A Phase Ib/II study of IGF-neutralising antibody xentuzumab with enzalutamide in metastatic castration-resistant prostate cancer.

BACKGROUND: This multicentre, open-label, Phase Ib/II trial evaluated the insulin-like growth factor (IGF) 1/2 neutralising antibody xentuzumab plus enzalutamide in metastatic castrate-resistant prostate cancer (mCRPC). METHODS: The trial included Phase Ib escalation and expansion parts and a randomised Phase II part versus enzalutamide alone. Primary endpoints in the Phase Ib escalation, Phase Ib expansion and Phase II parts were maximum tolerated dose (MTD), prostate-specific antigen response and investigator-assessed progression-free survival (PFS), respectively. Patients in the Phase Ib escalation and Phase II parts had progressed on/after docetaxel/abiraterone. RESULTS: In the Phase Ib escalation (n = 10), no dose-limiting toxicities were reported, and xentuzumab 1000 mg weekly plus enzalutamide 160 mg daily (Xe1000 + En160) was defined as the MTD and recommended Phase 2 dose. In the Phase Ib expansion (n = 24), median PFS was 8.2 months, and one patient had a confirmed, long-term response. In Phase II (n = 86), median PFS for the Xe1000 + En160 and En160 arms was 7.4 and 6.2 months, respectively. Subgroup analysis suggested trends towards benefit with Xe1000 + En160 in patients whose tumours had high levels of IGF1 mRNA or PTEN protein. Overall, the combination was well tolerated. CONCLUSIONS: Xentuzumab plus enzalutamide was tolerable but lacked antitumour activity in unselected patients with mCRPC. CLINICAL TRIAL REGISTRATION: EudraCT number 2013-004011-41.

Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.

BACKGROUND: Currently, metastatic renal cell carcinoma is treated with sequential single agents targeting VEGF or mTOR. Here, we aimed to assess lenvatinib, everolimus, or their combination as second-line treatment in patients with metastatic renal cell carcinoma. METHODS: We did a randomised, phase 2, open-label, multicentre trial at 37 centres in five countries and enrolled patients with advanced or metastatic, clear-cell, renal cell carcinoma. We included patients who had received treatment with a VEGF-targeted therapy and progressed on or within 9 months of stopping that agent. Patients were randomised via an interactive voice response system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The randomisation procedure dynamically minimised imbalances between treatment groups for the stratification factors haemoglobin and corrected serum calcium. The primary objective was progression-free survival in the intention-to-treat population. This study is closed to enrolment but patients' treatment and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT01136733. FINDINGS: Between March 16, 2012, and June 19, 2013, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged progression-free survival compared with everolimus alone (median 14·6 months [95% CI 5·9-20·1] vs 5·5 months [3·5-7·1]; hazard ratio [HR] 0·40, 95% CI 0·24-0·68; p=0·0005), but not compared with lenvatinib alone (7·4 months [95% CI 5·6-10·2]; HR 0·66, 95% CI 0·30-1·10; p=0·12). Single-agent lenvatinib significantly prolonged progression-free survival compared with everolimus alone (HR 0·61, 95% CI 0·38-0·98; p=0·048). Grade 3 and 4 events occurred in fewer patients allocated single-agent everolimus (25 [50%]) compared with those assigned lenvatinib alone (41 [79%]) or lenvatinib plus everolimus (36 [71%]). The most common grade 3 or 4 treatment-emergent adverse event in patients allocated lenvatinib plus everolimus was diarrhoea (ten [20%]), in those assigned single-agent lenvatinib it was proteinuria (ten [19%]), and in those assigned single-agent everolimus it was anaemia (six [12%]). Two deaths were deemed related to study drug, one cerebral haemorrhage in the lenvatinib plus everolimus group and one myocardial infarction with single-agent lenvatinib. INTERPRETATION: Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. Further study of lenvatinib is warranted in patients with metastatic renal cell carcinoma. FUNDING: Eisai Inc.

Evaluation of patients with metastatic renal cell carcinoma after failure of first-line treatment.

The approval and use of molecular targeted agents for the first-line treatment of metastatic renal cell carcinoma (mRCC) has substantially improved the clinical outcome of patients. Although eventually all patients progress, hopes have been renewed with the approval of everolimus for patients who progress on or after treatment with tyrosine kinase inhibitors. In order to improve the prognosis for these patients, it is imperative to understand the reasons why patients with mRCC fail on first-line treatment. Currently, progression is assessed on the basis of the Response Evaluation Criteria in Solid Tumors, but it is known that targeted agents tend to cause disease stabilization rather than a significant decrease in tumor mass. Therefore, it may be time to evaluate the need to incorporate additional diagnostic methods in the assessment of disease response. Equally important is the study of the factors that determine the success or failure of second-line therapy in order to increase the chances of delivering the most effective and personalized therapy possible. In this article, we review the evidence related to the evaluation of patients with mRCC who fail on first-line treatment with targeted agents, including the systems to assess response and progression, the prognostic factors, the prognostic models that have been created based on these factors, and what is known about predictive biomarkers of disease outcome.

Expert recommendations on the management of patients with metastatic castration-resistant prostate cancer who progress after CHAARTED or LATITUDE.

OBJECTIVE: Our aim was to provide practical recommendations on the management of patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after docetaxel plus androgen-deprivation therapy (ADT) or abiraterone plus ADT. METHODS: Systematic literature review (SLR), nominal group meeting, and Delphi process. A panel of 12 experts was established who defined the scope, users, and sections of the document. We performed an SLR in order to assess the efficacy and safety of available drugs in patients with mCRPC. Abstracts from the American Society of Oncology and European Society for Medical Oncology meetings were also examined. The results were discussed during an expert meeting in which 14 recommendations were generated. The level of agreement with the recommendations was also tested by 13 additional experts following the Delphi process. Recommendations were voted by means of scores ranging from 0 (total disagreement) to 10 (total agreement). We defined agreement when at least 70% of the experts voted ⩾7. Next, we assigned a level of evidence and grade to the recommendation using the Oxford Centre for Evidence-based Medicine Levels of Evidence, following which the final document was drafted. RESULTS: The literature search did not find any articles meeting the inclusion criteria. Finally, 13 out of 14 recommendations were accepted after two Delphi rounds (two were modified after the first round). They pertain to general and individual case-based treatment recommendations. CONCLUSIONS: In mCRPC patients who have progressed after docetaxel or abiraterone plus ADT in the metastatic hormone-sensitive prostate cancer setting, these recommendations may support treatment decision-making, due to the lack of evidence or other globally accepted sequencing algorithms.

Experience with Sunitinib in metastatic renal cell carcinoma (mRCC) patients: pooled analysis from 3 Spanish observational prospective studies.

BACKGROUND: A pivotal, randomized, phase III trial demonstrated a statistically significant superiority of sunitinib over interferon-α in metastatic renal cell carcinoma (mRCC) patients. OBJECTIVE: To evaluate the effectiveness and safety of sunitinib in patients with advanced or mRCC in routine clinical practice. METHODS: Retrospective pooled analysis of clinical data from three observational and prospective studies carried out between 2007 and 2011 in 33 Spanish hospitals. Tumor response, Progression-free survival (PFS) and overall survival (OS), and main sunitinib-related toxicities were registered. RESULTS: 224 patients were analyzed. Median PFS 10.6 months (95% CI: 9.02-12.25), median OS 21.9 months (95% CI: 17.2-26.6). Objective response rate (ORR) 43.8% (95% CI: 36.8-50.7). Median time to PR was 3.8 months (95% CI: 3.86-5.99) and to CR 8.2 months (95% CI: 4.75-9.77). The most common ≥ grade-3 AEs were asthenia/fatigue (18.7%), hand-foot syndrome (6.2%), hypertension (5.8%) and neutropenia (4.8%). Hand-foot syndrome, diarrhea and mucositis were confirmed as independent predictors for PFS and/or OS in a multivariate analysis (p < 0.05) Conclusions: Outcomes with sunitinib in daily clinical practice resemble those obtained in clinical trials. Long-term benefit with sunitinib is possible in advanced RCC patients but the appropriate management of toxicities is mandatory to enable patients to remain on treatment.

Novel potential predictive markers of sunitinib outcomes in long-term responders versus primary refractory patients with metastatic clear-cell renal cell carcinoma.

BACKGROUND: Several potential predictive markers of efficacy of targeted agents in patients with metastatic renal cell carcinoma (mRCC) have been identified. Interindividual heterogeneity warrants further investigation. PATIENTS AND METHODS: Multicenter, observational, retrospective study in patients with clear-cell mRCC treated with sunitinib. Patients were classified in two groups: long-term responders (LR) (progression-free survival (PFS)≥22 months and at least stable disease), and primary refractory (PR) (progressive disease within 3-months of sunitinib onset). Objectives were to compare baseline clinical factors in both populations and to correlate tumor expression of selected signaling pathways components with sunitinib PFS. RESULTS: 123 patients were analyzed (97 LR, 26 PR). In the LR cohort, overall response rate was 79% and median duration of best response was 30 months. Median PFS and overall survival were 43.2 (95% confidence intervals[CI]:37.2-49.3) and 63.5 months (95%CI:55.1-71.9), respectively. At baseline PR patients had a significantly lower proportion of nephrectomies, higher lactate dehydrogenase and platelets levels, lower hemoglobin, shorter time to and higher presence of metastases, and increased Fuhrman grade. Higher levels of HEYL, HEY and HES1 were observed in LR, although only HEYL discriminated populations significantly (AUC[ROC]=0.704; cut-off=34.85). Increased levels of hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p were also associated with prolonged survival. No statistical significant associations between hsa-miR-23b or hsa-miR-27b and the expression of c-Met were found. CONCLUSIONS: Certain mRCC patients treated with sunitinib achieve extremely long-term responses. Favorable baseline hematology values and longer time to metastasis may predict longer PFS. HEYL, hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p could be potentially used as biomarkers of sunitinib response.

Phase II clinical trial of PM00104 (Zalypsis(®)) in urothelial carcinoma patients progressing after first-line platinum-based regimen.

PURPOSE: This exploratory phase II clinical trial evaluated the antitumor activity, safety profile and pharmacokinetics of PM00104 (Zalypsis(®)) 3 mg/m(2) 1 h every 3-week intravenous infusion in patients with advanced and/or metastatic urothelial carcinoma progressing after first-line platinum-based chemotherapy. METHODS: The primary efficacy end point was the disease control rate (DCR), defined as the percentage of patients with confirmed objective response or progression-free at 3 months, according to the response evaluation criteria in solid tumors. RESULTS: In a first stage (n = 19 patients evaluable for efficacy), only one patient achieved DCR (stable disease as best response and progression-free survival of 3.1 months). According to the 2-stage design used, the primary efficacy objective was unmet, and therefore, the trial was finalized without opening the second stage. The most common adverse events related to PM00104 were fatigue, anorexia, nausea, troponin I increase and neutropenia, which were transient and manageable with dose modifications or administration delays. Mean PK results (Cmax = 48.57 µg/l and area under the curve (AUC) = 154.97 h µg/l) were similar to those observed in a previous phase I trial evaluating the same dose and schedule. Few troponin I concentrations were higher than 0.10 ng/ml, and none of them were related to parameters of PM00104 exposure such as AUC or Cmax. CONCLUSIONS: No recommendation is given for further evaluation of PM00104 as single-agent treatment of patients with pretreated advanced and/or metastatic urothelial carcinoma. No new safety signals were observed.

Expert opinion on chemotherapy use in castration-resistant prostate cancer progressing after docetaxel.

The term castration-resistant prostate cancer (CRPC) encompasses a wide variety of patients with different prognoses. The combination of docetaxel and prednisone is considered as the standard first-line chemotherapy. For years, patients progressing on docetaxel have been managed with second- and third-line hormone therapies, re-treatment with docetaxel, or combined mitoxantrone and prednisone. Recently published results of four studies using different drugs: cabazitaxel (CBZ), abiraterone (AA), enzalutamide (ENZ), and radium 223, showed an increased survival in such patients. In this article, authors make some considerations about criteria guiding the choice of a second-line chemotherapy after docetaxel in patients with metastatic CRPC, and propose an algorithm based on scientific evidence and consensus for rational use of cabazitaxel in this scenario.

Recommendations for the optimal management of early and advanced urothelial carcinoma.

The field of urothelial carcinoma has shown considerable advances in terms of diagnosis, staging, and treatment. The increasing knowledge of molecular pathways and genes involved in the occurrence of this tumor has encouraged the search for new, more effective and less toxic therapies, and has prompted the design and development of clinical trials. However, the speed at which results are published makes it difficult for clinicians to cover the vast amount of information available. Moreover, in clinical practice some gaps remain concerning treatment options for patients who have progressed after first-line cisplatin-based combinations, who cannot tolerate cisplatin-based chemotherapy, or who have received platinum-based neoadjuvant or adjuvant therapy, and thus cannot be offered this option on disease progression. The purpose of this review is to issue a series of recommendations on the optimal management of early and advanced urothelial carcinoma based on current evidence and the available updated guidelines.

Sorafenib in renal cell carcinoma.

Metastatic renal cell carcinoma is resistant to conventional treatment with chemotherapy. Recently the use of molecular-targeted therapies with multikinase inhibitors has been recommended as first-choice therapy because they inhibit cell proliferation and tumour angiogenesis. Sorafenib is a well tolerated tyrosine kinase inhibitor that initially demonstrated efficacy in the treatment of patients with metastatic RCC who progressed after immunotherapy. Expanded-access studies in Europe and North America showed the safety and efficacy of sorafenib in special populations such as elderly, renal failure and cerebral metastases, as well as patients with no prior therapy. No cross-resistance has been suggested in non-randomized trials when used in second line treatment after other targeted therapies. Ongoing clinical trials will better define the role of sorafenib in first and second line either as monotherapy or in combination, as well as the best strategies for the sequential use of this drug.

Drug-related pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus.

PURPOSE: Pneumonitis has occurred in patients treated with inhibitors of the mammalian target of rapamycin (mTOR). In a phase III study of patients with previously untreated, poor-prognosis, advanced renal cell carcinoma (ARCC), the mTOR inhibitor temsirolimus improved survival compared with interferon. We performed a retrospective, independent, blinded radiographic review of chest computed tomography (CT) images of patients in this study to characterize temsirolimus-related pneumonitis. PATIENTS AND METHODS: Patients were treated with intravenous temsirolimus 25 mg once weekly or subcutaneous interferon alfa 3 million units, with an increase to 18 million units, thrice weekly. Drug-related pneumonitis was identified based on sequential chest CT images, required every 8 weeks, showing changes consistent with pneumonitis and not pneumonia (infection) or disease progression as correlated with clinical data. Cumulative probability of drug-related pneumonitis was estimated using the Kaplan-Meier method. RESULTS: Eight (6%) of 138 and 52 (29%) of 178 evaluable patients on interferon and temsirolimus treatment, respectively, developed radiographically identified drug-related pneumonitis. Time to onset of pneumonitis was significantly shorter on the temsirolimus arm than on the interferon arm (log-rank P < .001). Estimated cumulative probability of pneumonitis at 8 and 16 weeks from first dose was 21% and 31%, respectively, on the temsirolimus arm and 6% and 8%, respectively, on the interferon arm. Respiratory symptoms were observed around time of onset of radiographically diagnosed temsirolimus-related pneumonitis in 16 (31%) of 52 patients. CONCLUSION: Patients with ARCC receiving temsirolimus should be monitored closely for development of pneumonitis, and their management should be altered if clinical symptoms appear.

[Allogeneic transplantation of peripheral blood hematopoietic stem-cells with low intensity conditioning for the treatment of a metastatic clear cell carcinoma. Preliminary results after two years of follow-up]. / Trasplante alogénico de células progenitoras hematopoyéticas de sangre periférica con acondicionamiento de baja intensidad como tratamiento del carcinoma de células claras metastásico. Resultados preliminares con dos alnos de seguimiento mínimo.

OBJECTIVES: To evaluate the toxicity and outcomes of the allogeneic transplantation of peripheral blood hematopoietic stem-cells with low intensity conditioning (mini-alo Bone Marrow transplantation-BMT) in metastatic renal cell carcinoma refractory to at least one line of systemic treatment. METHODS: From 30 patients submitted to the Sant Pau's Hospital for immunotherapy between 1/2001 and 1/2003, six patients finally underwent mini-alo BMT within a clinical trial. Conditioning: Fludarabine: 30 minute i.v. infusion of 13 mg/m2 on days -9, -8, -7, -6 and -5. Busulfan: 1 mg/kg (real weight) q 6 hours, PO on days -6, -5, and -4 (4 doses per day on days -6 and -5, and 2 doses only on day -4, total number of doses 10). RESULTS: Two patients achieved partial response, one patient stabilized disease, and two patients had progression on days +30 and +60. Therefore, 2/3 patients surviving more than six months achieved partial response. One patient died on day +30 after acute hepatic graft-versus-host disease. Complete chimerism was demonstrated in all patients. CONCLUSIONS: The mimni-alo BMT is feasible in patients with metastatic renal cell carcinoma and provides objective responses, although its efficacy should be confirmed by phase III clinical trials.

Trasplante alogénico de células progenitoras hematopoyéticas de sangre periférica con acondicionamiento de baja intensidad como tratamiento del carcinoma de células claras metastático. Resultados preliminares con dos años de seguimiento mínimo / Allogeneic transplantation of peripheral blood hematopoietic stem-cells with low intensity conditioning for the treatment of a metastatic clear cell carcinoma. Preliminary results after two years of follow-up

OBJETIVO: Evaluar la toxicidad y resultadosde transplante alogénico de células progenitoras hematopoyéticascon intensidad reducida (mini-alo TMO) en carcinoma renal metastásico refractario al menos a 1 línea de tratamiento sistémico.MÉTODOS: De 30 pacientes remitidos al Hospital de Sant Pau para inmunoterapia entre I/2001 y I/2003, 6 pacientes fueron finalmente sometidos a mini-alo TMO en régimen de ensayo. Acondicionamiento: Fludarabina:30 mg/m2 en los días -9, -8, -7, -6 y -5 en infusión IV de 30 minutos. Busulfán: 1 mg/kg (peso real) cada 6 horas v.o. los días -6, -5 y -4 (4 dosis al día -6 y -5 y sólo 2 dosis el -4, 10 dosis en total).RESULTADOS: Dos pacientes alcanzaron una RP, un pacienteuna EE y dos pacientes progresaron a +30 y +60. Por tanto, 2 de los 3 pacientes que sobrevivieron más de 6 meses alcanzaron una RP. Un paciente fallecióal día +30 por enfermedad injerto contra huésped aguda hepática. Se demostró un quimerismo completo en todos los pacientes.CONCLUSIÓN: El mini-alo TMO es factible en pacientescon carcinoma renal metastásico y proporciona respuestasobjetivas, si bien su eficacia debería confirmarseen ensayos fase III

OBJECTIVES: To evaluate the toxicity and outcomes of the allogeneic transplantation of peripheral blood hematopoietic stem-cells with low intensityconditioning (mini-alo Bone Marrow transplantation-BMT) in metastatic renal cell carcinoma refractory to at least one line of systemic treatment.METHODS: From 30 patients submitted to the Sant Pau`s Hospital for immunotherapy between 1/2001 and 1/2003, six patients finally underwent mini-alo BMT within a clinical trial. Conditioning: Fludarabine: 30 minute IV infusion of 13 mg/m2 on days - 9, - 8, - 7, - 6 and - 5. Busulfan: 1 mg/kg (real weight) q 6 hours, PO on days - 6, -5, and - 4 (4 doses per day on days - 6 and - 5, and 2 doses only on day - 4, total number of doses 10).RESULTS: Two patients achieved partial response, one patient stabilized disease, and two patients hadprogression on days + 30 and + 60. Therefore, 2/3 patients surviving more than six months achieved partial response. One patient died on day + 30 after acute hepatic graft-versus-host disease. Complete chimerism was demonstrated in all patients.CONCLUSIONS: The mimni-alo BMT is feasible inpatients with metastatic renal cell carcinoma and provides objective responses, although its efficacy should beconfirmed by phase III clinical trials