Matthew D. Galsky

Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial

BACKGROUND Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population. METHODS For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged ≥18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an α level of 0·05. This study is registered with ClinicalTrials.gov, number NCT02108652. FINDINGS Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvironment was defined by the percentage of PD-L1-positive immune cells: IC0 (<1%), IC1 (≥1% but <5%), and IC2/3 (≥5%). The primary analysis (data cutoff May 5, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% [95% CI 19-37], p<0·0001; IC1/2/3: 18% [13-24], p=0·0004) and in all patients (15% [11-20], p=0·0058). With longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates were 26% (95% CI 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15% (11-19) overall in all 310 patients. With a median follow-up of 11·7 months (95% CI 11·4-12·2), ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. Grade 3-4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study. INTERPRETATION Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma. FUNDING F Hoffmann-La Roche Ltd.

Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial

BACKGROUND Patients with metastatic urothelial carcinoma have a dismal prognosis and few treatment options after first-line chemotherapy. Responses to second-line treatment are uncommon. We assessed nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for safety and activity in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed or recurred despite previous treatment with at least one platinum-based chemotherapy regimen. METHODS In this multicentre, phase 2, single-arm study, patients aged 18 years or older with metastatic or surgically unresectable locally advanced urothelial carcinoma, measurable disease (according to Response Evaluation Criteria In Solid Tumors v1.1), Eastern Cooperative Oncology Group performance statuses of 0 or 1, and available tumour samples for biomarker analysis received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was overall objective response confirmed by blinded independent review committee in all treated patients and by tumour PD-L1 expression (≥5% and ≥1%). This trial is registered with ClinicalTrials.gov, number NCT02387996, and is completed. Follow-up is still ongoing. FINDINGS Between March 9, 2015, and Oct 16, 2015, 270 patients from 63 sites in 11 countries received nivolumab, and 265 were evaluated for activity. Median follow-up for overall survival was 7·00 months (IQR 2·96-8·77). Confirmed objective response was achieved in 52 (19·6%, 95% CI 15·0-24·9) of 265 patients. Confirmed objective response was achieved in 23 (28·4%, 95% CI 18·9-39·5) of the 81 patients with PD-L1 expression of 5% or greater, 29 (23·8%, 95% CI 16·5-32·3) of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16·1%, 95% CI 10·5-23·1) of the 143 patients with PD-L1 expression of less than 1%. Grade 3-4 treatment-related adverse events occurred in 48 (18%) of 270 patients-most commonly grade 3 fatigue and diarrhoea, which each occurred in five patients. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure). INTERPRETATION Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma. FUNDING Bristol-Myers Squibb.

Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder

Perioperative cisplatin‐based chemotherapy has shown benefit in patients with high‐risk localized urothelial bladder cancer, but it is not widely used. Renal impairment may be a major factor limiting its use. The current study was designed to determine the proportion of patients ineligible to receive adjuvant cisplatin‐based chemotherapy based on inadequate renal function alone.

Multi-Institutional Randomized Phase II Trial of the Epothilone B Analog Ixabepilone (BMS-247550) With or Without Estramustine Phosphate in Patients With Progressive Castrate Metastatic Prostate Cancer

PURPOSE To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer. PATIENTS AND METHODS Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5. RESULTS Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm. CONCLUSION Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer.

CONTEXT Muscle-invasive bladder cancer (MIBC) is a disease with a pattern of predominantly distant and early recurrences. Neoadjuvant cisplatin-based combination chemotherapy has demonstrated improved outcomes for MIBC. OBJECTIVE To review the data supporting perioperative chemotherapy and emerging regimens for MIBC. EVIDENCE ACQUISITION Medline databases were searched for original articles published before April 1, 2012, with the search terms bladder cancer, urothelial cancer, radical cystectomy, neoadjuvant chemotherapy, and adjuvant chemotherapy. Proceedings from the last 5 yr of major conferences were also searched. Novel and promising drugs that have reached clinical trial evaluation were included. EVIDENCE SYNTHESIS The major findings are addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed. CONCLUSIONS Cisplatin-based neoadjuvant combination chemotherapy is an established standard, improving overall survival in MIBC. Pathologic complete response appears to be an intermediate surrogate for survival, but this finding requires further validation. Definitive data to support adjuvant chemotherapy do not exist, and there are no data to support perioperative therapy in cisplatin-ineligible patients. Utilization of neoadjuvant cisplatin is low, attributable in part to patient/physician choice and the advanced age of patients, who often have multiple comorbidities including renal and/or cardiac dysfunction. Trials are using the neoadjuvant paradigm to detect incremental pathologic response to chemobiologic regimens and brief neoadjuvant single-agent therapy to screen for the biologic activity of agents.

Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy

BACKGROUND Systemic therapy options are limited for metastatic castration-resistant prostate cancer (CRPC) patients who progress following docetaxel (Taxotere). This phase II trial evaluated sunitinib malate in patients with progressing metastatic CRPC following prior docetaxel. PATIENTS AND METHODS Patients with metastatic CRPC progressing following one to two chemotherapy regimens including docetaxel were included. The primary end point was progression-free survival (PFS) per radiographic and clinical evaluations. Oral sunitinib was administered 50 mg/day 4-weeks on followed by 2-weeks off per cycle up to a maximum of eight cycles or until clinical progression or intolerable toxicity. RESULTS Thirty-six patients with a median age of 69.5 years were accrued. The median PFS was 19.4 weeks with a 12-week PFS of 75.8%. Four patients (12.1%) had a > or =50% prostate-specific antigen (PSA) decline and seven (21.2%) had a > or =30% PSA decline. Two of 18 patients (11.1%) with measurable disease demonstrated 30% declines by RECIST and eight (44.4%) displayed some shrinkage. A decline in pain score > or =2 points occurred in 13.6% of 22 assessable patients. Drug discontinuation due to toxic effects occurred in 52.8% of patients. CONCLUSION Sunitinib malate demonstrated promising activity in metastatic CRPC progressing after prior docetaxel.

Randomized phase II trial of single-agent amrubicin or topotecan as second-line treatment in patients with small-cell lung cancer sensitive to first-line platinum-based chemotherapy.

PURPOSE This phase II study evaluated the safety and efficacy of single-agent amrubicin versus topotecan in patients with small-cell lung cancer (SCLC) sensitive to first-line platinum-based chemotherapy. PATIENTS AND METHODS Patients were randomly assigned 2:1 to amrubicin (40 mg/m(2)/d in a 5-minute intravenous [IV] infusion, days 1 through 3, every 21 days) or topotecan (1.5 mg/m(2)/d in a 30-minute IV infusion, days 1 through 5, every 21 days). The primary efficacy end point was overall response rate (ORR) for amrubicin. Secondary end points included time to progression, median progression-free survival (PFS), and median overall survival (OS). RESULTS Of 76 patients enrolled, 50 patients were randomly assigned to amrubicin, and 26 patients were randomly assigned to topotecan. Amrubicin treatment resulted in a significantly higher ORR than topotecan (44% v 15%; P = .021). Median PFS and median OS were 4.5 months and 9.2 months with amrubicin and 3.3 months and 7.6 months with topotecan, respectively. Tolerability was similar with both agents. However, grade 3 or worse neutropenia and thrombocytopenia seemed to be more frequent in the topotecan group as compared with the amrubicin group (78% and 61% v 61% and 39%, respectively). CONCLUSION Amrubicin shows promising activity, with an ORR of 44% compared with an ORR of 15% for topotecan as second-line treatment in patients with SCLC sensitive to first-line platinum-based chemotherapy. In addition, the safety profiles were comparable; however, a trend was noted for more frequent grade 3 or worse neutropenia and thrombocytopenia in the topotecan group as compared with the amrubicin group. Additional studies are ongoing.

Targeting cancer stem cells to suppress acquired chemotherapy resistance

Acquired resistance has curtailed cancer survival since the dawn of the chemotherapy age more than half a century ago. Although the application of stem cell (SC) concepts to cancer captured the imagination of scientists for many years, only the last decade has yielded substantial evidence that cancer SCs (CSCs) contribute to chemotherapy resistance. Recent studies suggest that the functional and molecular properties of CSCs constitute therapeutic opportunities to improve the efficacy of chemotherapy. Here we review how these properties have stimulated combination strategies that suppress acquired resistance across a spectrum of malignancies. The clinical implementation of these strategies promises to rejuvenate the effort against an enduring challenge.

ICUD-EAU International Consultation on Bladder Cancer 2012: Chemotherapy for Urothelial Carcinoma—Neoadjuvant and Adjuvant Settings

CONTEXT We present a summary of the Second International Consultation on Bladder Cancer recommendations on chemotherapy for the treatment of bladder cancer using an evidence-based strategy. OBJECTIVE To review the data regarding chemotherapy in patients with clinically localized and metastatic bladder cancer with a focus on its use for patients in the neoadjuvant and adjuvant settings. EVIDENCE ACQUISITION Medline databases were searched for original articles published prior to April 1, 2012, using the following search terms: bladder cancer, urothelial cancer, metastatic, advanced, neoadjuvant, and adjuvant therapy. Proceedings of major conferences from the last 5 yr also were searched. Novel and promising drugs currently in clinical trials were included. EVIDENCE SYNTHESIS The major findings are addressed in an evidence-based manner. Prospective trials and important cohort data were analyzed. CONCLUSIONS Cisplatin-based combination chemotherapy for advanced and metastatic bladder cancer is an established standard, improving overall survival. In the advanced setting, cisplatin-ineligible patients may benefit from gemcitabine and carboplatin. Meta-analyses undertaken for neoadjuvant cisplatin-based combination chemotherapy show a 5% benefit in overall survival. Pathologic complete remission may be an intermediate surrogate for survival, but requires further validation. Use of neoadjuvant chemotherapy is low, and is attributable to patient and physician choice because of limited benefit, advanced age, and comorbidities including renal and/or cardiac dysfunction. Sufficient data to support adjuvant chemotherapy are lacking.

Second-line systemic therapy and emerging drugs for metastatic transitional-cell carcinoma of the urothelium

Front-line platinum-based combination chemotherapy leads to high response rates but suboptimum overall survival for patients with advanced transitional-cell carcinoma of the urothelium. Bevacizumab is being assessed in combination with platinum-based first-line chemotherapy in a large phase 3 trial. Current second-line systemic therapies, including taxanes, yield disappointing outcomes. Vinflunine, a novel vinca alkaloid, showed some activity and was recently approved in Europe based on results of the first completed phase 3 trial in the second-line setting. Better understanding of molecular biology and the emergence of novel biological agents now offer the possibility of improved outcomes. Neoadjuvant therapy before cystectomy and consolidation therapy with biological agents after first-line therapy provide a framework for the development of new drugs. We propose that trials to approve new drugs target two separate populations; multicentre non-randomised phase 2 trials should include patients with chemotherapy-resistant disease progressing within 6 months of first-line therapy, and randomised trials might be appropriate for chemotherapy-sensitive disease progressing more than 6 months after first-line therapy. A multidisciplinary approach is necessary to make therapeutic advances. This review discusses current second-line therapy and emerging drugs for advanced transitional-cell carcinoma.