prolonged overall survival and improved progression-free survival. We investigated capecitabine added to maintenance bevacizumab after initial treatment with bevacizumab and docetaxel in this setting. METHODS: We did this open-label randomised phase 3 trial at 54 hospitals in Brazil, China, Egypt, France, Hong Kong, India, Italy, Poland, Spain, and Turkey. We enrolled patients with HER2-negative measurable metastatic breast cancer; each received three to six cycles of first-line bevacizumab (15 mg/kg) and docetaxel (75-100 mg/m(2)) every 3 weeks. Progression-free patients were randomly assigned with an interactive voice-response system by block (size four) randomisation (1:1) to receive either bevacizumab and capecitabine or bevacizumab only (bevacizumab 15 mg/kg on day 1; capecitabine 1000 mg/m(2) twice per day on days 1-14, every 3 weeks) until progression, stratified by oestrogen receptor status (positive vs negative), visceral metastases (present vs absent), response status (stable disease vs response vs non-measurable), and lactate dehydrogenase concentration (≤1·5 vs >1·5 × upper limit of normal). Neither patients nor investigators were masked to allocation. The primary endpoint was progression-free survival (from randomisation) in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00929240. FINDINGS: Between July 16, 2009, and March 7, 2011 (when enrolment was prematurely terminated), 284 patients received initial bevacizumab and docetaxel; 185 (65%) were randomly assigned (91 to bevacizumab and capecitabine versus 94 to bevacizumab only). Progression-free survival was significantly longer in the bevacizumab and capecitabine group than in the bevacizumab only group (median 11·9 months [95% CI 9·8-15·4] vs 4·3 months [3·9-6·8]; stratified hazard ratio 0·38 [95% CI 0·27-0·55]; two-sided log-rank p<0·0001), as was overall survival (median 39·0 months [95% CI 32·3-not reached] vs 23·7 months [18·5-31·7]; stratified HR 0·43 [95% CI 0·26-0·69]; two-sided log-rank p=0·0003). Results for time to progression were consistent with those for progression-free survival. 78 (86%) patients in the bevacizumab and capecitabine group and 72 (77%) in the bevacizumab only group had an objective response. Clinical benefit was recorded in 92 (98%) patients in the bevacizumab alone group and 90 (99%) in the bevacizumab and capecitabine group. Mean change from baseline in global health score did not differ significantly between groups. Grade 3 or worse adverse events during the maintenance phase were more common with bevacizumab and capecitabine than with bevacizumab only (45 [49%] of 91 patients vs 25 [27%] of 92 patients). The most common grade 3 or worse events were hand-foot syndrome (28 [31%] in the bevacizumab and capecitabine group vs none in the bevacizumab alone group), hypertension (eight [9%] vs three [3%]), and proteinuria (three [3%] vs four [4%]). Serious adverse events were reported by ten (11%) patients in the bevacizumab and capecitabine group and seven (8%) patients in the bevacizumab only group. INTERPRETATION: Despite prematurely terminated accrual and the lack of information about post-progression treatment, both progression-free survival and overall survival were significantly improved with bevacizumab and capecitabine compared with bevacizumab alone as maintenance treatment. These results might inform future maintenance trials and current first-line treatment strategies for HER2-negative metastatic breast cancer. FUNDING: F Hoffmann-La Roche.