TGFß attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.

Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor ß (TGFß) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8+ T cells from the tumour parenchyma that were instead found in the fibroblast- and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-administration of TGFß-blocking and anti-PD-L1 antibodies reduced TGFß signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFß shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration.

First-In-Human, First-In-Class, Phase I Trial of the Fucosylation Inhibitor SGN-2FF in Patients with Advanced Solid Tumors.

LESSONS LEARNED: Inhibition of glycoprotein fucosylation, as monotherapy and in combination with immune checkpoint blockade, is a promising therapeutic strategy for treating a broad range of cancers. In this first-in-human, first-in-class, phase I study in advanced solid tumors, SGN-2FF demonstrated dose-proportional pharmacokinetics, evidence of pharmacodynamic target inhibition of glycoprotein fucosylation, and preliminary antitumor activity. SGN-2FF was associated with thromboembolic events that led to study termination. BACKGROUND: We conducted a first-in-human, first-in-class, phase I study of SGN-2FF, a potent small-molecule inhibitor of glycoprotein fucosylation, in patients with advanced solid tumors. METHODS: The study consisted of four parts: SGN-2FF monotherapy dose-escalation (part A) and expansion (part B), and SGN-2FF + pembrolizumab dose-escalation (part C) and expansion (part D). The objectives were to evaluate safety and tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of SGN-2FF monotherapy and SGN-2FF + pembrolizumab. RESULTS: Forty-six patients were enrolled (part A, n = 33; part B, n = 6; part C, n = 7; part D did not enroll any patients). During part A (n = 32) exploring 1-15 g once daily (QD) and 2-5 g twice daily (b.i.d.), grade 3 dose-limiting toxicities were diarrhea (2 g and 15 g QD) and increased lipase (2 g QD). The MTD was 10 g daily. In part A, common toxicities were grades 1-2 diarrhea, fatigue, and nausea (each 47%); thromboembolic events (grades 2-5) occurred in 5 of 32 patients (16%). Safety measures included concurrent prophylactic anticoagulation with low-molecular weight heparin (LMWH). In part C, despite the safety measures implemented, a thromboembolic event occurred in one of seven patients (14%) during the SGN-2FF lead-in period. Of 28 evaluable patients in part A, 1 patient with advanced head and neck squamous cell carcinoma achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 complete response (CR) and 10 (36%) had RECIST v1.1 stable disease, including 1 patient with advanced triple-negative breast cancer with 51% tumor burden reduction. SGN-2FF administration led to dose-proportional increases in exposure and PD reduction in protein fucosylation. CONCLUSION: SGN-2FF demonstrated proof-of-mechanism and preliminary antitumor activity but was associated with thromboembolic events leading to study termination.

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

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: F Hoffmann-La Roche, Genentech.

Targeted therapy in the treatment of castration-resistant prostate cancer.

In the field of metastatic castration-resistant prostate cancer, a bevy of novel therapeutics have recently been proven to extend survival via distinct mechanisms of action. Although revolutionary, these recent developments have not led to improved cure rates, and resistance eventually develops.Thus, further exploration into the biologic mechanisms of resistance to these new agents in prostate cancer has been necessary. This has opened the door to the development of agents designed to manipulate alternative biologic targets. In this review, we focus on the testosterone/androgen receptor pathway that is being targeted with potent new agents; we also discuss other important alternative biologic pathways that have given rise to new therapeutics that may attenuate prostate cancer growth, survival, and propagation.

Systematic Literature Review (SLR) and Network Meta-Analysis (NMA) of First-Line Therapies (1L) for Locally Advanced/Metastatic Urothelial Carcinoma (la/mUC).

To compare efficacy outcomes for all approved and investigational first-line (1L) treatment regimens for locally advanced or metastatic urothelial carcinoma (la/mUC) with standard of care (SOC), a network meta-analysis (NMA) was conducted. A systematic literature review (SLR) identified phase 2 and 3 randomized trials investigating 1L treatment regimens in la/mUC published January 2001-September 2021. Three networks were formed based on cisplatin (cis) eligibility: cis-eligible/mixed (cis-eligible patients and mixed populations of cis-eligible/ineligible patients), cis-ineligible (strict; exclusively cis-ineligible patients), and cis-ineligible (wide; including studies with investigator's choice of carbo). Analyses examined comparative efficacy by hazard ratio (HR) for overall survival (OS), and progression-free survival (PFS), and odds ratio (OR) for overall response rate (ORR), with 1L regimens vs. SOC. SOC was gemcitabine + cis (GemCis) or carboplatin (GemCarbo), cis-eligible/mixed network, and GemCarbo cis-ineligible networks. Of 1906 SLR identified citations, 55 trials were selected for data extraction. The NMA comprised 11, 6, and 8 studies in the cis-eligible/mixed, cis-ineligible (strict), cis-ineligible (wide) networks, respectively. In a meta-analysis of SOC control arms, median (95% CI) overall survival (OS) in months varied by network: 13.19 (12.43, 13.95) cis-eligible/mixed, 11.96 (10.43, 13.48) cis-ineligible (wide), and 9.74 (6.71, 12.76) cis-ineligible (strict). Most differences in OS, PFS, and ORR with treatment regimens across treatment networks were not statistically significant compared with SOC. Outcomes with current 1L regimens remain poor, and few significant improvements over SOC have been made, despite inclusion of recent clinical trial data, highlighting an unmet need in the la/mUC patient population.

Increased Bacillus Calmette-Guérin Treatment Intensity Associated With Improved Outcomes in Elderly Patients With Non-Muscle-invasive Bladder Cancer in United States Clinical Practice.

OBJECTIVE: To characterize Bacillus Calmette-Guérin (BCG) treatment patterns and associated outcomes in a large cohort of patients with non-muscle-invasive bladder cancer (NMIBC). METHODS: Our retrospective analysis of patients aged ≥66 years with stage 0-1 urothelial bladder carcinoma diagnosed between 2000 and 2012 in the United States Surveillance, Epidemiology, and End Results-Medicare database estimated proxies for recurrence and secondary events and both all-cause and bladder cancer-specific mortality. Proportional hazards models were used in conditional landmark analyses to compare adequate (≥5 induction instillations and ≥2 maintenance instillations) and inadequate BCG, stratified by National Comprehensive Cancer Network risk group. RESULTS: Of 39,532 patients who met the selection criteria, 16,225 (41.0%) received BCG; of them, 4602 (28.4%; 11.6% overall) received adequate treatment. Adequately treated patients were slightly younger and healthier than inadequately treated patients. Half of patients with intermediate- and high-risk NMIBC did not receive BCG; few received adequate treatment. At the 12-month landmark, adequate BCG treatment was associated with decreased risks of recurrence and of cancer-specific and all-cause mortality in patients with intermediate- and high-risk disease. CONCLUSION: We observed lower than expected use of adequate BCG treatment in patients with intermediate- to high-risk NMIBC despite evidence of improved outcomes, which suggested that practice patterns may not be in line with management recommendations in this population.

Real-World Effectiveness of Chemotherapy in Elderly Patients With Metastatic Bladder Cancer in the United States.

BACKGROUND: Outcomes for patients with metastatic bladder cancer (mBC) are generally poor and progressively worse following first-line (1L) chemotherapy. OBJECTIVE: To evaluate treatment patterns, survival outcomes, and characteristics of a large, real-world US population of elderly patients with advanced mBC receiving 1L and second-line (2L) treatment retrospectively. METHODS: We identified patients with advanced mBC (aged ≥66 years)-newly diagnosed between January 1, 2004, and December 31, 2011-in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program-Medicare linked database and assessed their palliative systemic chemotherapy treatments and survival outcomes. RESULTS: Of 1703 eligible patients, 42% received 1L chemotherapy; 1L-treated patients tended to be younger and healthier than nontreated patients. Only 27% of 1L-treated patients received cisplatin-based chemotherapy, most commonly cisplatin-gemcitabine. Cisplatin-treated patients were younger and had fewer comorbidities than non-cisplatin-treated patients. Thirty-five percent of 1L-treated patients subsequently received 2L chemotherapy. Patients received a variety of 2L agents as combination chemotherapy (52%) or single-agent chemotherapy (39%). Median overall survival durations in 1L-treated and 2L-treated patients were 8.5 and 7.9 months, respectively. CONCLUSIONS: Results from this retrospective SEER-Medicare database analysis underscore the historical inadequacies of 1L and 2L treatments in elderly patients with advanced mBC. Few patients were treated with 1L chemotherapy, a minority of whom received 1L cisplatin-based chemotherapy, and even fewer received 2L chemotherapy. These findings highlight the disconnect between 1L treatment in clinical trials and treatment in the real-world setting and the lack of standard approaches to 2L treatment in the United States.

Nomogram to Assess the Survival Benefit of New Salvage Agents for Metastatic Urothelial Carcinoma in the Era of Immunotherapy.

INTRODUCTION: Optimal end points in phase 2 trials evaluating salvage therapy for metastatic urothelial carcinoma are necessary to identify promising drugs, particularly immunotherapeutics, where response and progression-free survival may be unreliable. We developed a nomogram using data from phase 2 trials of historical agents to estimate the 12-month overall survival (OS) for patients to which observed survival of nonrandomized data sets receiving immunotherapies could be compared. PATIENTS AND METHODS: Survival and data for major prognostic factors were obtained from phase 2 trials: hemoglobin, performance status, liver metastasis, treatment-free interval, and albumin. A nomogram was developed to estimate 12-month OS. Patients were randomly allotted to discovery:validation data sets in a 2:1 ratio. Calibration plots were constructed in the validation data set and data bootstrapped to assess performance. The nomogram was tested on external nonrandomized cohorts of patients receiving pemetrexed and atezolizumab. RESULTS: Data were available from 340 patients receiving sunitinib, everolimus, docetaxel + vandetanib, docetaxel + placebo, pazopanib, paclitaxel, or docetaxel. Calibration and prognostic ability were acceptable (c index = 0.634; 95% confidence interval [CI], 0.596-0.652). Observed 12-month survival for patients receiving pemetrexed (n = 127, 23.5%; 95% CI, 16.2-31.7) was similar to nomogram-predicted survival (19%; 95% CI, 16.5-21.5; P > .05), while observed results with atezolizumab (n = 403, 39.0%; 95% CI, 34.1-43.9) exceeded predicted results (24.6%; 95% CI, 23.4-25.8; P < .001). CONCLUSION: This nomogram may be a useful tool to interpret results of nonrandomized phase 2 trials of salvage therapy for metastatic urothelial carcinoma by assessing the OS contributions of drug intervention independent of prognostic variables.

Atezolizumab in Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: Outcomes by Prior Number of Regimens.

BACKGROUND: Patients with metastatic urothelial carcinoma (mUC) who progress after platinum-based chemotherapy have had few treatment options and uniformly poor outcomes. Atezolizumab (anti-programmed death-ligand 1) was approved in the USA for cisplatin-ineligible and platinum-treated mUC based on IMvigor210, a phase 2, single-arm, two-cohort study. OBJECTIVE: To evaluate the efficacy and safety of atezolizumab by the number of prior lines of systemic therapy in patients with pretreated mUC. DESIGN, SETTING, AND PARTICIPANTS: IMvigor210 enrolled 315 patients with mUC with progression during or following platinum-based therapy at 70 international sites between May 2014 and November 2014. Key inclusion criteria included age ≥18 yr, creatinine clearance ≥30ml/min, and Eastern Cooperative Oncology Group performance status 0-1, with no limit on prior lines of treatment. INTERVENTION: Patients in this cohort received atezolizumab 1200mg intravenously every 3 wk until loss of clinical benefit. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Centrally assessed Response Evaluation Criteria In Solid Tumors v1.1 objective response rate (ORR), median duration of response, overall survival (OS), and adverse events were evaluated by prior treatment. Potential differences between subgroups were evaluated using log-rank (for OS) and chi-square (for ORR and adverse events frequencies) testing. RESULTS AND LIMITATIONS: Three hundred and ten patients were efficacy and safety evaluable (median follow-up, 21 mo). Objective responses and prolonged OS occurred across all prespecified subgroups; median duration of response was not reached in most subgroups. In patients without prior systemic mUC therapy (first-line subgroup), ORR was 25% (95% confidence interval: 14-38), and median OS was 9.6 mo (95% confidence interval: 5.9-15.8). No significant differences in efficacy or toxicity by therapy line were observed. CONCLUSIONS: Atezolizumab demonstrated comparable efficacy and safety in previously treated patients with mUC across all lines of therapy evaluated. PATIENT SUMMARY: We investigated effects of previous treatment in patients with metastatic urothelial carcinoma that progressed after platinum-based therapy. Atezolizumab was active and tolerable no matter how many treatment regimens patients had received. ClinicalTrials.gov, NCT02108652.

A multicenter phase I study of cabazitaxel, mitoxantrone, and prednisone for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer: A department of defense prostate cancer clinical trials consortium study.

BACKGROUND: Cabazitaxel plus prednisone has significant activity in patients with chemotherapy-naïve and pretreated metastatic castration-resistant prostate cancer (mCRPC). Mitoxantrone has antitumor activity in mCRPC and nonoverlapping mechanism of action and toxicity profile. OBJECTIVE: To establish the maximally tolerated dose of the combination of cabazitaxel, mitoxantrone, and prednisone. METHODS AND MATERIALS: Patients with chemotherapy-naïve mCRPC were prospectively enrolled in a multicenter phase 1 trial. Cabazitaxel 20 and 25mg/m2 were each evaluated in combination with escalating doses of mitoxantrone (starting dose 4mg/m2), given with prednisone 5mg twice daily. RESULTS: A total of 25 patients were enrolled, with median age of 67 (range: 51-78) and prostate-specific antigen of 66.8ng/ml (range: 3-791.2). There were 4 dose-limiting toxicities (febrile neutropenia, n = 3; sepsis, n = 1). The maximally tolerated dose was cabazitaxel 20mg/m2 plus mitoxantrone 12mg/m2. The most common treatment-related grade≥3 related adverse events included neutropenia (n = 8; 32%), febrile neutropenia (n = 5; 20%), and thrombocytopenia (n = 4; 16%). The median number of treatment cycles was 8 (range: 2 to 19+). Decline in prostate-specific antigen to≥50% from baseline was observed in 15 patients (60%). Objective responses were observed in 10/14 (71%) evaluable patients. The median radiographic progression-free survival was 14.5 months (95% CI: 8.0-not reached (NR)), and median overall survival was 23.3 months (95% CI: 14.3-NR). CONCLUSIONS: The approved single-agent doses of mitoxantrone and cabazitaxel were safely combined. The combination led to durable tumor responses in most patients. Further study of the combination is warranted.

Antiangiogenic therapies in early-stage breast cancer.

Angiogenesis, which is crucial for the growth and spread of cancer cells, has become an important target for antineoplastic therapies in a variety of malignant tumors. Vascular endothelial growth factor and its receptor promote formation of new blood vessels in tumors. Several drugs, most notably the monoclonal antibody bevacizumab, have been developed to inhibit this process. Clinical trials utilizing bevacizumab and other antiangiogenic drugs in metastatic breast cancer have demonstrated enhanced response rates and prolonged progression-free survival, though no overall survival benefit has been seen. Trials are now under way exploring the use of antiangiogenic agents in patients with early stage breast cancer. We performed a comprehensive review of the published literature (English language), US National Institutes of Health clinical trials registry (ClinicalTrials.gov), and established cooperative groups that revealed approximately 75 clinical trials, completed or ongoing, utilizing antiangiogenic drugs in early-stage breast cancer. A number of phase II trials in the neoadjuvant setting have reported preliminary results suggesting response rates similar to those seen with traditional anthracycline-plus-taxane combination regimens. Most of these early trials have not yet met any survival endpoints. Studies are also ongoing in the adjuvant setting, and these have not yet been reported. The toxicities associated with these agents are similar to those that have been reported in the metastatic trials. Most of these side effects are grade 1 or 2 and are easily manageable; however, there remain a small percentage of patients who sustain life-threatening vascular events, bleeding, or wound-healing complications. This number is significantly higher in patients receiving antiangiogenic drugs when compared with controls. While we eagerly await completion and results of this impressive portfolio of studies in early breast cancer with antiangiogenic agents, there is an urgent need for a more rational patient/antiangiogenic therapy selection with greater insight into predictive factors for toxicities, therapy efficacy, and clinical benefit.

The influence of age, gender, and training on exercise efficiency.

OBJECTIVES: The aim of this study was to determine whether changes in oxygen efficiency occur with aging or exercise training in healthy young and older subjects. BACKGROUND: Exercise capacity declines with age and improves with exercise training. Whether changes in oxygen efficiency, defined as the oxygen cost per unit work, contributes to the effects of aging or training has not yet been defined. METHODS: Sixty-one healthy subjects were recruited into four groups of younger women (ages 20 to 33 years, n = 15), younger men (ages 20 to 30 years, n = 12), older women (ages 65 to 79 years, n = 16), and older men (ages 65 to 77 years, n = 18). All subjects underwent cardiopulmonary exercise testing to analyze aerobic parameters before and after three to six months of supervised aerobic exercise training. RESULTS: Before training, younger subjects had a much higher exercise capacity, as shown by a 42% higher peak oxygen consumption (VO2) (ml/kg/min, p < 0.0001). This was associated with an 11% lower work VO2/W (p = 0.02) and an 8% higher efficiency than older subjects (p = 0.03). With training, older subjects displayed a larger increase in peak W/kg (+29% vs. +12%, p = 0.001), a larger decrease in work VO2/W (-24% vs. -2%, p < 0.0001), and a greater improvement in exercise efficiency (+30% vs. 2%, p < 0.0001) compared to the young. CONCLUSIONS: Older age is associated with a decreased exercise efficiency and an increase in the oxygen cost of exercise, which contribute to a decreased exercise capacity. These age-related changes are reversed with exercise training, which improves efficiency to a greater degree in the elderly than in the young.