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.
To determine the safety and efficacy of atezolizumab in an international real-world setting.
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).
Atezolizumab 1200mg every 3wk until progression or unacceptable toxicity.
The primary endpoint was safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR).
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%).
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.
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.
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.
Atezolizumab is an approved therapy for urothelial carcinoma based on results from the IMvigor 210 and IMvigor211 phase II and III trials. The global SAUL study evaluated atezolizumab in a broader ...patient population more representative of real-world populations. Among approximately 1000 patients treated in SAUL, 25 were treated in Swiss oncology centres. We evaluated outcomes in these patients to provide a better understanding of atezolizumab treatment for urinary tract carcinoma in Swiss clinical practice.
Eligible patients had locally advanced or metastatic urothelial or non-urothelial urinary tract carcinoma that had progressed during or after one to three prior therapies for inoperable, locally advanced or metastatic disease. Patient populations typically excluded from clinical trials (e.g., patients with renal impairment, treated central nervous system CNS metastases, stable controlled autoimmune disease or Eastern Cooperative Oncology Group performance status 2) were also eligible. All patients received atezolizumab 1200 mg every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included overall survival (OS), overall response rate (ORR) and disease control rate (DCR).
All 25 Swiss patients had previously received a gemcitabine/platinum doublet. Disease had progressed within 12 months of platinum-based therapy in all but one patient, and 19 (76%) had received one prior line of therapy for metastatic disease. The median duration of atezolizumab therapy was six cycles (range 1-27) corresponding to 3.6 months. Five patients (20%) had received >20 cycles and four (16%) remained on treatment at the data cut-off. Grade 3 adverse events (AEs) occurred in 13 patients (52%) and were considered to be treatment-related in four patients (16%; liver enzyme increases, musculoskeletal pain, diverticulitis and autoimmune hepatitis). There was one grade 4 AE (hypercalcaemia) and no grade 5 AEs. After median follow-up of 17.3 months, median OS was 7.9 months (95% confidence interval CI 5.3-not evaluable), the 1-year OS rate was 47% (95% CI 27-65%), the ORR was 12% (95% CI 3-31%) and the DCR was 40% (95% CI 21-61%). Durable clinical benefit (>1 year on treatment) was observed in seven patients (28%), including one with CNS metastases and one with small-cell carcinoma.
Atezolizumab is an active treatment option for platinum-pretreated urinary tract carcinoma, including patients with conditions that typically exclude them from clinical trials. (Trial registration no.: NCT02928406).
Heroes or villains? Fear, Simon
British dental journal,
04/2021, Letnik:
230, Številka:
7
Journal Article
Recenzirano
This is the tale of two soldiers serving in the Army Dental Corps, who conducted an unsupported and unauthorised commando mission into occupied France during World War II (WW2).In 1942, Sergeant King ...and Private Cuthbertson planned and executed one of the most daring and ambitious raids of WW2. Their perceived lack of utility to the war effort spawned their personal invasion of France, which became of interest to not only the Special Operations Executive (SOE), but Winston Churchill himself. The couple stole weapons from the armoury, commandeered a vessel, and journeyed to France where they inflicted damage and disruption to the enemy.Their mission caused ripples of pride throughout those serving, especially those in the Army Dental Corps. The question still remains though; should they have been treated as heroes or villains?
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.
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.
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%).
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.
NCT02928406.
•Data are limited on patients with autoimmune disease (AID) receiving immunotherapy.•SAUL evaluated atezolizumab in a broad population with urinary tract carcinoma.•Subgroup analyses of 35 atezolizumab-treated patients with AID were prespecified.•Treatment-related adverse events were manageable.•Treating AID patients with atezolizumab requires caution, but AID is not a barrier.
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1039
Background: KAMILLA is an open-label, single-arm, phase 3b safety study of T-DM1 in pts with HER2-positive advanced BC (NCT01702571). The treated (safety) population of KAMILLA ...comprises 2 cohorts: a larger global Cohort 1 (n=2002) and a smaller Asia Cohort 2 (n=181 China, n=154; Thailand, n=15; Indonesia, n=12). Here we report results from Cohort 2 in the context of those previously reported for Cohort 1. Methods: Pts had HER2-positive, locally advanced or mBC with progression after chemotherapy and anti-HER2 therapy or ≤6 months (mo) of completing adjuvant therapy. T-DM1 3.6 mg/kg was given intravenously every 3 weeks until disease progression, consent withdrawal, or unacceptable toxicity. Primary endpoints were grade ≥3 (G≥3) adverse events of primary interest (AEPIs), specifically hepatic events, allergic reactions, thrombocytopenia (TCP), and hemorrhage events; all other G≥3 treatment-related AEs (TRAEs); and all-grade pneumonitis. Results: As of 31 July 2019,KAMILLA enrolled 2185 pts (Cohort 1, n=2003; Cohort 2, n=182), of which 2002 and 181 in each cohort, respectively, received ≥1 study dose and were included in the safety population. Baseline characteristics were generally similar between cohorts. Median (range) T-DM1 exposure was 5.6 mo (0–46) for Cohort 1 and 5.0 mo (0–31) for Cohort 2. The overall G≥3 AEPI rate was higher in Cohort 2 vs Cohort 1 (Table), mostly driven by a higher G≥3 TCP rate in Cohort 2. In Cohort 2, G≥3 TCP (the most frequently reported G≥3 AEPI) did not appear to be associated with G≥3 hemorrhagic events — the majority of G≥3 TCP events (128/138) fully resolved, with a duration of ≤15 days for 98/138 of these events. G≥3 TRAE rates were 18.4% in Cohort 1 and 48.6% in Cohort 2, the latter mainly due to TCP and platelet count decreased; any-grade pneumonitis rates were 1.0% and 2.2%, respectively. No other safety signals were identified. Median progression-free survival and overall survival were similar for both cohorts (Table). Conclusions: These data confirm prior observations in an Asian subgroup of the phase 3 EMILIA trial of T-DM1 in pts with previously treated mBC. Although the G≥3 TCP rate was higher in the Asia cohort, the majority of these events resolved fully. OS and PFS were similar in both cohorts. These data reinforce the favorable T-DM1 benefit-risk profile in mBC. Clinical trial information: NCT01702571 .Table: see text
PURPOSEAtezolizumab 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 METHODSPatients 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. RESULTSA 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. CONCLUSIONSThe 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.
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492
Background: Atezo is an approved therapy for mUC based on the IMvigor210 (IM210) and IMvigor211 (IM211) phase 2 and 3 trials. The single-arm phase 3b SAUL study in a broader patient ...(pt) population showed consistent efficacy and safety. The value of complete response to immunotherapy is well recognized, but less is known about the benefit of partial response (PR) or stable disease (SD). We performed post hoc analyses of outcomes in pts with PR/SD in atezo trials. Methods: Pts with mUC received atezo 1200 mg q3w until disease progression (PD) or unacceptable toxicity. Baseline characteristics, efficacy and safety were analyzed in pts achieving PR or SD in IM210 cohort 2 (2nd line), IM211 (atezo and chemotherapy CT arms analyzed separately) and SAUL. Data cutoffs were 5/5/15, 3/13/17 and 9/16/18, respectively. Results: The analysis population included 229 PR and 583 SD pts (183 and 421, respectively, treated with atezo); ~40% of pts had 0 Bellmunt risk factors. Baseline characteristics were generally similar between trials. PD-L1 IC 2/3 was more common in PR than SD pts in atezo-treated (41% vs 26%) and CT-treated (37% vs 23%) pts. Median time to best response (PR or SD) was 2.1 mo across trials and treatments. In PR pts, disease control (DC) and overall survival (OS) durations were longer with atezo than CT (Table). Durations of DC and OS were shorter in SD than PR pts; OS was numerically longer with atezo than with CT in the SD population. Presence of more Bellmunt risk factors was associated with worse OS with CT but showed only a weak (SD pts) or no (PR pts) association in atezo-treated pts. Conclusions: Pts achieving a PR or SD have meaningful OS expectancy; pts with PR on atezo have sustained DC. Clinical trial information: NCT02108652 ; NCT02302807 ; NCT02928406 . Table: see text
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488
Background: UTUC is rarer than bladder UC and typically responds poorly to standard chemotherapy. Analysis of 220 biomarker-evaluable atezo-treated patients (pts) in phase II/III ...trials suggested worse outcomes in UT vs lower tract UC Galsky, ESMO 2018. We explored clinical outcomes in pts with UTUC (renal pelvis or ureter) treated with atezo in the SAUL study. Methods: The single-arm SAUL study (NCT02928406) Sternberg, Eur Urol 2019 enrolled a broader pt population, including pts with poor clinical characteristics and/or immune-mediated conditions, more representative of real-world practice than typically enrolled in randomized phase III immunotherapy trials. Pts with urinary tract carcinoma received atezo 1200 mg q3w until disease progression/unacceptable toxicity. Baseline characteristics, safety and efficacy were analyzed in subgroups of pts with UTUC (subdivided into renal pelvis or ureter UC) vs bladder UC. Results: Baseline characteristics in the 4 subgroups were generally similar, except for a numerically lower proportion of pts with 0 prior lines of therapy for metastatic disease in the UTUC vs bladder UC subgroup (30% vs 41%). Treatment exposure, safety and efficacy are shown below. Conclusions: These exploratory analyses of SAUL showed very similar efficacy and safety in UT vs bladder UC. This provides reassurance that atezo is active and has an acceptable safety profile in pts with UTUC, who are generally expected to have worse outcomes than bladder UC pts. Clinical trial information: NCT02928406 . Table: see text
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5036
Background: Atezo, which targets PD-L1, is an approved therapy for LA/M urothelial carcinoma based on the IMvigor210 and IMvigor211 trials. The single-arm SAUL study (NCT02928406) ...showed consistent activity and safety in a broader population, including understudied scenarios, eg pts with renal impairment or other IMvigor211 exclusion criteria. Methods: Pts with LA/M UTC received atezo 1200 mg q3w until disease progression or unacceptable toxicity. The primary endpoint was safety; secondary endpoints included overall response rate (ORR) and overall survival (OS). Post hoc analyses explored outcomes in pts classified as: chemotherapy (CT) ineligible (calculated creatine clearance CrCl 15– < 30 mL/min); cisplatin ineligible and carboplatin eligible (CrCl 30– < 60 mL/min); or cisplatin eligible (CrCl ≥60 mL/min). Results: Of 1004 enrolled pts, 46 (5%) were classified as CT ineligible and 420 (42%) as cisplatin ineligible. Results are summarized below. Conclusions: These post hoc analyses suggest pts typically considered cisplatin or CT ineligible are candidates for atezo. Pts with renal impairment achieved similar ORR and DCR to pts with CrCl ≥60 mL/min, without increased toxicity. Imbalances in pt characteristics may explain numerical differences in OS. Clinical trial information: NCT02928406 . Table: see text
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5035
Background: Pts with PS > 1 have a poor prognosis and are often excluded from clinical trials. The single-arm SAUL study (NCT02928406) evaluated atezo in a ‘real-world’ population. ...Overall, safety and efficacy were consistent with prior trials. However, ECOG PS 2 pts had worse overall survival (OS) but fewer adverse events (AEs) than ECOG PS 0/1 pts Sternberg, 2019, likely reflecting shorter treatment duration and warranting exploration. Methods: Pts with mUTC received atezo 1200 mg q3w until loss of clinical benefit or unacceptable toxicity. The primary endpoint was safety. Post hoc analyses compared baseline factors, AEs and efficacy in pts with ECOG PS 2 vs 0/1. In this analysis, AE incidences were restricted to the first 45 days of atezo to adjust for differing treatment exposure. Results: None of the baseline factors explored was significantly associated with worse OS or disease control rate (DCR) in ECOG PS 2 pts. However, pts with visceral metastases and ECOG PS 2 had particularly poor outcomes. Safety appeared similar between subgroups. Conclusions: ECOG PS 2 pts have a dismal prognosis. The higher proportion with poor prognostic factors despite similar age in ECOG PS 2 vs 0/1 pts may suggest that poor PS was related to disease rather than comorbidities. Risk/benefit should be considered especially carefully when treating pts with ECOG PS 2 due to high-burden/visceral disease. Clinical trial information: NCT02928406 . Table: see text
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