Platinum-refractory Metastatic Urothelial Carcinoma Research Articles

Gustave Roussy Immune score as a prognostic biomarker in patients with platinum-refractory metastatic urothelial carcinoma treated with pembrolizumab: YUSHIMA study.

This study aimed to investigate the prognostic value of the Gustave Roussy Immune score (GRIm-score) in platinum-refractory metastatic urothelial carcinoma (UC) treated with pembrolizumab. This multicenter retrospective study (YUSHIMA study) evaluated 331 patients with metastatic UC treated with pembrolizumab after platinum-based chemotherapy between January 2018 and June 2023 at 13 institutions. We collected pretreatment variables, including the GRIm-score based on serum albumin, lactate dehydrogenase, and neutrophil-to-lymphocyte ratio. The patients were divided into low and high GRIm-score groups. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were determined using the multivariate Cox proportional hazard model. During the median follow-up period of 7.3months, 278 (84%) patients showed disease progression, and 223 (67%) died from any cause. Multivariate analysis revealed that the high GRIm-score group was an independent and significant adverse prognostic factor of both OS and PFS (hazard ratio, 1.65 and 1.82, respectively; both p < 0.001) along with Eastern Cooperative Oncology Group Performance Status of ≥ 2 (both p < 0.001), presence of visceral metastasis (both p < 0.001), and hemoglobin of < 9.2g/dL (p = 0.030 and p = 0.038). C-reactive protein of > 42mg/L was a significant prognostic factor for OS (p = 0.001). The GRIm-score is an independent prognostic marker for survival outcomes in patients with platinum-refractory metastatic UC treated with pembrolizumab.

Predicting Objective Response of Pembrolizumab in Platinum-Refractory Urothelial Carcinoma Based on Neutrophil-Lymphocyte Ratio Fluctuation and Liver Metastases

Introduction: It is well known that patients with objective response to pembrolizumab have a durable duration of response, leading to favorable survival outcomes. We investigated the possibility of predicting the objective response with concise indicators obtained from daily clinical practice. Methods: In our multi-institutional cohort, 220 platinum-refractory metastatic urothelial carcinoma (mUC) patients treated with pembrolizumab for at least 6 weeks with complete information of objective response were investigated. Results: The median follow-up was 7.3 months, and 119 patients deceased during the follow-up. A multivariate logistic regression analysis exhibited two independent variables predicting the objective response, including the neutrophil-lymphocyte ratio (NLR) change at 6 weeks of treatment and liver metastasis. We proposed a risk group using these two indicators. Patients with no predictive indicators/one of those were assigned to favorable (42%)/intermittent (47%) risk groups. Patients with both indicators were assigned to poor risk (11%). Notably, the objective response rate was well delineated in 41%, 25%, and 0% for favorable-, intermediate-, and poor-risk groups, respectively (p < 0.001). Distinct overall survival (OS) between the risk groups was also confirmed with the median OS of 14.1, 11.7, and 4.2 months in favorable-, intermediate-, and poor-risk groups, respectively. Conclusions: At the 6 weeks of the pembrolizumab treatment, our risk model predicts the objective response rate precisely. Notably, those classified as “poor risk” – marked by liver metastasis and an increased NLR – should be considered for alternative therapy with a different mode of action, highlighting a critical decision point in treatment optimization.

Tolerability and treatment outcome of pembrolizumab in patients with advanced urothelial carcinoma and severe renal dysfunction.

Pembrolizumab, an anti-PD-1 monoclonal antibody, revolutionized the treatment of advanced urothelial carcinoma. However, the tolerability and outcomes of pembrolizumab in patients with severe renal dysfunction [creatinine clearance (CrCl) <30 ml/min] are unclear because no clinical trials included such patients. We analyzed the safety profile and outcomes of these patients in the real world. We extracted data for 739 pembrolizumab-treated patients from a Japanese nationwide cohort of platinum-refractory metastatic urothelial carcinoma. Using propensity score matching, the overall survival (OS) and adverse events (AEs) of patients with CrCl <30 and ≥30 were compared. Ninety-two patients (12.4%) had CrCl <30 ml/min. The median number of doses was similar between the CrCl ≥ 30 and CrCl <30 groups (5 and 4, respectively), and there was no difference in the frequency of grade ≥2 treatment-related AEs between the groups (35.5% vs. 35.7%). The overall response rate was similar between the groups (27.2% vs. 29.7%, P = 0.184). Using propensity score matching, the median OS times in the CrCl ≥30 and CrCl <30 groups were 10.3 (95% confidence interval [CI] = CI 7.3-13.0) and 8.1 months (95% CI = 5.4-14.6, P = 0.626), respectively. The 1-year OS rates in these groups were 41.5% and 38.2%, respectively, and the 2-year OS rates were 21.3% and 20.2%, respectively. In multivariate Cox regression analysis, performance status ≥2 (hazard ratio [HR] = 5.56, 95% CI = 2.64-11.71, P < 0.0001) and neutrophil-to-lymphocyte ratio ≥3 (HR = 2.20, 95% CI =1.15-4.19, P = 0.013) were independently associated with patient prognosis in the CrCl <30 group. This report illustrated that pembrolizumab can be safely administered to patients with severe renal dysfunction, who had similar outcomes as patients without severe renal dysfunction.

Targeting the FGFR Pathway in Urothelial Carcinoma: the Future Is Now.

As we come to better understand cancer genomics, we are increasingly shifting towards precision medicine. FGFR has been elucidated as one of the oncogenic driver pathways in urothelial carcinoma, leading to exciting targeted drug development. Although many agents are being investigated, erdafitinib is the only FGFR inhibitor currently approved by the FDA for treating platinum-refractory metastatic urothelial carcinoma harboring susceptible FGFR2/3 alterations, with seemingly higher response rates than second-line chemotherapy or immunotherapy. In this review, we summarize the clinical data supporting FGFR inhibition, ways to optimize its use in routine clinical practice including FGFR testing, dosing, and toxicity management. We also highlight ongoing efforts evaluating combination strategies and testing in earlier treatment settings to further expand this targeted therapeutic approach in urothelial carcinoma.

Discontinuation of pembrolizumab for advanced urothelial carcinoma without disease progression: Nationwide cohort study.

Pembrolizumab, an anti-programmed death 1 monoclonal antibody, has revolutionized the treatment of metastatic urothelial carcinoma. However, the optimal treatment duration for treatment responders has not been established. To address this, we retrospectively assess the treatment outcomes and duration of pembrolizumab for patients whose best response was complete response (CR) or partial response (PR) in a Japanese nationwide cohort of platinum-refractory metastatic urothelial carcinoma. Of 203 patients whose best response was CR or PR, 83 patients discontinued pembrolizumab before progression. The median pembrolizumab treatment duration was 6.9months. The 2-year relapse-free survival (RFS), treatment-free survival, and OS rates after discontinuation were 49.0%, 57.4%, and 74.5%, respectively. CR, higher hemoglobin levels, and a better Eastern Cooperative Oncology Group performance status at the time of discontinuation were associated with significantly better RFS. Pembrolizumab was re-administered to 12 patients. Pembrolizumab re-challenge resulted in CR, PR, stable disease, and progressive disease in six, three, two, and one patient, respectively. Propensity score-matched landmark analysis revealed no significant OS difference between patients who continued or discontinued pembrolizumab at 6, 12, and 18 months (p=0.91, 0.99, and 0.25, respectively). Our findings demonstrated that patients with objective responses had favorable survival outcomes and suggested that pembrolizumab could be discontinued safely in this population. This study should drive further efforts to optimize the treatment duration for pembrolizumab responders.

Primary results of STRONG: An open-label, multicenter, phase 3b study of fixed-dose durvalumab monotherapy in previously treated patients with urinary tract carcinoma

BackgroundPrior durvalumab (anti-PD-L1 agent) studies in platinum-refractory metastatic urothelial carcinoma evaluated a dose of 10 mg/kg administered every two weeks. The nonrandomised phase 3b STRONG study (NCT03084471) evaluated the safety and efficacy of fixed-dose durvalumab at a more convenient dosing schedule in a previously treated patient population, more similar to a real-world clinical setting. Patients and methods867 patients with urothelial or nonurothelial urinary tract carcinoma (UTC) who progressed on or after platinum or nonplatinum chemotherapy were treated with durvalumab 1500 mg every four weeks; 87% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1, and 13% had an ECOG PS of 2. The primary end-point was the incidence of adverse events of special interest (AESIs), including immune-mediated AEs (imAEs). Secondary and exploratory end-points included overall survival (OS), objective response rate (ORR) and disease control rate (at six and 12 months) (DCR). ResultsAESIs of any grade were reported in 51% of patients (8% grade ≥ 3). The incidence of imAEs was 11% (2% grade ≥ 3). The median OS was 7.0 months (95% confidence interval [CI]: 6.4–8.2) and ORR was 18% (95% CI: 14.8–20.6), with complete responses in 5% of patients and a DCR at six months of 19% (95% CI: 16.1–22.1). ConclusionFixed-dose durvalumab monotherapy every four weeks has an acceptable safety profile and yields durable clinical activity in previously chemotherapy-treated patients with UTC. Safety and efficacy are consistent with previous durvalumab studies and other anti-PD-1/PD-L1 agents in this setting. Clinicaltrials.gov identifierNCT03084471https://clinicaltrials.gov/ct2/show/NCT03084471.

Efficacy of pembrolizumab and comprehensive CD274/PD-L1 profiles in patients previously treated with chemoradiation therapy as radical treatment in bladder cancer

BackgroundChemoradiation therapy (CRT) has been increasingly reported as a possible alternative to total cystectomy (TC) for localized bladder cancer (BC). Pembrolizumab is the standard of care for platinum-refractory metastatic urothelial...

Risk Classification for Overall Survival by the Neutrophil-Lymphocyte Ratio and the Number of Metastatic Sites in Patients Treated with Pembrolizumab-A Multicenter Collaborative Study in Japan.

Simple SummaryPembrolizumab improves overall survival (OS) in patients with platinum-refractory metastatic urothelial carcinoma (mUC), whereas objective response was observed in a modest number of patients (<25%) for this treatment, implying the distinct survival outcomes for those patients. Thus, the optimal risk stratification to predict survival outcomes at the initiation of pembrolizumab treatment would be helpful for physicians. In the present study, we examined a risk model developed using two clinical factors, including the number of metastatic sites and neutrophil–lymphocyte ratio (NLR), for predicting OS at the initiation of pembrolizumab treatment. This risk stratification seemed to be well-balanced (26.5%, 44.3%, and 29.2% in the favorable-risk, intermediate-risk, and poor-risk groups, respectively), and Kaplan–Meier curves illustrated clear discrimination of OS among the risk groups. Since the model proposed in the present study can be concisely determined at the initiation of pembrolizumab treatment, physicians may be encouraged to consider the risk group for daily practice.Pembrolizumab has emerged as the new standard of care in patients with platinum-refractory metastatic urothelial carcinoma (mUC), whereas the optimal risk stratification to predict survival outcomes is still controversial. We examined a risk model for overall survival (OS) in mUC treated with pembrolizumab using our multi-institutional dataset (212 patients). The median age was 72 years old. Median OS from the initiation of pembrolizumab treatment was 11.7 months. The objective response rate (ORR) was 26.4%. On multivariate analysis, multiple metastatic sites and an NLR > 3.50 at the initiation of pembrolizumab treatment were identified as independent predictors for OS. We next developed a risk model using those two predictors. Patients without any factors were assigned to the favorable-risk group (26.5%). Patients with either factor and both factors were assigned to the intermediate-risk group (44.3%), and poor-risk group (29.2%), respectively. Kaplan–Meier curves showed clear discrimination of OS among the risk groups (p < 0.001). The ORR in each group was 35.7% in the favorable-risk group, 27.7% in the intermediate-risk group, and 17.7% in the poor-risk group. Given that the model can be concisely determined at the initiation of pembrolizumab treatment, physicians may be encouraged to consider the risk group for daily practice.

Treatment Strategies and Metabolic Pathway Regulation in Urothelial Cell Carcinoma: A Comprehensive Review.

For a long time, cisplatin-based chemotherapy had been viewed as first-line chemotherapy for advanced and metastatic urothelial carcinoma (UC). However, many patients with UC had been classified as cisplatin-ineligible who can only receive alternative chemotherapy with poor treatment response, and the vast majority of the cisplatin-eligible patients eventually progressed, even those with objective response with cisplatin-based chemotherapy initially. By understanding tumor immunology in UC, immune checkpoint inhibitors, targeting on programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) pathways, had been proven as first-line treatment for cisplatin-ineligible metastatic UC and as second-line treatment for patients with platinum-refractory metastatic UC by the U.S Food and Drug Administration (FDA). In 2020, JAVEIN bladder 100 further reported that PD-L1 inhibitors showed benefits on prolonged survival and progression-free survival as maintenance therapy. Besides targeting on immune checkpoint, manipulation of the tumor microenvironment by metabolic pathways intervention, including inhibition on tumor glycolysis, lactate accumulation and exogenous glutamine uptake, had been investigated in the past few years. In this comprehensive review, we start by introducing traditional chemotherapy of UC, and then we summarize current evidences supporting the use of immune checkpoint inhibitors and highlight ongoing clinical trials. Lastly, we reviewed the tumor metabolic characteristic and the anti-tumor treatments targeting on metabolic pathways.

Outcomes and the impact of genomic characteristics on patients with metastatic urothelial carcinoma enrolled in early phase trials.

5029 Background: With the recent approvals of checkpoint inhibitors (CPIs), a fibroblast growth factor receptor (FGFR) inhibitor, and an antibody-drug conjugate, patients with platinum-refractory metastatic urothelial carcinoma (mUC) have several treatment options available. However, many patients with platinum-refractory mUC need novel therapies after progressing on current therapies. We assessed the role of early phase trials in treatment of mUC and the impact of genomic alterations on their outcomes. Methods: We retrospectively analyzed medical records of patients with mUC who received an investigational therapy at the phase 1 clinic and had CLIA-certified clinical next generation sequencing. Clinical parameters and mutations were abstracted. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods. Hazard ratios (HR) were calculated using the Cox proportional hazard model. Results: Among the 57 pts enrolled in 41 unique phase 1 trials between 2015 and 2019, 16% (9/57) had variant histology: neuroendocrine carcinoma (n = 3) and urachal carcinoma (n = 6). Median age was 64. Majority were males (72%). 97% received prior platinum therapy and 60% had received prior CPI therapy. Across the pure urothelial carcinoma cohort (n = 48), median PFS was 4.2 months (m), median OS was 9.8 m, and the overall response rate (ORR) was 19%. TP53, FGFR, TERT, and ARID1A alterations (alt) were detected in 54%, 41%, 21% and 17% of UC patients, respectively. Patients harboring a TP53 alt, compared to no alt, had a shorter median PFS of 3.2m vs 9.6 m (HR = 2.738 [1.247 - 6.011], p = 0.0121). On the contrary, median PFS was longer in FGFR alt, compared to no alt, 6.3m vs 3.2m (HR = 0.4662 [0.224 - 0.971], p = 0.0415). Of note, 64% of FGFR alt patients were treated under an early phase FGFR targeting trial. Median OS was numerically longer in FGFR alt and shorter in TP53 alt but did not reach statistical significance (table). Conclusions: Patients with mUC may derive clinical benefit from enrollment in phase I clinical trials. Patients with TP53 alterations had numerically worse outcomes. Patients with mUC should be considered for an FGFR targeting therapy in the setting of an FGFR alteration. [Table: see text]

Docetaxel with or without Ramucirumab after Platinum-Based Chemotherapy and Checkpoint Inhibitors in Advanced Urothelial Carcinoma: A Pre-Specified Subgroup Analysis from the Phase 3 RANGE Trial

BACKGROUND: The phase 3 RANGE trial found ramucirumab/docetaxel improved progression-free survival (PFS) versus placebo/docetaxel (median 4.1 vs 2.8 months; hazard ratio [HR] = 0.757, p = 0.0118) for treatment of platinum-refractory metastatic urothelial carcinoma (UC). Some patients received an immune checkpoint inhibitor (ICI) prior to RANGE. In other studies, unselected patients with platinum-refractory UC exhibited an overall response rate (ORR) of 15–31% to ICIs. OBJECTIVE: Efficacy and safety data from the subgroup of patients treated with prior ICI were examined using prespecified analyses to compare outcomes between RANGE treatment arms. METHODS: Randomized, double-blind RANGE study (n = 530) took place July 2015-April 2017 in 23 countries. Forty-five patients (8.5%) received prior ICI. PFS was evaluated using the Kaplan-Meier method and unstratified Cox proportional hazards model. RESULTS: 17 ramucirumab/docetaxel arm, 28 placebo/docetaxel arm patients were treated with an ICI. The prior-ICI ramucirumab subgroup had worse Bellmunt scores at baseline versus placebo (score of 2-3 : 70.6% vs 25%, respectively). Most patients (84.4%) received the ICI immediately following platinum and immediately prior to RANGE. ORR to prior ICI was 6.7% Responses were achieved by 5/17 (29.4%) on ramucirumab/docetaxel, compared to 2/28 (7.1%) on placebo/docetaxel. Median PFS was 3.15 months on ramucirumab/docetaxel versus 2.73 months on placebo/docetaxel (HR = 0.786, 95% CI = 0.404–1.528, p = 0.4877). The frequency of grade≥3 adverse events was similar between arms. Limitations include sample size and treatment setting of the analyzed population. CONCLUSIONS: Ramucirumab/docetaxel may provide a clinical benefit with acceptable safety in the third-line setting for metastatic UC patients whose disease has progressed on both prior platinum chemotherapy and ICI therapy.

Second-line therapy for metastatic urothelial carcinoma: Defining the best treatment option among immunotherapy, chemotherapy, and antiangiogenic targeted therapies. A systematic review and meta-analysis

There is no second-line standard of care universally accepted for platinum-refractory metastatic urothelial carcinoma. Immunotherapy and anti-VEGF(R) targeted therapies are 2 emerging strategies with promising though inconclusive results. We perform a systematic meta-analysis to assess the available options. We searched MEDLINE/PubMed, the Cochrane Library, and American society of clinical oncology (ASCO) Meeting abstracts to identify prospective studies. Data extraction was conduced according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. The measured outcomes were overall survival (OS) and progression free survival (PFS). Seven randomized controlled trials were selected for final analysis, with a total of 2,451 evaluable patients. Chemotherapy with vinflunine did not reduce the risk of progression (HR = 1.11; 95%CI 0.78-1.57; P = .56) or death (HR = 0.97; 95%CI 0.70-1.34; P = .87) compared to taxanes. Immunotherapy with anti-PD-1/PD-L1 mAb improved OS over chemotherapy (HR = 0.81; 95% CI 0.71-0.92; P<.0009). The OS benefit of immunotherapy was retained when compared to taxanes, but not compared to vinflunine, although without a significant difference between the 2 subgroups (P = .30). A lack of PFS (HR = 0.73; P = .08) and OS (HR = 1.0; P = .99) benefit was observed with an anti-VEGF(R) plus chemotherapy compared to chemotherapy alone. No PFS (P = .14) or OS (P = .13) differences were detected when comparing anti-VEGF(R) ± chemotherapy and immunotherapy. Immunotherapy significantly improved OS compared to chemotherapy in metastatic urothelial carcinoma unselected for PD-L1 status. The addition of anti-VEGF(R) to chemotherapy did not provide any statistically significant benefit in terms of PFS or OS. Single agent taxanes or vinflunine can be considered given their similar efficacy but different toxicity profiles.

Immunotherapy Advances in Urothelial Carcinoma.

Checkpoint inhibitors have monumentally transformed the treatment of metastatic urothelial carcinoma. While the efficacy and safety of the different agents are similar in platinum-refractory metastatic urothelial carcinoma, pembrolizumab is the only agent that was superior to chemotherapy in a randomized phase III trial. Pembrolizumab and atezolizumab are also approved as first-line therapies in cisplatin-ineligible metastatic urothelial carcinoma. Several immunotherapy trials are ongoing in non-metastatic setting to maximize responses upfront. Despite the promising responses with immunotherapy, majority of patients do not respond to monotherapy and combination approaches would be the path moving forward to maximize responses. In addition, novel therapies are needed for patients who progress on checkpoint inhibitors. There is still a lot to be done to better understand predictive biomarkers, optimal combination, and sequences to improve clinical outcomes in urothelial carcinoma.

Docetaxel with or without ramucirumab after immune checkpoint inhibition in platinum-refractory metastatic urothelial carcinoma (mUC): Prespecified subgroup analysis from the phase 3 RANGE trial.

434 Background: Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 have shown objective response rates (ORR) of 15-21% in PD-L1 unselected patients (pts) with platinum-refractory mUC. Overall results of RANGE, a randomized, double-blinded phase 3 trial comparing ramucirumab and docetaxel (R+D) to placebo and docetaxel (P+D) in pts with platinum-refractory mUC demonstrated an ORR of 24.5% to R+D and a statistically significant improvement in progression free survival (PFS; median 4.07 vs 2.76 mo; HR 0.757). Here we present a pre-specified subgroup analysis of pts who received a prior ICI. Methods: RANGE enrolled pts with progressive mUC during or after platinum-based chemotherapy. Additional prior treatment with one ICI was permitted. Pts were randomized (1:1) to receive D 75 mg/m2 up to 10 cycles with R 10 mg/kg or P on day 1 of a 21-day cycle until disease progression or other discontinuation criteria. Primary endpoint, investigator-assessed PFS, was analyzed in the first 437 randomized pts. Secondary endpoints included overall survival, objective response, and safety. Radiographic assessment occurred every 6 weeks. Results: Thirty three of the 437 pts (8%) in the PFS population received a prior ICI. The majority (91%) received the ICI immediately following platinum and immediately prior to RANGE. Most pts received atezolizumab (55%) or pembrolizumab (36%); ORR to prior ICI was 6% and the majority (67%) had progressive disease as best response. Median duration of the ICI was 3.5 mo (IQR 1.6-5.2). Disease sites at entry onto RANGE included lymph node (79%), lung (48%), liver (39%) and bone (18%). At data cutoff, responses were achieved by 5/14 (35.7%) on R+D, compared to 2/19 (10.5%) on P+D. Responses to R+D were independent of disease site. Of pts with liver metastases, 3/8 responded to R+D compared to 0/5 on P+D. Overall, median PFS was 5.29 mo on R+D and 2.76 mo on P+D (HR 0.920). The frequency of grade ≥3 adverse events was similar between arms. Conclusions: Acknowledging limitations of sample size, R+D showed higher ORR than P+D in pts who had progressed on platinum and ICI therapy, including those with liver metastases. Clinical trial information: NCT02426125.

Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial

Few options exist for patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. We aimed to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) versus chemotherapy in this patient population. We conducted this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at 217 academic medical centres and community oncology practices mainly in Europe, North America, and the Asia-Pacific region. Patients (aged ≥18 years) with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy were randomly assigned (1:1), via an interactive voice and web response system with a permuted block design (block size of four), to receive atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m2, paclitaxel 175 mg/m2, or 75 mg/m2 docetaxel) intravenously every 3 weeks. Randomisation was stratified by PD-L1 expression (expression on <1% [IC0] or 1% to <5% [IC1] of tumour-infiltrating immune cells vs ≥5% of tumour-infiltrating immune cells [IC2/3]), chemotherapy type (vinflunine vs taxanes), liver metastases (yes vs no), and number of prognostic factors (none vs one, two, or three). Patients and investigators were aware of group allocation. Patients, investigators, and the sponsor were masked to PD-L1 expression status. The primary endpoint of overall survival was tested hierarchically in prespecified populations: IC2/3, followed by IC1/2/3, followed by the intention-to-treat population. This study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT02302807. Between Jan 13, 2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11·1 months [95% CI 8·6-15·5; n=116] vs 10·6 months [8·4-12·2; n=118]; stratified hazard ratio [HR] 0·87, 95% CI 0·63-1·21; p=0·41), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15·9 months [95% CI 10·4 to not estimable] vs 8·3 months [5·6-13·2]; HR 0·57, 95% CI 0·26-1·26). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3-4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients). Atezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favourable compared with chemotherapy, Exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting. F Hoffmann-La Roche, Genentech.

Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial

The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients. In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing. Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0-19·7) and followed up for a median of 9·9 months (4·3-12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11-24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1-2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis). Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis. Merck KGaA, and Pfizer Inc.

LBA4_PR - RANGE: A randomized, double-blind, placebo-controlled phase 3 study of docetaxel (DOC) with or without ramucirumab (RAM) in platinum-refractory advanced or metastatic urothelial carcinoma

Background: Limited treatment options are available for patients (pts) with platinum-refractory advanced or metastatic urothelial carcinoma (UC). In a previous randomized phase 2 study (NCT01282463) of platinum-refractory metastatic UC, RAM plus DOC significantly improved median progression-free survival (PFS) over DOC (5.4 vs 2.8 months; HR, 0.389; 95% CI, 0.235-0.643; P = 0.0002) with no unexpected toxicities. To confirm these results, we conducted a randomized phase 3 trial in a similar pt population. Methods: In this randomized, double-blind, phase 3 trial, pts with progressive advanced or metastatic UC during or after platinum-based chemotherapy were enrolled. Additional prior treatment with 1 immune checkpoint inhibitor was permitted. Pts were randomized (1:1) to receive DOC 75 mg/m2 with RAM 10 mg/kg or placebo (PL) on day 1 of a 21-day cycle until disease progression or other discontinuation criteria. Primary endpoint was investigator-assessed PFS, analyzed in the first 437 randomized (intention-to-treat, ITT) pts. Secondary endpoints included overall survival (OS), objective response rate (ORR), safety, and quality of life as assessed with the EORTC QLQ-C30. Radiographic assessment occurred every 6 weeks. Results: 530 pts were randomized to RAM plus DOC (n = 263) or PL plus DOC (n = 267). PFS was significantly prolonged in pts treated with RAM plus DOC versus PL plus DOC (median, 4.1 vs 2.8 months; HR, 0.757; 95% CI, 0.607-0.943; p = 0.0118). A blinded central analysis demonstrated consistent PFS results (HR, 0.672; 95% CI, 0.536-0.842; p = 0.0005). ORR in the first 437 ITT population was 24.5% (95% CI, 18.8-30.3) in the RAM arm and 14.0% (95% CI, 9.4-18.6) in the PL arm. OS data are immature. Grade ≥3 adverse events (AEs) were reported at a similar frequency in both arms with no unexpected toxicities; neutropenia was the most common grade ≥3 AE (15% RAM arm vs 14% PL arm). Mean scores for global quality of life were relatively unchanged over time, with no differences between arms. Conclusions: RAM plus DOC is the first regimen in a phase 3 study to show superior PFS over chemotherapy in pts with platinum-refractory advanced UC. Clinical trial identification: NCT02426125 Legal entity responsible for the study: Eli Lilly and Company Funding: Eli Lilly and Company Disclosure: K.N. Chi: Clinical trial costs from Eli Lilly and Company, during the conduct of the study. C.N. Sternberg: Personal fees for participating in an advisory board and institutional research funding from Eli Lilly and Company, during the conduct of the study. R. de Wit: Grant support or personal fees from Lilly, Merck, Roche and Sanofi. E.Y. Yu: Honorarium and institutional research funding from Eli Lilly and Company A. Fléchon: Personal fees and non-financial support from Janssen, Novartis, Astellas, Sanofi, Roche, MSD, Pfizer, Ipsen, Bayer, Astra Zeneca, outside the submitted work; . M.S. van der Heijden: Personal fees from Roche/Genentech, AstraZeneca, Astellas, BMS, and grants from Astellas, outside the submitted work. N. Matsubara: Honoraria from MSD, AstraZeneca, Eisai, Ono, Kissei, Sanofi Taiho, Takeda, Chugai, Novartis, Bayer Yakuhin, Pfizer Japan, Merck Serono Co., Janssen; research funding from Shionogi, Bayer Yakuhin, Janssen, Chugai, Eli Lilly Japan, Eisai, MSD R.A. Walgren, O. Hamid, A.H. Zimmermann, K.M. Bell-Mcguinn: Employee and shareholder of Eli Lilly and Company T. Powles: Honoraria from Roche, Merck, AstraZeneca, BMS, Lilly, Pfizer; and research funding from Roche and AstraZeneca. All other authors have declared no conflicts of interest.

Association of HER2 and ErbB3 molecular alterations with afatinib sensitivity in platinum-refractory metastatic urothelial carcinoma (UC) in a phase II trial.

Association of <i>HER2 </i>and <i>ErbB3 </i>molecular alterations with afatinib sensitivity in platinum-refractory metastatic urothelial carcinoma (UC) in a phase II trial.