Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study.

BACKGROUND: IMvigor130 demonstrated statistically significant investigator-assessed progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial carcinoma. Overall survival was not improved in interim analyses. Here we report the final overall analysis for group A versus group C. METHODS: In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged ≥18 years) with previously untreated locally advanced or metastatic urothelial cancer and who had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), with a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin risk factor score, and investigator's choice of platinum-based chemotherapy, to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo (ie, group A and group C) and atezolizumab monotherapy (group B) was open label. For groups A and C, all patients received gemcitabine (1000 mg/m2 intravenously; day 1 and day 8 of each 21-day cycle), plus investigator's choice of carboplatin (area under curve 4·5 mg/mL per min or 5 mg/mL per min; intravenously) or cisplatin (70 mg/m2 intravenously), plus either atezolizumab (1200 mg intravenously) or placebo on day 1 of each cycle. Co-primary endpoints of the study were investigator-assessed progression-free survival and overall survival for group A versus group C in the intention-to-treat (ITT) population (ie, all randomised patients), and overall survival for group B versus group C, tested hierarchically. Final overall survival and updated safety outcomes (safety population; all patients who received any amount of any study treatment component) for group A versus group C are reported here. The final prespecified boundary for significance of the overall survival analysis was one-sided p=0·021. The trial is registered with ClinicalTrials.gov, NCT02807636, and is active but no longer recruiting. FINDINGS: Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 851 were assigned to group A (n=451) and group C (n=400). 338 (75%) patients in group A and 298 (75%) in group C were male, 113 (25%) in group A and 102 (25%) in group C were female, and 346 (77%) in group A and 304 (76%) in group C were White. At data cutoff (Aug 31, 2022), after a median follow up of 13·4 months (IQR 6·2-30·8), median overall survival was 16·1 months (95% CI 14·2-18·8; 336 deaths) in group A versus 13·4 months (12·0-15·3; 310 deaths) in group C (stratified hazard ratio 0·85 [95% CI 0·73-1·00]; one-sided p=0·023). The most common grade 3-4 treatment-related adverse events were anaemia (168 [37%] of 454 patients who received atezolizumab plus chemotherapy vs 133 [34%] of 389 who received placebo plus chemotherapy), neutropenia (167 [37%] vs 115 [30%]), decreased neutrophil count (98 [22%] vs 95 [24%]), thrombocytopenia (95 [21%] vs 70 [18%]), and decreased platelet count (92 [20%] vs 92 [24%]). Serious adverse events occurred in 243 (54%) patients who received atezolizumab plus chemotherapy and 196 (50%) patients who received placebo plus chemotherapy. Treatment-related deaths occurred in nine (2%; acute kidney injury, dyspnoea, hepatic failure, hepatitis, neutropenia, pneumonitis, respiratory failure, sepsis, and thrombocytopenia [n=1 each]) patients who received atezolizumab plus chemotherapy and four (1%; unexplained death, diarrhoea, febrile neutropenia, and toxic hepatitis [n=1 each]) who received placebo plus chemotherapy. INTERPRETATION: Progression-free survival benefit with first-line combination of atezolizumab plus platinum-based chemotherapy did not translate into a significant improvement in overall survival in the ITT population of IMvigor130. Further research is needed to understand which patients might benefit from first-line combination treatment. No new safety signals were observed. FUNDING: F Hoffmann-La Roche.

Atezolizumab monotherapy versus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis from a randomised, controlled, phase 3 study.

BACKGROUND: The primary analysis of IMvigor130 showed a significant progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial cancer. However, this finding did not translate into significant overall survival benefit for group A versus group C at the final analysis, precluding formal statistical testing of outcomes with atezolizumab monotherapy (group B) versus group C. Here we report the final overall survival results for group B versus group C; this report is descriptive and should be considered exploratory due to the study's statistical design. METHODS: In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged ≥18 years) who had locally advanced or metastatic urothelial cancer previously untreated in the metastatic setting and Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), using a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin score, and investigator's choice of platinum-based chemotherapy, to receive either atezolizumab plus platinum-based chemotherapy (group A), atezolizumab alone (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo in group A and group C; atezolizumab monotherapy in group B was open label. For groups B and C, atezolizumab (1200 mg) or placebo was administered intravenously every 3 weeks. Chemotherapy involved 21-day cycles of gemcitabine (1000 mg/m2 body surface area on day 1 and day 8 of each cycle) plus the investigator's choice of carboplatin (area under the curve 4·5 mg/mL per min or 5 mg/mL per min) or cisplatin (70 mg/m2 body surface area), administered intravenously. Co-primary endpoints were progression-free survival and overall survival in group A versus group C, and overall survival in group B versus group C, tested hierarchically, in the intention-to-treat (ITT) population, and then the populations with high PD-L1 tumour expression (immune cell [IC] expression score of IC2/3) if the results from group A versus group C were significant. Here, we report the co-primary endpoint of overall survival for group B versus group C in the ITT and IC2/3 populations. The ITT population for this analysis comprised concurrently enrolled patients in groups B and C who were randomly assigned to treatment. For the safety analysis, all patients enrolled in group B and group C who received any study treatment were included. The trial is registered with ClinicalTrials.gov, NCT02807636, and is active but no longer recruiting. FINDINGS: Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 362 patients were assigned to group B and 400 to group C, of whom 360 and 359, respectively, were enrolled concurrently (ITT population). 543 (76%) of 719 patients were male, 176 (24%) were female, and 534 (74%) were White. As of data cutoff (Aug 31, 2022), after a median follow-up of 13·4 months (IQR 6·2-30·8), median overall survival was 15·2 months (95% CI 13·1-17·7; 271 deaths) in group B and 13·3 months (11·9-15·6; 275 deaths) in group C (stratified hazard ratio 0·98 [95% CI 0·82-1·16]). The most common grade 3-4 treatment-related adverse events were anaemia (two [1%] in patients who received atezolizumab monotherapy vs 133 [34%] in those who received placebo plus chemotherapy), neutropenia (one [<1%] vs 115 [30%]), decreased neutrophil count (0 vs 95 [24%]), and decreased platelet count (one [<1%] vs 92 [24%]). Serious adverse events occurred in 163 (46%) patients versus 196 (50%). Treatment-related deaths occurred in three (1%; n=1 each, pneumonia, interstitial lung disease, large intestinal obstruction) patients who received atezolizumab monotherapy and four (1%; n=1 each, diarrhoea, febrile neutropenia, unexplained death, toxic hepatitis) who received placebo plus chemotherapy. INTERPRETATION: The final analysis from IMvigor130 did not show a significant improvement in overall survival with first-line atezolizumab monotherapy compared with platinum-based chemotherapy in the intention-to-treat population. The safety profile of atezolizumab monotherapy remained acceptable after extended follow-up, with no new safety signals. FUNDING: F Hoffmann-La Roche.

Overall Survival by Response to First-line Induction Treatment with Atezolizumab plus Platinum-based Chemotherapy or Placebo plus Platinum-based Chemotherapy for Metastatic Urothelial Carcinoma.

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 summary: The 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.

Association of Circulating Tumor Cells, Megakaryocytes and a High Immune-Inflammatory Environment in Metastatic Breast Cancer.

Liquid biopsy is becoming an important source of new biomarkers during the treatment of metastatic cancer patients. Using size-based microfluid technology, we isolated circulating tumor cells (CTCs) from metastatic breast cancer patients to evaluate their presence and cluster formation, as well as the presence of megakaryocytes and immune-inflammatory blood cells, and to correlate their presence with clinicopathological data and overall survival (OS). In total, 59 patients (median age 60.4 years) were included in the study: 62.7% luminal A/B-like, 20.3% HER2-positive, and 17% triple-negative. Our results showed that at least one CTC was present in 79.7% and ≥5 CTCs in 35.2% of the patients. CTC clusters were present in patients with ≥5 CTCs only (in 19.2% of them), and megakaryocytes were present in 52% of all patients. The presence of CTC clusters and megakaryocytes was positively associated with the CTC count. Patients with low pan-inflammatory value (PIV), low systemic immune-inflammatory index (SII), and low relative change from baseline (ΔPIV%, ΔSII%) were associated with significantly higher OS than their counterparts. ΔPIV%, the presence of infection in the last month, and a long duration of metastatic disease were identified as independent prognostic factors for OS. The interplay of CTCs, CTC clusters, megakaryocytes, and PIV needs to be further explored.

Establishment of a virtual transborder tumor board for cancer patients in Central and Southeastern Europe : An initiative of the Central European Cooperative Oncology Group (CECOG).

PURPOSE: To establish a transborder virtual tumor board (VTB) fostering state-of-the-art management of cancer patients by exchanging knowledge and expertise among oncologists in Central and Southeastern Europe (CEE). METHODS: We established and implemented a VTB based on the WebEx platform. This allowed for password-protected and secure upload of patient cases to be presented and discussed among colleagues from various oncology centers scattered throughout CEE in order to arrive at a recommendation for further diagnoses and/or treatment. RESULTS: A total of 73 cases from 16 oncology centers located in 11 CEE countries were uploaded by 22 physicians; 71 were discussed over the course of 17 virtual meetings between June 2018 and May 2019 and 12 different kinds of malignant diseases were discussed with lung cancer (46.6%), melanoma (19.2%) and bladder cancer (13.6%) being the most commonly presented tumor entities. Of the discussed patients, 93.3% had stage IV disease at the time of presentation, 62.6% received chemotherapy or targeted treatment and 67.1% were treated with immune checkpoint inhibitors (ICPIs). The most common causes for presentation and discussion of patient cases were related to the use of ICPIs (80%). CONCLUSION: When the need for expertise exceeds locally available resources, web-based VTBs provide a feasible way to discuss patient cases and arrive at conclusions regarding diagnoses and/or treatment across large geographic distances. Moreover, VTBs provide an innovative way for proper, state-of-the-art management of patients with malignant diseases in times of social distancing and the resulting need for restricted interaction during the current SARS-CoV­2 (severe acute respiratory syndrome coronavirus type 2) pandemic.

Disease control with prior platinum-based chemotherapy is prognostic for survival in patients with metastatic urothelial cancer treated with atezolizumab in real-world practice.

BACKGROUND: Atezolizumab, a programmed-death ligand-1 (PD-L1) inhibitor, is a novel treatment option for patients with metastatic urothelial cancer (mUC). Clinical prognostic factors, survival outcomes, and the safety of patients with mUC treated with atezolizumab, in a real-world setting, were investigated. PATIENTS AND METHODS: 62 patients with mUC, treated at the Institute of Oncology Ljubljana between May 8th 2018 and Dec 31st 2019, were included. Response rates and immune-related adverse events (irAE) were collected. Progression-free survival and overall survival times were assessed using the Kaplan-Meier method. The Cox proportional hazards model was applied to identify the factors affecting survival. RESULTS: Of 62 patients, five (8.1%) have not yet been evaluated and 20 (32%) died prior to the first radiographic evaluation. We observed clinical benefit in 19 (33%), objective response in 12 (21%), and complete response in five (9%) patients. Median overall survival for the whole population was 6.8 (95% CI, 2.6-11.0), for platinum-naïve 8.7 (95% CI: 0.8-16.5), and for the platinum-treated group 6.8 (95% CI, 3.7-10) months. At the 5.8 (0.3-23.1) month median follow-up, the median duration of the response was not reached. IrAE occurred in 20 (32%) patients and seven (11%) of them discontinued the treatment. Multivariate analysis in platinum-treated patients showed that a treatment-free interval of more than six months was prognostic for overall survival (OS). CONCLUSIONS: Responses to atezolizumab led to long disease remission in a subset of our patients. The median OS in our real-world population was compromised by a large percentage of patients with poor ECOG performance status (PS). A treatment-free interval from chemotherapy was associated with the longer survival of platinum-treated patients with mUC receiving further atezolizumab.

Efficacy and safety of selective cyclin-dependent kinases 4/6 inhibitors in hormone-receptor-positive, HER2-negative advanced breast cancer - results from a real-world setting.

BACKGROUND: Selective cyclin-dependent kinases 4/6 inhibitors (CDKi) have become the standard of care in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer (ABC). We performed retrospective analysis in patients treated with CDKi in the first year of their routine clinical use in Slovenia. METHODS: The primary goals were time-to-treatment failure (TTF) and overall survival (OS), analysed via Kaplan-Meier method, the secondary goals were clinical benefit rate (CBR) and safety. RESULTS: Overall, 218 patients' data were evaluated. The median age was 61.8 years (30.6-84.6). The median number of previous ET lines for ABC was 2 (range 0-5). At the time of inclusion, 128 patients (58.7%) had visceral metastases, 45 patients (20.6%) had bone-only disease. At the median follow-up of 15.2 months, disease progressed in 74 patients and 60 patients died. The median TTF was 8.3 months for the whole group, 19.3, 10.3 and 5.5 months for patients treated in the first-, second- and further lines of systemic therapy, respectively. The median OS from the start of CDKi treatment was not reached in any of the groups. CBR was 59.6% for the whole group, 42.7% for further lines of therapy. The most common grade 3/4 adverse event was neutropaenia in 108 patients (49.5%), followed by an increase of hepatic aminotransferases in 13 patients (6.0%). CONCLUSIONS: Even in the diverse real-world population treatment with CDKi in combination with ET showed clinical benefit, most prominently in the first- and second lines of systemic therapy.

Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Atezolizumab can induce sustained responses in metastatic urothelial carcinoma. We report the results of IMvigor130, a phase 3 trial that compared atezolizumab with or without platinum-based chemotherapy versus placebo plus platinum-based chemotherapy in first-line metastatic urothelial carcinoma. METHODS: In this multicentre, phase 3, randomised trial, untreated patients aged 18 years or older with locally advanced or metastatic urothelial carcinoma, from 221 sites in 35 countries, were randomly assigned to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Patients received 21-day cycles of gemcitabine (1000 mg/m2 body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m2 body surface area administered intravenously) on day 1 of each cycle with either atezolizumab (1200 mg administered intravenously on day 1 of each cycle) or placebo. Group B patients received 1200 mg atezolizumab, administered intravenously on day 1 of each 21-day cycle. The co-primary efficacy endpoints for the intention-to-treat population were investigator-assessed Response Evaluation Criteria in Solid Tumours 1.1 progression-free survival and overall survival (group A vs group C) and overall survival (group B vs group C), which was to be formally tested only if overall survival was positive for group A versus group C. The trial is registered with ClinicalTrials.gov, NCT02807636. FINDINGS: Between July 15, 2016, and July 20, 2018, we enrolled 1213 patients. 451 (37%) were randomly assigned to group A, 362 (30%) to group B, and 400 (33%) to group C. Median follow-up for survival was 11·8 months (IQR 6·1-17·2) for all patients. At the time of final progression-free survival analysis and interim overall survival analysis (May 31, 2019), median progression-free survival in the intention-to-treat population was 8·2 months (95% CI 6·5-8·3) in group A and 6·3 months (6·2-7·0) in group C (stratified hazard ratio [HR] 0·82, 95% CI 0·70-0·96; one-sided p=0·007). Median overall survival was 16·0 months (13·9-18·9) in group A and 13·4 months (12·0-15·2) in group C (0·83, 0·69-1·00; one-sided p=0·027). Median overall survival was 15·7 months (13·1-17·8) for group B and 13·1 months (11·7-15·1) for group C (1·02, 0·83-1·24). Adverse events that led to withdrawal of any agent occurred in 156 (34%) patients in group A, 22 (6%) patients in group B, and 132 (34%) patients in group C. 50 (11%) patients in group A, 21 (6%) patients in group B, and 27 (7%) patients in group C had adverse events that led to discontinuation of atezolizumab or placebo. INTERPRETATION: Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival in patients with metastatic urothelial carcinoma. The safety profile of the combination was consistent with that observed with the individual agents. These results support the use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma. FUNDING: F Hoffmann-La Roche and Genentech.