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Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Abstract Preventing the ototoxicity caused by cisplatin is a major issue yet to be overcome. Useful preventive treatments will soon be available. Consequently, the next step is to filter out those patients who are more prone to develop ototoxicity. The aim of this study was to prospectively evaluate potential predictive markers of acute ototoxicity as determined by measures of distortion product otoacoustic emissions (DPOAEs). A total of 118 patients from our previous DPOAE analysis were put under evaluation. Ototoxic cases were divided according to unilateral (n = 45) or bilateral (n = 23) involvement. The clinicopathological characteristics, hearing test results, germline GSTT1, GSTM1, and GSTP1 polymorphisms, and common laboratory parameters were included in the new analysis. Univariate and multivariate statistical tests were applied. According to multivariate logistic regression, the only independent predictor of unilateral ototoxicity (vs. non-affected) was a GSTM1 null genotype (OR = 4.52; 95%CI = 1.3–16.3), while for bilateral damage, the GSTT1 null genotype (OR = 4.76; 1.4–16) was a predictor. The higher starting serum urea level was characteristic of bilateral ototoxicity; however, the only independent marker of bilateral (vs. unilateral) ototoxicity was the presence of GSTT1 null genotype (OR = 2.44; 1.23–4.85). Different processes, involving the GSTM1 and GSTT1 genotypes, respectively, govern the development of acute unilateral and bilateral ototoxicities. Further research is needed to clarify these processes. Based on the above findings, patients whom are at risk may be selected for otoprotective therapies. Key messages The acute ototoxicity was determined by DPOAE in 118 testicular cancer patients. GSTM1 null was the only marker of unilateral ototoxicity (vs. non-affected). The only marker of bilateral hearing loss (vs. non-affected) was the GSTT1 null. GSTT1 null was also the marker of bilateral vs. unilateral ototoxicity. A high-risk group may be selected for new, individualized otoprotective treatment.

Background Targeted therapies significantly improve clinical outcomes among patients with metastatic renal cell carcinoma (mRCC). Several new agents have been approved for first- and second-line use. However, there is a lack of compelling evidence comparing sequencing strategies, and available comparative data regarding the real-world effectiveness of different therapeutic sequences are limited. Materials and Methods We identified mRCC patients who initiated targeted therapy between January 1, 2008 and May 31, 2017 from the National Health Insurance Fund (NHIF) database of Hungary. Overall survival (OS) and duration of first-line treatment (DFT) were obtained for patients receiving sunitinib-everolimus, sunitinib-axitinib, or pazopanib-everolimus treatment sequences. OS of sunitinib-everolimus and sunitinib-axitinib sequences was also determined for patients having better or worse response to sunitinib first-line therapy. Results Median OS was significantly longer among patients treated with sunitinib-axitinib compared to those receiving sunitinib-everolimus. Median DFT was also significantly longer in the sunitinib-axitinib vs. sunitinib-everolimus group. Sunitinib-axitinib was associated with significantly longer median OS compared to sunitinib-everolimus in patients with better response to first-line sunitinib in the pooled sunitinib population. In patients with worse response to sunitinib, sunitinib-axitinib was associated with a trend towards greater OS compared to sunitinib-everolimus, but the difference did not reach statistical significance. Conclusions In this nationwide database analysis, mRCC patients treated with the sunitinib-axitinib sequence had significantly longer OS compared to those receiving sunitinib-everolimus therapy. The OS benefits of second-line axitinib were consistent among patients with better response to sunitinib defined by DFT values.

Background Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonistplus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m 2 (60 mg/m 2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.Findings Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7.4 months (IQR 3.5-13.9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4.1 months [95% CI 3.3-4.8] vs 2.8 months [2.6-2.9]; HR 0.696 [95% CI 0.573-0.845]; p=0.0002). Median overall survival was 9.4 months (95% CI 7.9-11.4) in the ramucirumab group versus 7.9 months (7.0-9.3) in the placebo group (stratified HR 0.887 [95% CI 0.724-1.086]; p=0.25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.Interpretation Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

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.

Lessons Learned Background Endoglin is an angiogenic receptor expressed on proliferating tumor vessels and renal cell carcinoma (RCC) stem cells that is implicated as a mechanism of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors. This study evaluated an antiendoglin monoclonal antibody (carotuximab, TRC105) combined with axitinib in patients with advanced or metastatic clear cell renal cell carcinoma (mccRCC) who had progressed following one or more prior VEGF inhibitors. Methods TRAXAR was a multicenter, international randomized 1:1 (stratified by ECOG, 0 vs. 1), phase II study of carotuximab combined with axitinib versus axitinib alone in mccRCC patients who had progressed following one or more prior VEGF inhibitors. The primary endpoint was progression-free survival (PFS) assessed by independent central review (ICR) per RECIST 1.1 Results A total of 150 patients were randomized. The combination therapy resulted in shorter median PFS by RECIST 1.1 than axitinib monotherapy (6.7 vs. 11.4 months). The combination was tolerated similarly to axitinib monotherapy, and there were no treatment related deaths. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels. Conclusion The combination of carotuximab with axitinib did not demonstrate additional efficacy over single agent axitinib in patients with mccRCC who progressed following one or more prior VEGF inhibitor treatment.

Importance The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participants Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Results Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P

The objective of our study was to assess the real-world safety and efficacy of nivolumab in the second- or later-line treatment of metastatic renal cell carcinoma (mRCC). We conducted a multicenter, retrospective, observational study of real-world data from patients who were treated with nivolumab under a patient expanded access program from 2015 to 2017 in Croatia, Hungary, and Malta. The primary safety endpoint was the discontinuation of therapy because of adverse events. The primary efficacy endpoint was overall survival (OS). We collected data from 87 patients with a median (interquartile range (IQR)) age of 63 (57-68) years, and 21% were females. The median (IQR) follow-up was 11 (5-31) months. Treatment was discontinued because of toxicity in 4 (5%) patients. Four (5%) patients experienced treatment-related adverse events of grade 3 or 4. The OS was 18.0 (95% CI: 11.0 to 28.6) months, and the PFS was 8.5 (95% CI: 4.9 to 12.1) months. Our study indicated a good safety and efficacy profile of nivolumab in the second- or later-line treatment of mRCC patients in a real-world clinical practice environment, which is comparable with the findings of the registrational trial.

Background. There is a lack of real-world data on the safety and efficacy of nivolumab in patients with previously treated advanced non-small-cell lung cancer (NSCLC) especially in South East Europe, a region with particularly high incidence and an unfavorable mortality-to-incidence ratio for lung cancer. Objectives. To evaluate the real-world safety and efficacy of nivolumab in patients with previously treated advanced squamous and nonsquamous NSCLC in South East Europe. Methods. This is a multicenter, retrospective cohort study on patients with stage IIIB or IV disease with at least one previous systemic treatment who received nivolumab through an expanded-access program between 2015 and 2017 in Croatia, Malta, and Hungary. The primary endpoint was the proportion of patients whose therapy was discontinued because of toxicity. Secondary endpoints were the incidence of adverse events (AEs), objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results. We analyzed data on 239 patients with a median (IQR) age of 62 (57–68), and 33% of them were women. Treatment was discontinued because of toxicity in 11.6% (95% CI 7.8% to 16.5%) of patients. The PFS was 6.4 (95% CI 5.2 to 8.6) months, and the median OS was 14.1 (10.6 to 18.0) months. Conclusions. The safety and efficacy of nivolumab in previously treated patients with advanced NSCLC in the real-world South East Europe clinical settings were consistent with the results of randomized clinical trials and comparable to the results from other countries.

Real-world evidence from clinical practices is fundamental for understanding the efficacy and tolerability of medicinal products. Patients with renal cell cancer were studied to gain data not represented by analyses conducted on highly selected patients participating in clinical trials. Our goal was to retrospectively collect data from patients with advanced renal tumours treated with pazopanib (PZ) to investigate the efficacy, frequency of side effects, and searching for predictive markers. Eighty-one patients who had received PZ therapy as first-line treatment were retrospectively evaluated. Overall survival (OS), progression-free survival (PFS) were assessed as endpoints. Median PFS and OS were 11.8 months (95% CI: 8.8–22.4); and 30.2 months (95% CI: 20.3–41.7) respectively. Severe side effects were only encountered in 11 (14%) patients. The presence of liver metastasis shortened the median PFS (5.5 vs. 14.8 months, p = 0.003). Median PFS for patients with or without side effects was 25.6 vs. 7.3 months, respectively (p = 0.0001). Patients younger than 65 years had a median OS of 41.7 months vs. 25.2 months for those over 65 years of age (p = 0.008). According to our results absence of liver metastases, younger age (

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Abstract: The treatment of metastatic prostate cancer can be divided into two pathophysiological phases: hormone-sensitive and castration-resistant phases. Huggins’ observation in the year 1941, which was awarded with the Nobel Prize in 1966, has a key role in treatment during the hormone-sensitive phase, stating that if the testicles are removed, the size of the prostate cancer decreases. Inducing androgen deprivation, i.e., testosterone depletion is the basic treatment of metastatic prostate cancer that patients have to receive life-long. In the past eight years, five new agents have been approved besides docetaxel in the treatment of metastatic castration-resistant prostate cancer: sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, and radium-223. With the sequential application of these agents, significant improvement can be achieved in survival. Besides the latest developments, the hormone-sensitive phase has become the focus of attention, especially in the treatment of patients with de novo metastases and poor prognosis. Many studies have proven the outstanding efficacy of adding early docetaxel and abiraterone to androgen deprivation therapy. The authors give a detailed overview of clinical studies leading to a paradigm change in treatment during the hormone-sensitive phase, and call attention to the difficulties encountered in Hungarian practice. Orv Hetil. 2018; 159(41): 1664–1671.

Everolimus is indicated for adults with metastatic renal cell carcinoma (mRCC) after failure of vascular endothelial growth factor receptor-tyrosine kinase inhibitors (TKI). Currently, the therapeutic applicability of EVE has been changing. Multicenter evaluation of efficacy and safety of everolimus in daily routine and definition of patient characteristics with favorable outcome. Data of 165 patients from 9 oncology institutes in Hungary were analyzed retrospectively. Everolimus therapy was used after one TKI in 10 mg starting dose. Physical and laboratory examinations and imaging tests were performed monthly and every 3 months, respectively. Median progression-free survival (PFS) was 5.4 months. Median overall survival (OS) was 16.2 months. PFS and OS results were more favorable in patients with ECOG 0–1 (pPFS = 0.033, pOS = 0.008) and after >9 months of TKI therapy (pPFS = 0.019, pOS = 0.045). Survival was longer in nonanemic patients with ECOG 0–1 than in anemic patients with ECOG 2–3, 30.9 and 7.7 months, respectively (p = 0.029). Dose reduction and treatment delay was required in 6.2% and 8.9% of patients, respectively. Common adverse events were exanthema, edema, stomatitis, anemia, and abnormal kidney functions and glucose levels. Results of this study show that everolimus is safe and efficacious in a real-world setting. Everyday practice showed that nonanemic patients with good performance status receiving TKI therapy for >9 months are favorable candidates for this treatment. Despite the efficiency of novel, registered drugs, everolimus still plays an important role during and after second-line therapy for mRCC when availability of modern remedies is limited.

Purpose Cabazitaxel 25 mg/m2 (C25) significantly improved overall survival (OS) versus mitoxantrone ( P < .001) in postdocetaxel patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase III TROPIC study. The phase III PROSELICA study ( ClinicalTrials.gov identifier: NCT01308580) assessed the noninferiority of cabazitaxel 20 mg/m2 (C20) versus C25 in postdocetaxel patients with mCRPC. Methods Patients were stratified by Eastern Cooperative Oncology Group performance status, measurability of disease per Response Evaluation Criteria in Solid Tumors (RECIST), and region, and randomly assigned to receive C20 or C25. To claim noninferiority of C20 (maintenance of ≥ 50% of the OS benefit of C25 v mitoxantrone in TROPIC) with 95% confidence level, the upper boundary of the CI of the hazard ratio (HR) for C20 versus C25 could not exceed 1.214 under a one-sided 98.89% CI after interim analyses. Secondary end points included progression-free survival, prostate-specific antigen (PSA), tumor and pain responses and progression, health-related quality of life, and safety. Results Overall, 1,200 patients were randomly assigned (C20, n = 598; C25, n = 602). Baseline characteristics were similar in both arms. Median OS was 13.4 months for C20 and 14.5 months for C25 (HR, 1.024). The upper boundary of the HR CI was 1.184 (less than the 1.214 noninferiority margin). Significant differences were observed in favor of C25 for PSA response (C20, 29.5%; C25, 42.9%; nominal P < .001) and time to PSA progression (median: C20, 5.7 months; C25, 6.8 months; HR for C20 v C25, 1.195; 95% CI, 1.025 to 1.393). Health-related quality of life did not differ between cohorts. Rates of grade 3 or 4 treatment-emergent adverse events were 39.7% for C20 and 54.5% for C25. Conclusion The efficacy of cabazitaxel in postdocetaxel patients with mCRPC was confirmed. The noninferiority end point was met; C20 maintained ≥ 50% of the OS benefit of C25 versus mitoxantrone in TROPIC. Secondary efficacy end points favored C25. Fewer adverse events were observed with C20.

Abstract: Until the past decade, therapeutic options for unresectable and/or metastatic renal cell carcinoma were limited. Renal cell carcinoma is generally resistant to conventional chemotherapy, and only a small percentage of patients with renal cell carcinoma benefit from cytokine treatment. Since 2005, the advances in target-based therapy and immunotherapy modalities have created a paradigm shift in the treatment of renal cell carcinoma. Herein, we review the most up-to-date practices and emerging therapies for the treatment of renal cell carcinoma and focus on the threrapy caused side-effects and side-effect management. Orv Hetil. 2017; 158(38): 1488–1502.

PURPOSE Previous studies suggested that serum levels of microRNA (miR)-371a-3p (so-called M371 test) have a much higher sensitivity and specificity than the classic markers of testicular germ cell tumors (GCTs) and are applicable toward both seminoma and nonseminoma. We sought to confirm the usefulness of this test as a novel biomarker for GCT. PATIENTS AND METHODS In a prospective, multicentric study, serum samples of 616 patients with testicular GCTs and 258 male controls were examined for serum levels of miRNA-371a-3p (miR levels) by quantitative polymerase chain reaction. The GCT population encompassed 359 patients with seminoma and 257 with nonseminoma; 371 had clinical stage I disease, 201 had systemic disease, and 46 had relapses. Paired measurements before and after orchiectomy were performed in 424 patients; 118 with systemic disease had serial measurements during treatment. miR levels were compared with those of β-human chorionic gonadotropin, α-fetoprotein, and lactate dehydrogenase. RESULTS For the primary diagnosis of GCT, the M371 test showed a sensitivity of 90.1%, a specificity of 94.0%, an area under the curve of 0.966 upon receiver operating characteristic analysis, and a positive predictive value of 97.2%. α-Fetoprotein, β-human chorionic gonadotropin, and lactate dehydrogenase had sensitivities of less than 50% in seminoma and slightly higher sensitivities in nonseminomas. miR levels were significantly associated with clinical stage, primary tumor size, and response to treatment. Relapses had elevated miR levels that subsequently dropped to normal upon remission. Teratoma did not express miR-371a-3p. CONCLUSION The M371 test outperforms the classic markers of GCT with both a sensitivity and a specificity greater than 90%. All histologic subgroups, except teratoma, express this marker. The test could be considered for clinical implementation after further validation.

450 Background: 1L pembro is approved in advanced UC for cisplatin-ineligible pts with PD-L1 combined positive score (CPS) ≥10 and any platinum-ineligible pts regardless of CPS in the United States based on single-arm trial data. In the phase III KEYNOTE-361 study, 1L pembro + chemo did not statistically significantly improve PFS or OS vs chemo for pts with advanced UC; formal testing of 1L pembro vs chemo was not performed. We present an exploratory analysis of outcomes with pembro vs chemo for choice-of-carboplatin (carbo) pts in KEYNOTE-361 (NCT02853305). Methods: At randomization, choice of platinum agent (cisplatin or carbo) plus gemcitabine for each pt was selected based on investigator’s assessment of cisplatin ineligibility. ORR/DOR per RECIST v1.1 by blinded independent central review and OS were determined for all pts selected for carbo (“choice-of-carbo”) and also choice-of-carbo pts with CPS ≥10. Risk difference assessment for select AEs for pembro vs chemo was conducted in choice-of-carbo pts who received ≥1 dose study treatment. Results: As of Apr 29, 2020, the median (range) time from randomization to data cutoff in the full study cohort was 31.7 (22.0-42.3) mo. At randomization, renal impairment was the most common reason for choice of carbo by investigators (36% of all pts). 170 choice-of-carbo pts were randomized to the pembro arm, and 196 choice-of-carbo pts to the chemo arm. Median OS in this subgroup was 14.6 mo with pembro vs 12.3 mo with chemo (HR 0.83 [95% CI 0.65-1.06]). 18-mo OS rate was 42% with pembro vs 40% with chemo. ORR to pembro vs chemo was 27.6% vs 41.8%. Median (range) DOR with pembro vs chemo was not reached (NR) (3.2+-36.1+ mo) vs 6.3 (1.8+-33.8+) mo. 84/170 (49%) and 89/196 (45%) choice-of-carbo pts in the pembro and chemo arms, respectively, had CPS ≥10. In this subgroup, median OS was 15.6 mo with pembro vs 13.5 mo with chemo (HR 0.82 [95% CI 0.57-1.17]). 18-mo OS rate was 44% with pembro vs 43% with chemo. ORR to pembro vs chemo was 29.8% vs 46.1%. Median (range) DOR with pembro vs chemo was NR (4.2-36.1+ mo) vs 8.3 (2.1+-33.8+) mo. Among treated pts (N=166 for pembro, N=190 for chemo), 112 pts (68%) in the pembro arm and 163 pts (86%) in the chemo arm had grade 3-5 AEs of any cause. Pembro was associated with a higher risk of pruritus, while chemo was associated with a higher risk of decreased white blood cell, neutrophil, and platelet counts, nausea, thrombocytopenia, neutropenia, and anemia. Conclusions: Due to the trial design, this subset was not statistically tested and is exploratory. Median OS and 18-mo OS rates did not appear markedly different in the two arms; some parameters such as DOR favored pembro, although longer follow-up is needed to determine median DOR for pembro. The PD-L1 CPS ≥10 did not clearly enrich for responders to pembro in choice-of-carbo pts. Pembro was associated with a lower rate of grade 3-5 AEs of any cause than chemo. Clinical trial information: NCT02853305.

448 Background: 1L pembro + chemo did not show statistically superior PFS and OS vs chemo for pts with advanced UC in the phase III KEYNOTE-361 study; OS for pembro vs chemo was not formally tested. We analyzed PFS2 (time from randomization to progressive disease [PD] on first subsequent therapy, or death from any cause, whichever occurs first) by study treatment and subsequent therapy in KEYNOTE-361 (NCT02853305) to determine the effects, if any, of therapy sequence on PFS2. Methods: PFS2 was estimated for pts in each treatment arm, who received any subsequent therapy including any anti–PD-(L)1, any therapy other than anti–PD-(L)1, or no therapy. These were exploratory analyses; no formal comparisons were done. Results: 1010 pts were randomized: 351 pts to receive pembro + chemo, 307 to pembro, and 352 to chemo. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 31.7 (22.0-42.3) mo. Subsequent therapy was received by 124/351 (35%), 126/307 (41%), and 215/352 (61%) pts in the pembro + chemo, pembro, and chemo arms, respectively. Subsequent anti–PD-(L)1 therapy was received by 169/352 (48%) pts in the chemo arm vs 23/351 (7%) in the pembro + chemo arm and 14/307 (5%) in the pembro arm. Of pts in the pembro arm who received subsequent therapy, >90% received 2L cisplatin-based or carboplatin-based treatment. Median (m) PFS2 (95% CI) for all pts by treatment arm was 14.1 mo (12.6-16.2) with pembro + chemo, 10.9 mo (9.5-12.9) with pembro, and 10.4 mo (9.8-11.2) with chemo. Across treatment arms, pts in the pembro + chemo arm had the longest mPFS2 with any subsequent therapy (14.5 mo [95% CI 13.1-16.6]) (Table). Pts in the pembro arm who received no subsequent therapy had a longer mPFS2 (12.9 mo [95% CI 8.1-17.9]) vs pts in the chemo arm who received no subsequent therapy (9.4 mo [95% CI 7.6-10.6]). Finally, pts treated with 1L pembro in the trial followed by 2L therapy other than anti−PD-(L)1 had comparable mPFS2 (10.2 mo [95% CI 8.6-12.1]) to pts treated with 1L chemo in the trial followed by 2L anti−PD-(L)1 (11.1 mo [95% CI 10.2-12.9]). Conclusions: In this exploratory analysis, treatment sequence of chemo followed by anti−PD-(L)1 upon PD vs anti–PD-(L)1 followed by chemo upon PD did not appear to impact mPFS2. Among pts who did not receive 2L therapy, 1L pembro appeared to be associated with longer mPFS2 than chemo, potentially driven by long-term responders to pembro. Clinical trial information: NCT02853305 . [Table: see text]

439 Background: The phase III KEYNOTE-361 study examined the efficacy and safety of 1L pembro + chemo or pembro alone vs chemo for pts with advanced UC. The PFS and OS benefit of pembro + chemo vs chemo did not reach statistical significance; no further formal tesing was done. We present an exploratory analysis of OS by subsequent therapy in KEYNOTE-361 (NCT02853305) to assess how 1L and 2L therapy selection affected survival outcomes; no formal comparisons were conducted. Methods: OS was estimated for pts by whether they received subsequent therapy, and by whether subsequent therapy included an anti–PD-(L)1 agent. Results: 351 pts were randomized to pembro + chemo, 307 pts to pembro, and 352 pts to chemo. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 31.7 (22.0-42.3) mo. 124/351 pts (35%) in the pembro + chemo arm, 126/307 pts (41%) in the pembro arm, and 215/352 pts (61%) in the chemo arm received any subsequent therapy. Similar rates of subsequent therapy (pembro + chemo: 32%; pembro: 43%; chemo: 59%) were observed for pts who experienced progressive disease (PD) by blinded independent central review (BICR). A higher rate of pts (169/352 [48%]) in the chemo arm received subsequent anti–PD-(L)1 therapy than in either the pembro + chemo arm (23/351 [7%]) or pembro arm (14/307 [5%]). Due to the small pt numbers, pts in the pembro + chemo or pembro arms who received subsequent anti−PD-(L)1 were not considered further. This analysis included all pts who received 2L therapy (465/1010 pts [46%]); the rate of 2L therapy was similar in pts with PD by BICR (274/615 [45%]). Chemo agents alone or in combination, specifically carboplatin, cisplatin, docetaxel, doxorubicin, gemcitabine, and paclitaxel, were the most commonly received subsequent therapies for pts who did not receive anti–PD-(L)1 in 2L. Pts who received 1L chemo followed by subsequent anti–PD-(L)1 had longer mOS (19.1 mo [95% CI 16.2-22.2]) than pts with 1L pembro followed by 2L therapy not including an anti−PD-(L)1 agent (16.0 mo [95% CI 11.8-19.2]) (Table). Conclusions: In this exploratory analysis, favorable survival outcomes were observed for pts who received 1L chemo followed by anti–PD-(L)1 compared with pts who received 1L pembro followed by 2L therapy not including an anti–PD-(L)1 agent. These data underline the continued importance of immunotherapy as 2L therapy for advanced UC. Clinical trial information: NCT02853305 . Research Sponsor: Merck & Co., Inc[Table: see text]

435 Background: The phase III KEYNOTE-361 study compared efficacy and safety of 1L pembro + chemo or pembro vs chemo in pts with advanced UC. The trial did not meet its primary endpoints of PFS or OS superiority for pembro + chemo vs chemo; formal testing for OS for pembro vs chemo was not performed. We present a post hoc landmark analysis to examine the durability of CR/PR/SD and long-term survival in pts with CR, PR, or SD to pembro vs chemo at week 9 in KEYNOTE-361 (NCT02853305). Methods: Landmark analyses of OS by CR/PR/SD at 9 weeks after randomization in the ITT population were performed. Pts were included if they had a best response of CR/PR/SD per RECIST v1.1 by blinded independent central review at the landmark date of week 9 (first imaging assessment per study protocol). Duration of CR/PR/SD and OS were estimated by the Kaplan-Meier method. No formal comparisons were performed. Results: 307 pts were randomized to receive pembro and 352 pts to receive chemo in the KEYNOTE-361 study. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 32.5 (22.0-42.4) mo for the pembo arm and 31.4 (22.1-41.6) mo for the chemo arm. In the landmark analysis, fewer pts had CR/PR/SD at week 9 with pembro (n=137 [45%]) than with chemo (n=253 [72%]). Median (range) duration of response for pembro vs chemo was 18.7 (4.4+-35.4+) vs 12.3 (0.0+-29.7+) mo for pts with CR, and 35.0 (1.1-36.1+) vs 6.1 (0.0+-36.3+) mo for pts with PR. Median (range) duration of SD was 4.8 mo (0.0-38.2+) with pembro and 4.6 mo (0.0-16.1+) with chemo. Median OS (95% CI) for pembro vs chemo was not reached (NR) (25.5-NR) vs NR (19.1-NR) for pts with CR; NR (NR-NR) vs 14.8 mo (12.1-21.0) for pts with PR; and 18.5 mo (13.8-28.8) vs 11.1 mo (8.1-14.6) for pts with SD, respectively. Long-term OS rates were higher with pembro vs chemo across all groups (CR/PR/SD) at week 9 (Table). Conclusions: In this post hoc landmark analysis, chemo was associated with more initial responses than pembro, whereas pembro was associated with longer median duration of CR and PR, and generally longer median OS than chemo. Among pts who achieved CR/PR/SD at week 9, the relative OS benefit for pembro vs chemo increased over time. Clinical trial information: NCT02853305. [Table: see text]

The aim was to assess the relationship between treatment efficacy and adverse events (AEs) for patients with advanced renal cell carcinoma treated with first-line sunitinib.274 patients were treated with sunitinib (50 mg/d, 4-weeks-on and 2-weeks-off schedule). Physical and laboratory evaluations were done every sixth week. AEs were diagnosed at every visit. Clinical response was assessed every 3 months. The objective response rate (ORR), median progression-free (mPFS) and median overall survival (mOS) and AEs were evaluated. Besides χ(2) and log rank tests, multivariate Cox regression analysis and for synergism 1-sided t tests were used.The ORR was 25%. After a median follow-up of 32 months, the mPFS and mOS were 9 and 19 months, respectively. Hypertension, diarrhea, hypothyroidism, mucositis, hand-foot syndrome (HFS), skin toxicity, and leukopenia were the most frequent treatment-associated AEs. Significantly longer (P .01) mPFS and mOS were observed when hypertension, diarrhea, HFS, hypothyroidism, skin toxicity, or leukopenia occurred. A statistically significant synergistic effect of the listed AEs was observed for progression-free survival (P .001) and overall survival (P .001). Multivariate analysis revealed that besides the prognostic category, the higher number of AEs (3-6 vs. 0-2) was an independent marker of longer mPFS (24 vs. 5 months, respectively; P .001) and mOS (51 vs. 9 months, respectively; P .001).Results of this study provide evidence for the synergistically enhanced efficacy of sunitinib treatment in patients who present multiple AEs. These AEs are diagnosed routinely and their coexistence can help physicians to predict which group of patients would benefit the most from first-line sunitinib treatment.

TPS268 Background: Docetaxel IV and prednisone is a standard of care in mCRPC with demonstrated overall survival benefit. ModraDoc006 is a novel oral tablet formulation of docetaxel and to enhance bioavailability, it is co-administered with ritonavir (/r), an inhibitor of cytochrome p450 3A4 and P-glycoprotein. The oral combination, denoted as ModraDoc006/r, could be preferable due to patient convenience and elimination of infusion reactions and prophylactic steroids administration. Due to its weekly administration and exposure levels, increased efficacy may be demonstrated. Methods: The study is an open label 1:1 randomized phase 2b trial of ModraDoc006/r bi-daily QW versus docetaxel IV 75 mg/m2 Q3W. Thirty (30) mg ModraDoc006 combined with 200 mg /r in morning and 20 mg ModraDoc006 with 100 mg /r in evening is administered on days 1, 8 and 15 of a 21 day cycle. Safety and preliminary efficacy of ModraDoc006/r have been established in a phase Ib trial in mCRPC pts. All patients will receive 5 mg oral prednisone twice daily. Treatment is continued until progression, unacceptable toxicity or patient wish. mCRPC pts with measurable disease per RECIST 1.1, suitable for docetaxel therapy, are eligible. No prior treatment with taxanes is allowed. Primary objective is objective response rate (ORR) as assessed by investigators. Secondary objectives include PSA response, PSA-PFS, time to skeletal related events and progression, duration of response, disease control rate and safety assessments. Patient reported outcomes and health-related quality of life will be captured with treatment satisfaction and FACT-P questionnaires. It is expected that ModraDoc006/r will be at least as effective as docetaxel IV. A sample size of 50 evaluable pts per arm will evaluate an estimated ORR of 25% in each arm, with a 5% two-sided alpha and power of 83.7%. Conclusions: ModraDoc006/r represents an advance in prostate cancer therapeutics with convenience of oral administration, reduced myelosuppressive toxicity and potential improved efficacy over IV docetaxel. Clinical trial information: NCT04028388.

Our study aimed to analyze the potential association between clinical parameters and ERG expression and the outcome of docetaxel chemotherapy among patients with metastatic hormone-sensitive prostate cancer.Fifty-five patients with metastatic hormone-sensitive prostate cancer were treated with docetaxel in addition to androgen deprivation therapy. Patient characteristics, clinical factors, and tumor expression of ERG by immunohistochemistry were analyzed with respect to therapeutic response and survival data.Relapse free survival (RFS) and overal survival (OS) were 10.5 and 40.4 months, respectively, and both correlated with PSA response (RFS: 16.8 with a ≥50% decrease in PSA vs. 5.9 months in the case of50% decrease, P0.001; OS: 40.4 vs. 11.6 months, respectively, P0.001). There was an association between OS and early progression (OS: 40.4 months with progression after 12 months vs. 17.9 months with progression within 12 months, P = 0.009). ERG expression was detected in 21 (42%) samples. ERG positivity was associated with favorable RFS (ERG pos. vs. neg.: 26.0 vs. 11.4 months, P = 0.003).ERG expression may have a potential predictive value with respect to the effectiveness and outcome of docetaxel chemotherapy combined with androgen deprivation therapy.

Introduction Oral mucositis is a frequent complication of cancer chemotherapy and radiotherapy. Ectoine is a natural extremolyte that can stabilize biological membranes and counteract inflammatory reactions. This study investigated ectoine-containing mouthwash for the prophylaxis and the treatment of oral mucositis. Its effectiveness, tolerability, and safety were compared to those of the local standard-of-care calcium phosphate mouthwash. Methods This prospective, active-controlled, observational study was conducted in two study centers in Hungary from January 2016 to October 2017. Sixty patients undergoing chemotherapy were to be recruited and allocated to one of three treatment arms: prophylactic treatment with ectoine (20 patients), active treatment with ectoine (20 patients), or calcium phosphate (20 patients). The study lasted 21 days, comprising four visits on day 0, day 7, day 14, and day 21. Results In all, 45 patients were included in the study (prophylactic ectoine, 10 patients; active ectoine, 20 patients; calcium phosphate, 15 patients). In the prophylactic ectoine group, few mucositis symptoms of mild or moderate severity occurred throughout the study. In the active ectoine and the calcium phosphate groups, symptoms of mild and moderate severity at inclusion were reduced significantly after 14 days of treatment and were mostly resolved at the end of the study. The difference between the active ectoine and the calcium phosphate groups was not significant. According to patients’ assessments, ectoine mouthwash was more effective and tolerable than calcium phosphate mouthwash. Conclusions Ectoine mouthwash is safe, well tolerated, and effective for the active treatment of oral mucositis following chemotherapy. Its effectiveness is comparable to that of calcium phosphate. Patients prefer ectoine mouthwash to calcium phosphate mouthwash. Trial Registration Number NCT02816515. Funding Bitop AG (Dortmund, Germany). Plain Language Summary Plain language summary available for this article. Electronic supplementary material The online version of this article (10.1007/s40487-018-0060-z) contains supplementary material, which is available to authorized users., Plain Language Summary Oral mucositis is the inflammation of the mucosa of the oral cavity. It is a frequent complication of cancer chemotherapy and radiotherapy. Approximately 20–40% of patients undergoing chemotherapy suffer from oral mucositis. It is very painful, impairs eating, drinking, and quality of life. One of the most effective yet simple measures to prevent and treat oral mucositis is oral care with mouthwash. Ectoine is a natural substance that was discovered in halophilic (salt-loving) bacteria. Ectoine can protect these bacteria against dehydration because it can attract water molecules and strengthen biological membranes. Ectoine is used to treat many diseases caused by allergens, UV light, air pollution, heat, and dryness. Ectoine (Ectoin®) mouthwash is produced by bitop AG (Dortmund, Germany) to treat dry mouth and other symptoms of inflamed oral mucosa. This study investigated ectoine mouthwash for the treatment of oral mucositis following chemotherapy. It was compared to the local standard-of-care calcium phosphate mouthwash. One group of patients was treated with ectoine mouthwash and the other with calcium phosphate mouthwash. After 14 days, mucositis symptoms were substantially reduced in both groups. After 21 days, all patients were almost cured of oral mucositis. Additionally, after the treatment, patients rated how effective and tolerable the treatment was. Here, more patients treated with ectoine rated their treatment as effective and tolerable than those treated with calcium phosphate. This study shows that ectoine mouthwash is tolerable and effective for the treatment of mucositis. Patients preferred ectoine mouthwash to calcium phosphate mouthwash. Electronic supplementary material The online version of this article (10.1007/s40487-018-0060-z) contains supplementary material, which is available to authorized users.

Background Endoglin is an essential angiogenic receptor expressed on proliferating tumor vessels and RCC stem cells that is implicated as a mechanism of VEGF resistance. TRC105 is an endoglin monoclonal antibody that potentiates the anti-tumor activity of VEGF inhibitors in preclinical models and demonstrated a 29% RECIST response rate when combined with AX in patients with mRCC in a Phase 1b trial. Methods TRAXAR was a multicenter, randomized 1:1 (stratified by ECOG, 0 vs. 1), Phase 2 study of TRAX vs AX in patients with mRCC who had progressed following one prior VEGF inhibitor at 33 centers in the US and EU. The primary endpoint was progression-free survival (PFS) assessed by RECIST by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), and safety. PFS and ORR were also assessed by Investigator review (INV) and according to Choi criteria (CC). Results Of 150 pts (TRAX, 75; AX, 75), 106 (71%) were male, 142 (95%) were white; median age was 64 years (range, 38-82). Treatment with TRAX did not prolong PFS compared to AX. ORR was not different based on IRC, INV or CC (Table). Most all-grade common adverse events (AEs) in TRAX vs AX: headache (65.8% vs. 16.2%), epistaxis (63.0% vs. 8.1%), and diarrhea (60.3% vs. 59.5%); most common serious AEs included: anemia (6.9% vs. 1.4%) and dehydration (4.1% vs. 0%). Table . 912PD IRC INV CC TRAX AX TRAX AX TRAX AX Median PFS, mo (95% CI) 6.7 (5.6-13.1) 11.4 (5.8-NE) 7.2 (5.5-9.1) 7.4 (5.5-12.8) 7.2 (5.6-9.4) 7.5 (5.6-20.3) HR (95% CI) p-value 1.42 (0.88-2.30) 0.15 1.41 (0.95-2.10) 0.09 1.30 (0.83-2.03) 0.26 ORR, % 33.8 32.9 34.8 30.6 66.2 67.1 Odds ratio (95% CI) p-value 1.04 (0.50-2.15) 0.92 1.19 (0.58-2.44) 0.63 0.96 (0.47-1.96) 0.91 NE: not estimable; CI: confidence interval; mo: months Conclusions TRC105 did not demonstrate activity when combined with AX in patients with mRCC who had received prior VEGF inhibitor treatment, whether assessed using RECIST or Choi criteria. TRAX was generally well tolerated in pts with advanced or metastatic RCC. Clinical trial identification NCT01806064. Legal entity responsible for the study TRACON Pharmaceuticals. Funding TRACON Pharmaceuticals. Disclosure T.K. Choueiri: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: TRACON; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Cerulean; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Foundation Medicine; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Genentech; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Roche Products Limited; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): GSM; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Peloton; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Prometheus; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Corvus; Honoraria (institution): Calithera. R.K. Pachynski: Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy: Jounce Therapeutics; Speaker Bureau / Expert testimony: Dendreon; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Genentech/Roche; Speaker Bureau / Expert testimony: Genomic Health; Advisory / Consultancy: Bayer. Y. Zakharia: Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Jansen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Castle Bioscience; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Array. T.H. Ho: Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: ipensenlivemeetings; Advisory / Consultancy: cardinal health; Advisory / Consultancy: Exelixis. B.E. Simpson: Shareholder / Stockholder / Stock options, Full / Part-time employment: TRACON Pharmaceuticals. B. Adams: Shareholder / Stockholder / Stock options, Full / Part-time employment: TRACON. L. Robertson: Shareholder / Stockholder / Stock options, Full / Part-time employment: TRACON. M. Darif: Advisory / Consultancy: TRACON. C. Theuer: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: TRACON. N. Agarwal: Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Argos; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Exelixis; Advisory / Consultancy: EMD Serono; Advisory / Consultancy, Research grant / Funding (self): Ely Lilly; Advisory / Consultancy: Foundation One; Advisory / Consultancy: Genentech; Advisory / Consultancy, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy: Medivation; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy: Nektar; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy: Pharmacyclics; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (self): TRACON. All other authors have declared no conflicts of interest.

In practice it is still not clear whether a drug holiday in sunitinib (Su) treatment can be safety, without impairing the overall outcome of patients with metastatic renal cell carcinoma (mRCC). The aim was to retrospectively evaluate the outcome in patients who restarted Su after an interruption of ≥3 months and a combined analysis of case studies from literature. From 556 patients treated between January 2006 and March 2016 a group of 38 patients were selected whose treatment was interrupted for other reasons than disease progression. During interruption Su was restarted in case of RECIST-defined progression. The primary objective was the objective response (OR) and progression free survival (PFS) of baseline and restarted therapy. The secondary objective was the overall survival (OS) calculated from the start of baseline treatment. Multivariate survival analysis was also applied. The major causes of interruption were toxicity (39%) and patient’ choice (24%). Median duration of interruption was 7 (range 3–41) months. The OR of baseline and restarted treatment was 63% and 39%, respectively. After a median follow-up of 76 (95% CI 65–79) months the median PFS of baseline and restarted treatment was 21 (18–27) and 14 (10–18) months, respectively. The median OS was 61 (56–80) months. In multivariate analysis the lack of OR of restated treatment was an independent predictor of shorter PFS of restarted Su. According to our findings and also on combined case studies from literature restarted Su can be effective in selected cases of patients who progressed during treatment holiday.

Testicular germ cell cancers are relatively rare with the incidence rate of 3.7 cases per 100,000 per year. Nevertheless they represent the most frequent malignant tumors in men aged 15–35 years. Pure choriocarcinoma comprises only 1 % of all testicular malignancies, but mixed germ cell cancers contain choriocarcinoma elements more frequently. Unlike other histological subtypes , chor iocarc inoma metas tas ize ear ly and hematogenously, so it is often diagnosed in advanced stage [1]. Metastatic, choriocarcinoma containing germ cell cancers can be complicated by serious bleeding from metastatic sites known as the choriocarcinoma syndrome [2].

4519 Background: Atezo, a monoclonal antibody targeting PD-L1, is an approved therapy for locally advanced/metastatic UC based on IMvigor210 and IMvigor211 phase II and III trials. The single-arm SAUL study (NCT02928406) with a broader patient (pt) population demonstrated median overall survival (OS) of 8.7 months and a safety profile consistent with previous atezo trials. Methods: Pts with locally advanced/metastatic UC or non-UC of the urinary tract received atezo 1200 mg every 3 weeks until disease progression or unacceptable toxicity. Populations excluded from IMvigor211 (renal impairment, ECOG PS 2, treated asymptomatic CNS metastases, stable controlled autoimmune disease, concomitant steroids, HIV positive, non-UC) were eligible. The primary endpoint was safety; OS and overall response rate (ORR) were secondary endpoints. Predefined subgroup analyses included outcomes according to PD-L1 status (VENTANA SP142) and age in the overall population (and the IMvigor211-like subgroup for PD-L1). Results: Between Nov 2016 and Mar 2018, 1004 pts were enrolled; 997 received atezo. Efficacy is summarized below. Incidences of grade ≥3 treatment-related adverse events were similar irrespective of PD-L1 status (overall IC 0/1 vs 2/3: 11% vs 16%; IMvigor211-like IC 0/1 vs 2/3: 11% vs 15%) or age (≥65 y: 13%; ≥75 y: 12%; ≥80 y: 10%). Conclusions: OS and ORR appear more favorable in IC 2/3 vs IC 0/1 subgroups (overall and in the IMvigor211-like population). Atezo was effective and well tolerated across subgroups including elderly pts. Clinical trial information: NCT02928406. [Table: see text]

Lung cancer is the leading cause of cancer related mortality all over the world, and a number of developments have indicated future clinical benefit recently. The development of molecular pathology methods has become increasingly important in the prediction of chemotherapy sensitivity and mutation analysis to identify driver mutations as important targets of new therapeutic agents. The most significant changes in the treatment of NSCLC revealed in new pathologic classification and in the introduction of molecularly targeted therapies, which include monoclonal antibodies and small molecule tyrosine kinase inhibitors. The side effects of these agents are generally better tolerated than those of conventional chemotherapy and show higher efficacy. The most important factor follows: histology subtypes, gene mutation status, patients’ selection, drug toxicities and occurence of drug resistance. In the advanced disease, the hope of cure is less than 3 %, but improvements in survival have been clearly achieved. Some years ago the median lung cancer survival rate was 10–12 months, now in case of available specific molecular targets, a significant increase in median survival rates to 24–36 months has been achieved. These agents give an opportunity to provide a new standard of care. Therefore testing EGFR mutations and ALK rearrangements in patients with advanced lung adenocarcinoma should be incorporated into routine clinical practice. This review focuses on the rationale for targeted agents and new treatment possibilities in case of advanced lung adenocarcinoma.

Radium-223 dichloride is an alpha-emitting radiopharmaceutical which significantly prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases. This was a retrospective analysis of the efficacy and safety of Radium-223 in the first 41 patients treated at a single center in Hungary. Radium-223 was given at a dose of 50 kBq/kg intravenously every 4 weeks for up to 6 cycles. Between 23rd July 2014 and 23rd February 2016, 41 patients were treated. Patient demographics, laboratory values, treatment outcomes and adverse events were collected from medical records. The mean age was 72.2 years (SD: 7.1). 24 patients received Radium-223 as first-line treatment (58%), 7 patients as second (17%), 3 as third (7.3%), 6 as (14.6%), and 1 as fifth-line therapy (2.4%). The mean number of cycles administered was 5.5 (SD: 1.1). The most common side effects were anemia (32% grade 1–3), nausea (28%, grade 1), diarrhea (4%, grade 2), thrombocytopenia (4%, grade 3). The mean baseline PSA level was 307.2 ng/ml (SD: 525.7), which increased to a mean value of 728.5 ng/ml (SD: 1277) by the end of treatment. The baseline mean ALP of 521.1 U/L (SD: 728) decreased to 245.1 U/L (SD: 283.5). The majority of patients experienced a decrease (37%) or complete cessation (43%) of bone pain intensity. In our symptomatic prostate cancer patient population, Radium-223 proved to be efficient in terms of pain relief, with moderate side effects. No PSA response was detected, while alkaline phosphatase levels significantly decreased.

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.

To investigate the overall survival (OS) of chemotherapy refractory patients with metastatic castration-resistant prostate cancer who were treated with abiraterone acetate + prednisolone (AA + P) beyond prostate specific antigen (PSA) and radiographic progression (PRP) until clinical progression in comparison to patients treated until PRP.At our institute the AA + P treatment started in 2011 in an early-access protocol trial. In October 2012 AA became generally available. From April 2011 to November 2014, 116 patients received AA + P. The clinical trial patients (T; n = 56) were treated beyond PRP until clinical progression. In the nonclinical trial group (NT; n = 57) the treatment was covered until PRP. Three patients are still under treatment. The 2 groups were statistically homogeneous, except AA + P treatment duration. The primary objective was the OS and the secondary the PSA progression-free and radiographic progression-free survivals.The median OS was significantly longer (P0.0001) in the T group compared to the NT group: 21.9 (95% CI: 16.9-25) vs. 12.5 (9.3-14.1) months, respectively. In univariate analysis there were 11 parameters, which significantly affected OS, but in multivariate Cox analysis only alkaline phosphatase (AP) level at the start of treatment, systemic therapy after AA + P and cohort type (T or NT) proved to independently influence the OS. The progression-free survival curves of T and NT groups did not differ significantly.In our retrospective analysis low levels of AP at the start of treatment, systemic therapy applied after AA + P and treatment beyond PRP proved to be independent factors of longer OS in metastatic castration-resistant prostate cancer.

Lung cancer is a heterogeneous group of disease and mutational profiling of lung adenocarcinomas is a routine practice in thoracic oncology. Kirsten-RAS (KRAS) and EGFR mutations play an important role in the carcinogenesis of a subset of lung adenocarcinomas. Our aim was to investigate the correlation between bone metastases and EGFR and KRAS mutation status in lung adenocarcinoma patients. Retrospectively we analysed 224 patients with recurrent or metastatic lung adenocarcinomas. Patients were treated with standard chemotherapy as first line therapy and with EGFR-TK inhibitors as a second or third line therapy. 72 of 224 patients (32 %) had verified bone metastases. Bone metastases and Skeletal Related Events (SRE) were more frequent in men, heavy smokers and without treatment of EGFR TK inhibitors. We have found that EGFR and KRAS mutation status are both predictive factors for the treatment efficacy and prognostic factors for the disease progression. However there were no significant correlation between mutation status and the presence of bone metastases (P = 0, 59). In our study the presence of bone metastases proved to be an independent prognostic factor related to poor performance status and worse Quality of Life (QL).

Международное открытое исследование расширенного доступа предусматривало лечение сунитинибом пациентов с метастатическим почечно-клеточным раком (мПКР) в период с 2005 по 2011 г. в рамках программы благотворительно-исследовательского применения. В данном ретроспективном анализе оценены исходы терапии у пациентов из стран Центральной и Восточной Европы (ЦВЕ), участвующих в международном открытом исследовании расширенного доступа. Сунитиниб (начальная доза 50 мг 1 раз в день перорально, со снижением дозы в случае развития токсичности) назначался в виде повторных 6-недельных циклов (4 нед лечения и 2 нед перерыв) до прогрессирования заболевания или развития неприемлемой токсичности. Оценку опухолевых очагов выполняли на основании критериев RECIST (Критерии оценки ответа при солидных опухолях) в соответствии с местными стандартами лечения. В общей сложности 401 пациент стран ЦВЕ получил лечение сунитинибом (медиана длительности лечения 9,6 мес), из которых у 378 оценивали ответ опухоли на терапию. Наиболее частыми нежелательными явлениями III степени тяжести и выше были утомляемость (7,5 %), артериальная гипертензия (7,0 %), тромбоцитопения (6,5 %), диарея (4,2 %), тошнота (3,7 %), ладонно-подошвенный синдром (3,7 %) и нейтропения (3,0 %). Медиана общей выживаемости составила 30,7 мес (95 % доверительный интервал (ДИ) 23,3… мес). Общая выживаемость, как правило, была выше у пациентов без предшествующей терапии цитокинами по сравнению с пациентами, получавшими цитокины в первой линии (медиана 60,8 мес против 27,5 мес; p = 0,1324). Среди пациентов, у которых оценивали ответ опухоли на терапию, 4,0 % достигли полного и 14,6 % частичного ответа (частота объективного ответа 18,5 % (95 % ДИ 14,7-22,8)). Медиана выживаемости без прогрессирования составила 11,6 мес (95 % ДИ 10,3-12,8). В условиях релаьной клинической практики Сунитиниб продемонстрировал эффективность и безопасность у больных мПКР в странах ЦВЕ. В рамках программы расширенного доступа регистрировалась более низкая частота ответа опухоли на терапию, однако результаты выживаемости были сопоставимы с данными показателями, полученными для сунитиниба в клиническом исследовании III фазы при мПКР.

Objective: The characteristics and risk factors of the long-term ototoxic effect of cisplatin in testicular cancer patients was studied by measuring distortion product otoacoustic emissions (DPOAEs), which is a highly sensitive, new method for detecting high-frequency hearing loss. Methods: 223 patients with a median follow-up time of 4.27 years (range 0.5–20 years) and a median age of 37 years (range 18–55 years) were assessed by DPOAE. 100 mg/m2 cisplatin were administered per cycle, in EP, BEP, VeIP, VIP or VPB regimens. The control group consisted of 40 testicular cancer patients without chemotherapy (median age 35 years, range 16–54 years). A detailed medical history evaluated audiological risk factors and hearing complaints. DPOAE was measured in eight frequencies from 750 to 8,000 Hz. Paired t test and Mann-Whitney test were used for statistical evaluation. Results: Symptomatic ototoxicity was observed in 20% of the patients. In patients receiving ≤300 mg/m2 cisplatin, no amplitude changes were detected. Beyond this dose, hearing impairment proved to be dose dependent. Contrary to the literature, not only high frequencies were affected. In patients receiving ≧400 mg/m2, our method could detect significant hearing impairment at lower frequencies that are important for speech perception. At 400 mg/m2, significant amplitude change was detected at 3,000 Hz (p = 0.01); at 500–600 mg/m2, significant amplitude change was detected at 1,500, 2,000 and 3,000 Hz (p = 0.004, 0.0001 and 0.0002, respectively), and at 700 mg/m2 significant amplitude change was detected at 3,000 Hz (p = 0.01). We detected the lowest amplitudes in those 44 patients who had symptomatic ototoxicity. The only statistically significant risk factor was the cumulative dose of cisplatin; neither smoking nor noise exposure were independent risk factors. Conclusion: DPOAE is a fast, noninvasive and reliable method in detecting late ototoxicity in testicular cancer patients. Contrary to the literature, not only high frequencies are affected. In patients receiving at least 400 mg/m2, using DPOAE we were able to detect significant hearing impairment at lower frequencies that are important for speech perception.

TPS4590 Background: Only 5%-15% of patients (pts) with advanced bladder cancer attain long-term survival with standard first-line cisplatin-based chemotherapy. Programmed death 1 (PD-1)/PD-L1 inhibitors have proven effective in recurrent, advanced urothelial cancer. Emerging data suggest these agents may also be useful in the first-line setting. In KEYNOTE-052, first-line pembro, an anti–PD-1 antibody, demonstrated antitumor activity and acceptable safety in cisplatin-ineligible pts with advanced urothelial cancer. KEYNOTE-361 (NCT02853305) is a randomized, open-label, phase 3 study of pembro with or without chemotherapy versus chemotherapy alone in pts with advanced urothelial carcinoma. Methods: Key eligibility criteria include age ≥18 years; histologically or cytologically confirmed unresectable/metastatic urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra; measurable disease (RECIST v1.1, investigator review); no prior systemic chemotherapy ([neo]adjuvant platinum-based chemotherapy with recurrence > 12 months after completion is allowed); ECOG PS 0-2; and provision of a tumor sample for biomarker analyses. Pts will be randomly assigned 1:1:1 to receive pembro 200 mg every 3 weeks (Q3W), pembro + investigator’s choice of chemotherapy (gemcitabine [1000 mg/m2 on day 1 and 8 Q3W] + cisplatin [70 mg/m2 Q3W]), or chemotherapy alone. Cisplatin-ineligible pts randomly assigned to chemotherapy will receive gemcitabine + carboplatin [AUC 5 Q3W]. Chemotherapy choice must be selected before randomization. Treatment will continue until progressive disease, unacceptable adverse events (AEs), or 35 cycles of pembro (pembro arms only). Response will be assessed Q9W for the first year and Q12W thereafter. AEs will be evaluated throughout and graded per NCI CTCAE v4.0. Primary end points are progression-free survival (RECIST v1.1 per central review) and overall survival; secondary end points include objective response rate and safety and tolerability. Efficacy outcomes will be compared for pembro vs chemotherapy and pembro + chemotherapy vs chemotherapy. Enrollment is ongoing; ~990 pts will be enrolled. Clinical trial information: NCT02853305.

e16522 Background: Cs are commonly used in the treatment of mCRPC, because of their inhibitory effects on the secretion of ACTH and their palliative effects. Inhibition of ACTH results in downregulation of adrenal androgens. Cs may have a cytotoxic effect on prostate cancer cells, mediated in part by the downregulation of androgen receptors and the activation of glucocorticoid receptor-mediated signaling and downstream antiangiogenic activity. The rationale for adding Cs to D chemotherapy is for the management of symptoms and adverse events rather than for improving responses. D (without Cs) + ADT (androgen-deprivation therapy) vs ADT alone in castration-sensitive prostate cancer has resulted in significant increase in survival (NEJM, 2015). Cs has been reported to adversely influence OS during enzalutamide (NEJM, 2012). In the COU-AA-301 trial Cs use at baseline was an independent prognostic factor in multivariate analysis, but not in a stepwise selection model (JCO, 2013). Methods: We performed a retrospective analysis of 117 mCRPC pts treated with D. All pts had standard Cs premedication before D and 74 pts received prednisone 5 mg po BID, but 43 pts didn’t get continuous Cs therapy. Kaplan-Meier estimates and Cox regression model were used. Results: Pts characteristics were as follows: median age 66 yrs (range 48-81), Gleason score ≤6: 22pts, ≥7: 61pts. (34 NA). Altogether 1015 cycles of D were given, median 8 (range 2-27). Subsequent therapies were as follows: Abiraterone Acetate (AA) (75), Mitoxantrone (46), Xofigo (5), other chemotherapies (7), none (21). Pts receiving Cs had an inferior OS in all subgroups, although none was significant (Table). Only the Gleason score was an independent prognostic factor in multivariate analysis. Conclusions: Our data suggest, that D therapy withouth Cs is at least as effective as the combination. More data is neccesary to support the suspicion of negative influence of Cs on OS. Thus unnecesarry Cs treatment might be ommited. [Table: see text]

In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy.We did a multicentre, open-label, early-access protocol trial in 23 countries. We enrolled patients who had metastatic castration-resistant prostate cancer progressing after taxane chemotherapy. Participants received oral doses of abiraterone acetate (1000 mg daily) and prednisone (5 mg twice a day) in 28-day cycles until disease progression, development of sustained side-effects, or abiraterone acetate becoming available in the respective country. The primary outcome was the number of adverse events arising during study treatment and within 30 days of discontinuation. Efficacy measures (time to prostate-specific antigen [PSA] progression and time to clinical progression) were gathered to guide treatment decisions. We included in our analysis all patients who received at least one dose of abiraterone acetate. This study is registered with ClinicalTrials.gov, number NCT01217697.Between Nov 17, 2010, and Sept 30, 2013, 2314 patients were enrolled into the early-access protocol trial. Median follow-up was 5·7 months (IQR 3·5-10·6). 952 (41%) patients had a grade 3 or 4 treatment-related adverse event, and grade 3 or 4 serious adverse events were recorded in 585 (25%) people. The most common grade 3 and 4 adverse events were hepatotoxicity (188 [8%]), hypertension (99 [4%]), cardiac disorders (52 [2%]), osteoporosis (31 [1%]), hypokalaemia (28 [1%]), and fluid retention or oedema (23 [1%]). 172 (7%) patients discontinued the study because of adverse events (64 [3%] were drug-related), as assessed by the investigator, and 171 (7%) people died. The funder assessed causes of death, which were due to disease progression (85 [4%]), an unrelated adverse experience (72 [3%]), and unknown reasons (14 [1%]). Of the 86 deaths not attributable to disease progression, 18 (1%) were caused by a drug-related adverse event, as assessed by the investigator. Median time to PSA progression was 8·5 months (95% CI 8·3-9·7) and median time to clinical progression was 12·7 months (11·8-13·8).No new safety signals or unexpected adverse events were found in this early-access protocol trial to assess abiraterone acetate for patients with metastatic castration-resistant prostate cancer who progressed after chemotherapy. Future work is needed to ascertain the most effective regimen of abiraterone acetate to optimise patients' outcomes.Janssen ResearchDevelopment.

Lung cancer is the leading cause of cancer related mortality all over the world. The development of molecular pathology methods has become increasingly important in the prediction of chemotherapy sensitivity and mutation analysis to identify driver mutations as important targets of new therapeutic agents. These agents give an opportunity to provide a new standard of care. Therefore testing EGFR, KRAS mutations and ALK rearrangements in patients with advanced lung adenocarcinoma should be incorporated into routine clinical practice. Bone is the most frequent type of distant metastases in case of Non-Small Cell Lung Cancer (NSCLC). During the disease this is developing 30-40%. Because of the short survival (6 months) the treatment possibilities were not in the aim of scope. After the changes of treatment guidelines – first the platinum based chemotherapy, later the step of EGFR TK inhibitors therapy – the Overall Survival (OS) became more longer. The relevant clinical studies concluded that: bone metastases and Skeletal Related Events (SRE) are more frequently observed in men, heavy smokers and without treatment of EGFR TK inhibitors. In our retrospective study we collected 224 most relevant clinical data patient with lung adenocarcinoma. We investigated the correlations between the EGFR, KRAS mutations status and the prevalence of bone metastases and survival. We have found that EGFR and KRAS mutation status are both predictive factors for the treatment efficacy and are prognostic factors for the disease progression but these are not predictors of the presence of bone metastases. The presence of bone metastases is an independent prognostic marker what correlates with the poor performance and worse Quality of Life (QL).

Objective: To determine whether a testicular self-examination-based early-detection program may help in the early diagnosis of testicular cancer. Methods: Advertisements were placed in the media describing the early signs of testicular cancer, the risk factors, the correct method of self-examination and the importance of early detection. Between April 1995 and April 1998, 5,056 men underwent physical and ultrasound examination of the testicles, and in case of suspicious findings tumor markers were checked. Results: Testicular tumors were found in 1.28% of the men with symptoms. No tumors were found in men without symptoms or in men with pain, sensitivity to palpation, or complaints unrelated to the testicle. Of those with a palpable lump or swollen testicle, 4.5 and 3.9% were found to have a tumor. In total, 28 testicular cancers (15 seminomas and 13 nonseminomas) in 26 volunteers and 4 benign tumors were detected. The occurrence of cancer was most frequent in the age group of 15–40 years (1.6%). Conclusion: The rate of cancer detection and the detected seminoma rate in the program are not sufficient to justify a widespread early detection program for testicular cancer (examination of men who reveal testicular abnormalities by self-examination) despite the increased tumor incidence. Early diagnosis should be based on an educational program for the population at risk, the training of staff engaged in the health care of the young, and the use of early ultrasound examination in men with palpable lumps and swollen testicles, especially in young men.

BACKGROUND The expression of bcl-2 has been studied extensively in a variety of human tumors. However, there is a lack of clinical data regarding its expression in germ cell testicular tumors (GCTTs). METHODS In this study, the authors screened 70 patients with GCTTs for bcl-2 expression using immunohistochemistry (IHC) and the streptavidin-biotin-alkaline phosphatase method. This expression was also correlated with the metastatic behavior, clinical stages, and multidrug resistance gene product protein (MDR1/Pgp) immunostaining of GCTTs. RESULTS Overall, 41 carcinomas (58%) stained positively with anti-bcl-2 monoclonal antibody. According to histologic type, these lesions with positive staining included 11 of 26 seminomas (42.3%) and 30 of 44 nonseminomatous germ cell testicular tumors (NSGCTs) (68%). The incidence of bcl-2 immunostaining was higher (P = 0.05, two-tailed Fisher's exact test) among NSGCTs than among seminomas. The expression of bcl-2 was more prevalent among tumors from patients with metastases than among tumors from metastasis free patients (P = 0.000). There was a significant difference between the three stages of disease in the expression of bcl-2 (χ2 = 0.000), i.e., bcl-2 expression was clearly dominant among tumors at advanced stages. A significant association between bcl-2 and Pgp immunostaining was established (P = 0.004). CONCLUSIONS These findings revealed that bcl-2 expression occurs in GCTTs. Furthermore, they suggest that bcl-2 is associated with a more advanced malignant phenotype of this tumor. Cancer 1998;83:331-336. © 1998 American Cancer Society.

e16504Background: The COU-AA-301 trial showed that abiraterone, an oral inhibitor of cytochrome p450 CYP17, improved survival in mCRPC patients progressing after docetaxel. Methods: Our first patie...