Final Results from SAUL, a Single-arm International Study of Atezolizumab in Unselected Patients with Pretreated Locally Advanced/Metastatic Urinary Tract Carcinoma.

BACKGROUND AND OBJECTIVE: We assessed the safety of atezolizumab in unselected patients (including understudied populations typically excluded from clinical trials) with pretreated urinary tract carcinoma (UTC). The prespecified final analysis updates previously reported safety and efficacy data. METHODS: The single-arm prospective SAUL study (NCT02928406) enrolled 1004 patients with locally advanced/metastatic urothelial/non-urothelial UTC that had progressed during/after one to three prior treatment lines for advanced UTC (or <12 mo after [neo]adjuvant therapy). Broad eligibility criteria allowed enrollment of patients with complex comorbidities approximating the real-world setting. Patients received atezolizumab 1200 mg every 3 wk until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included duration of response and overall survival (OS). KEY FINDINGS AND LIMITATIONS: The treated cohort included 10% of patients with poor performance status, 5% with creatinine clearance <30 ml/min, and 4% with autoimmune disease. At median follow-up of 55 mo, median atezolizumab duration was 2.8 mo (range 0-62); 68 patients (7%) continued atezolizumab for >4 yr. Treatment-related grade ≥3 adverse events occurred in 16% of patients (death in 1%); 8% discontinued atezolizumab for adverse events. Median OS was 8.6 mo (95% confidence interval 7.8-9.7) and 136 patients (14%) had OS longer than 4 yr. Limitations include the small sample size for some subgroups of special interest. CONCLUSIONS AND CLINICAL IMPLICATIONS: Long-term safety and efficacy data continue to show a benefit of atezolizumab in unselected patients with UTC. Remarkably, 14% of patients lived for >4 yr after starting atezolizumab. These results can inform multidisciplinary team discussions and treatment decision-making for patients with UTC with complex comorbidities. PATIENT SUMMARY: The SAUL study looked at how well tolerated a drug called atezolizumab was in patients with urinary tract cancer who had already received up to three previous treatments for their cancer, including people who are usually not included in clinical trials because of other medical conditions. The length of survival after starting treatment was also assessed. Overall, the results show that atezolizumab was well tolerated. People for whom other therapies had failed lived for about 8.6 months on average after starting treatment, and 14% of the patients were still alive after 4 years.

First-line Avelumab plus Chemotherapy in Patients with Advanced Solid Tumors: Results from the Phase Ib/II JAVELIN Chemotherapy Medley Study.

PURPOSE: Chemotherapy can potentially enhance the activity of immune checkpoint inhibitors by promoting immune priming. The phase Ib/II JAVELIN Chemotherapy Medley trial (NCT03317496) evaluated first-line avelumab + concurrent chemotherapy in patients with advanced urothelial carcinoma or non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Avelumab 800 or 1,200 mg was administered continuously every 3 weeks with standard doses of cisplatin + gemcitabine in patients with urothelial carcinoma, or carboplatin + pemetrexed in patients with nonsquamous NSCLC. Dual primary endpoints were dose-limiting toxicity (DLT; phase Ib) and confirmed objective response (phase Ib/II). RESULTS: In phase Ib, urothelial carcinoma and NSCLC cohorts received avelumab 800 mg (n = 13 and n = 6, respectively) or 1,200 mg (n = 6 each) + chemotherapy. In evaluable patients with urothelial carcinoma treated with avelumab 800 or 1,200 mg + chemotherapy, DLT occurred in 1/12 (8.3%) and 1/6 (16.7%), respectively; no DLT occurred in the NSCLC cohort. In phase II, 35 additional patients with urothelial carcinoma received avelumab 1,200 mg + chemotherapy. Across all treated patients, safety profiles were similar irrespective of avelumab dose. Objective response rates (95% confidence internal) with avelumab 800 or 1,200 mg + chemotherapy, respectively, across phase Ib/II, were 53.8% (25.1-80.8) and 39.0% (24.2-55.5) in urothelial carcinoma, and 50.0% (11.8-88.2) and 33.3% (4.3-77.7) in NSCLC. CONCLUSIONS: Preliminary efficacy and safety findings with avelumab + chemotherapy in urothelial carcinoma and NSCLC were consistent with previous studies of similar combination regimens. Conclusions about clinical activity are limited by small patient numbers. SIGNIFICANCE: This phase Ib/II trial evaluated avelumab (immune checkpoint inhibitor) administered concurrently with standard first-line chemotherapy in patients with advanced urothelial carcinoma or advanced nonsquamous NSCLC without actionable mutations. Efficacy and safety appeared consistent with previous studies of similar combinations, although patient numbers were small.

A new method to quantify the effect of co-medication on the efficacy of abiraterone in metastatic castration-resistant prostate cancer patients.

Background and Objective: Patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA) have co-morbidities treated with different drugs. The aim was to quantify the potential effect of co-medications on AA treatment duration (TD) and overall survival (OS). Methods: A new parameter, called "individual drug score" (IDS) was calculated by summing the "drug score"-s (DS) of all co-medications for each patient. The DS was determined by quantifying the effect of a given co-drug on enzymes involved in steroidogenesis and metabolism of AA. The correlation between log (IDS) and TD was tested by non-linear curve fit. Kaplan-Meier method and multivariate Cox regression was used for analysis of TD and OS. Results: The IDS and TD of AA+prednisolone showed a dose-response correlation (n = 166). Patients with high IDS had significantly longer TD and OS (p <0.001). In multivariate analysis IDS proved to be an independent marker of TD and OS. The same analysis was performed in a separate group of 81 patients receiving AA+dexamethasone treatment. The previously observed relationships were observed again between IDS and TD or OS. After combining the AA+prednisolone and AA+dexamethasone groups, analysis of the IDS composition showed that patients in the high IDS group not only used more drugs (p <0.001), but their drugs also had a higher mean DS (p = 0.001). Conclusion: The more co-drugs with high DS, the longer the duration of AA treatment and OS, emphasizing the need for careful co-medication planning in patients with mCRPC treated with AA. It is recommended that, where possible, co-medication should be modified to minimize the number of drugs with negative DS and increase the number of drugs with high DS. Our new model can presumably be adapted to other drugs and other cancer types (or other diseases).

[Immune combination possibilities in the first-line treatment of metastatic renal cell cancer]. / Immunkombinációs lehetoségek a metasztatikus világossejtes vesedaganat elso vonalas kezelésében.

First-line treatment of metastatic renal cancer can be divided into three main phases. The cytokine era was replaced by targeted therapies in 2006 with the introduction of tyrosine kinase inhibitors. Until 2018, the standard first-line therapy was the use of sunitinib or pazopanib. Over the past decade, numerous attempts have been made to combine these drugs, which are already approved or in development, but these attempts have not been successful, primarily because of intolerable toxicity. In 2018, we reached a new stage in the treatment of metastatic renal tumors. This year, the combination immunotherapy of ipilimumab and nivolumab was approved. Since then, the combination of immunotherapy and targeted therapies has led to success. The main objective of our summary is to present in chronological order the clinical trials of combination therapies already approved in Europe, as well as the most recent phase III clinical trials. It is also intended to provide a brief practical guide on how to decide on first-line therapy based on the results of these trials.

[Second and further lines treatment options for locally advanced or metastatic renal cell carcinoma]. / A terápiaválasztás lehetoségei a lokálisan elorehaladott, inoperábilis vagy áttétes, világossejtes vesedaganat második és további vonalban alkalmazható kezelése során.

The treatment of locally advanced, inoperable or metastatic kidney tumors is a dynamically changing field of oncology. Since the registration of the first targeted therapeutic product (2005), more and more new products have been internationally accepted and registered almost every year. The development of immune checkpoint inhibitors and their inclusion in care algorithms (2015) further expanded the therapeutic possibilities. Despite all this, the optimal selection of medication used in different therapeutic lines poses a significant challenge to clinicians. In this review we have collected the data, aspects, and results of clinical tests necessary for the choice of therapy that can be applied in second and further lines. We also present the domestic treatment options.

[Multicentric Hungarian results of cabozantinib therapy in patients with metastatic kidney cancer based on real-world data]. / Áttétes vesedaganatos betegek kabozantinibterápiájának multicentrikus magyarországi eredményei.

The aim of our analysis was to evaluate the efficacy of cabozantinib in patients with metastatic renal cell carcinoma. Cabozantinib therapy initiated between 01/01/2019 and 31/12/2022 was evaluated based on a retrospective review of data from 14 renal centers in Hungary. The starting dose was 60 or 40 mg. Physical examinations and laboratory tests were performed every 4 weeks and imaging studies 3-monthly. Tumor response was assessed according to RECIST 1.1, and toxicity according to NCI CTCAE 4.0. A total of 230 patient records were evaluated, 201 (87.4%) of them had clear cell RCC. Cabozantinib was administered as third, second and first-line treatment in 48.7%, 38.3% and <5% of cases, respectively. Dose reductions occurred in 62.6% and treatment interruption in 6.5%. Duration of therapy was 10.03 months, which was independent of dose reduction. Overall tumor response rate was 39.2% and clinical benefit was 82.8%. The duration of first-, second-, third- and fourth-line treatment was 11.47, 8.03, 11.57 and 10.13 months, respectively. Overall survival from the start of therapy was 22.0 months. Cabozantinib therapy in daily practice was more beneficial than according to registry study results. Dose reduction did not affect efficacy.

[Multicentric Hungarian results of cabozantinib therapy in patients with metastatic kidney cancer based on real-world data]. / Áttétes vesedaganatos betegek kabozantinibterápiájának multicentrikus magyarországi eredményei.

The aim of our analysis was to evaluate the efficacy of cabozantinib in patients with metastatic renal cell carcinoma. Cabozantinib therapy initiated between 01/01/2019 and 31/12/2022 was evaluated based on a retrospective review of data from 14 renal centers in Hungary. The starting dose was 60 or 40 mg. Physical examinations and laboratory tests were performed every 4 weeks and imaging studies 3-monthly. Tumor response was assessed according to RECIST 1.1, and toxicity according to NCI CTCAE 4.0. A total of 230 patient records were evaluated, 201 (87.4%) of them had clear cell RCC. Cabozantinib was administered as third, second and first-line treatment in 48.7%, 38.3% and <5% of cases, respectively. Dose reductions occurred in 62.6% and treatment interruption in 6.5%. Duration of therapy was 10.03 months, which was independent of dose reduction. Overall tumor response rate was 39.2% and clinical benefit was 82.8%. The duration of first-, second-, third- and fourth-line treatment was 11.47, 8.03, 11.57 and 10.13 months, respectively. Overall survival from the start of therapy was 22.0 months. Cabozantinib therapy in daily practice was more beneficial than according to registry study results. Dose reduction did not affect efficacy.

Atezolizumab for the treatment of advanced recurrent basal cell carcinoma and urothelial carcinoma of bladder: a case report.

BACKGROUND: The use of checkpoint inhibitors has become increasingly important in the treatment of different cancers, including advanced muscle-invasive urothelial cancer and even in basal cell carcinoma. We present the case of a patient with advanced basal cell carcinoma and metastatic muscle-invasive urothelial cancer, who was treated with the programmed death-ligand 1 inhibitor, atezolizumab for both cancers. CASE PRESENTATION: A 72-year-old Caucasian female patient, with a history of smoking without any comorbidities developed periocular basal cell carcinoma, which was surgically removed but relapsed 4 years later. Surgical excision was carried out twice, but with positive margins, therefore definitive radiotherapy was given. Subsequently, the patient developed non-muscle-invasive papillary urothelial carcinoma, which was removed by transurethral resection. Follow-up was irregular owing to the patient's inadequate compliance, and within 2 years, the patient's cancer relapsed and histology confirmed muscle-invasive urothelial carcinoma. Definitive radiochemotherapy was not accepted by the patient. Meanwhile, the patient's basal cell carcinoma had also progressed, despite receiving vismodegib therapy. Therefore, the patient was administered epirubicin-cisplatin. Having reached the maximum cumulative dose of epirubicin, treatment with this chemotherapeutic agent could not be continued. The patient developed bladder cancer metastasis in her left suprainguinal lymph nodes. Owing to the presence of both types of tumors, programmed death-ligand 1 inhibitor atezolizumab treatment was chosen. In just over 1 year, the patient received 17 cycles of atezolizumab altogether, which was tolerated well without any adverse or side effects. Follow-up imaging scans indicated complete remission of the metastatic bladder cancer and stable disease of the basal cell carcinoma. The patient subsequently passed away in hospital due to a complication of COVID-19 infection. CONCLUSIONS: Our patient attained stable disease in advanced basal cell carcinoma and complete remission in metastatic muscle-invasive urothelial cancer after receiving programmed death-ligand 1 inhibitor, atezolizumab, therapy. To our knowledge, this is the first paper to report the use of programmed death-ligand 1 inhibitor, atezolizumab, as treatment for advanced basal cell carcinoma. This case may also be of interest for clinicians when treating patients with two synchronous cancers.

Single-course bleomycin, etoposide, and cisplatin (1xBEP) as adjuvant treatment in testicular nonseminoma clinical stage 1: outcome, safety, and risk factors for relapse in a population-based study.

Introduction: Clinical stage 1 (CS1) nonseminomatous (NS) germ cell tumors involve a 30% probability of relapse upon surveillance. Adjuvant chemotherapy with one course of bleomycin, etoposide, and cisplatin (1xBEP) can reduce this risk to <5%. However, 1xBEP results are based solely on five controlled trials from high-volume centers. We analyzed the outcome in a real-life population. Patients and Methods: In a multicentric international study, 423 NS CS1 patients receiving 1xBEP were retrospectively evaluated. Median follow-up was 37 (range, 6-89) months. Primary end points were relapse-free and overall survival evaluated after 5 years. We also looked at associations of relapse with clinico-pathological factors using stratified Kaplan-Meier methods and Cox regression models. Treatment modality and outcome of recurrences were analyzed descriptively. Results: The 5-year relapse-free survival rate was 96.2%. Thirteen patients (3.1%; 95% confidence interval, 1.65-5.04%) relapsed after a median time of 13 months, of which 10 were salvaged (77%). Relapses were mostly confined to retroperitoneal nodes. Three patients succumbed, two to disease progression and one to toxicity of chemotherapy. Pathological stage >pT2 was significantly associated with relapse rate. Conclusion: The relapse rate of 3.1% found in this population of NS CS1 patients treated with 1xBEP at the routine care level was not inferior to the median rate of 2.3% reported from a meta-analysis of controlled trials. Also, the cure rate of relapses of 77% is consistent with the previously reported rate of 80%. This study clearly shows that the 1xBEP regimen represents a safe treatment for NS CS1 patients.

[New aspects of chemotherapy and indications for maintenance immunotherapy in urothelial cancers]. / A kemoterápia szerepének megújulása és a fenntartó immunterápia indikációi uroteliális daganatokban.

Chemotherapy for the treatment of urothelial and bladder cancers has focused on renewed indications in light of clinical trials of modern therapies, which are described in our review. In stage T2-T4a N0-1 M0 cases, that are suitable for cisplatin, surgery is performed after neoadjuvant cisplatin- based chemotherapy. Less significant result is observed with adjuvant chemotherapy, especially in pT3-4 and/or N+ stage, if no neoadjuvant chemotherapy was administered. Cisplatin-based chemotherapy is the first-line treatment of cisplatin-eligible metastatic patients. First-line choice in chemo-fit cases with cisplatin ineligibility can be carboplatin- based chemotherapy. 4-6 cycles of cisplatin or carboplatin cause stable disease or regression, maintenance avelumab immunotherapy improves patient's survival. For those patients who progress during or after platinum-based chemotherapy, the effectiveness of chemotherapy in the second/multiple lines is less favourable in comparison with immunotherapy and targeted therapy. Modern antibody - cytotoxic drug conjugates have been discovered in the form of enfortumab vedotin and sacituzumab govitecan, and currently they seem to be effective in the third line after chemotherapy and immunotherapy.

[Forward directions for targeted treatment of urothelial tumors]. / Uroteliális daganatok célzott kezelésének eloremutató irányai.

Platinum-based chemotherapy is the standard therapy for inoperable, locally advanced, or metastatic urothelial tumors. Although the initial response rate with combination chemotherapy is very high, the median survival is approximately 15 months. Secondary chemotherapy has had modest clinical benefit and toxicity, with the breakthrough coming from the introduction of checkpoint inhibitory immunotherapies. After chemotherapy and immunotherapy, there is currently no accepted standard of care in the third line. Based on the results of the two phase II and one phase III studies available so far, the use of targeted treatments in tertiary treatment may be a new direction. The purpose of our review is to present these clinical trials, and we would also like to draw attention to promising targeted therapies in the future.

[Immunotherapy in advanced urothelial cancer]. / Az immunterápia helye az elorehaladott uroteliális daganatok elso-, másodés többedvonalbeli kezelésében.

Cisplatin containing chemotherapy has proven benefit for muscle-invasive locally advanced and metastatic urothelial cancer. The carboplatin based combinations are less effective in these settings. In most cases for the platinum based chemotherapy ineligible patients only the best supportive care could be given. The treatment options have expanded in the past few years with the introduction of systemic immunotherapy with checkpoint inhibitors. We review the relevant clinical trials' data which can completely transform the treatment landscape of locally advanced or metastatic urothelial cancer.

Low socioeconomic position is a risk factor for delay to treatment and mortality of testicular cancer patients in Hungary, a prospective study.

BACKGROUND: In Hungary, the mortality rate for testicular germ cell cancer (TGCC) is 0,9/100000 which is significantly higher than the EU average. We prospectively evaluated the effect of socioeconomic position on patient delay and therapy outcomes. METHODS: Questionnaires on subjective social status (MacArthur Subjective Status Scale), objective socioeconomic position (wealth, education, and housing data), and on patient's delay were completed by newly diagnosed TGCC patients. RESULTS: Patients belonged to a relatively high socioeconomic class, a university degree was double the Hungarian average, Cancer-specific mortality in the highest social quartile was 1.56% while in the lowest social quartile 13.09% (p = 0.02). In terms of patient delay, 57.2% of deceased patients waited more than a year before seeking help, while this number for the surviving patients was 8.0% (p = 0.0000). Longer patient delay was associated with a more advanced stage in non-seminoma but not in seminoma, the correlation coefficient for non-seminoma was 0.321 (p < 0.001). For patient delay, the most important variables were the mother's and patient's education levels (r = - 0.21, p = 0.0003, and r = - 0.20, p = 0.0005), respectively. Since the patient delay was correlated with the social quartile and resulted in a more advanced stage in non-seminoma, the lower social quartile resulted in higher mortality in non-seminoma patients (p = 0.005) but not in seminoma patients (p = 0.36) where the patient delay was not associated with a more advanced stage. CONCLUSIONS: Based on our result, we conclude that to improve survival, we should promote testicular cancer awareness, especially among the most deprived populations, and their health care providers.

Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial.

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.

Clinical Results and Biomarker Analyses of Axitinib and TRC105 versus Axitinib Alone in Patients with Advanced or Metastatic Renal Cell Carcinoma (TRAXAR).

LESSONS LEARNED: The combination of carotuximab with axitinib did not provide a benefit over axitinib monotherapy in patients with metastatic clear cell renal cell carcinoma who had previously progressed on one or more vascular endothelial growth factor (VEGF)-targeted therapies. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels. 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.

[Fertility preservation in testicular cancer patients]. / Heretumoros betegek termékenyítoképességének vizsgálata.

Germ cell tumors of the testicle account for 1% of all tumors. Testicular cancer (TC) is the most common malignancy in men aged 15-35 years. Patients with TC have an excellent survival rate but often have not yet attempted to father children, and fertility is one of the main concerns of survivors, therefore it is important to preserve it. The most commonly used method is sperm banking. Retrospective analysis of the Hungarian data showed that in case of testicular cancer spermatogenesis is more impaired in the more advanced disease. No correlation was found among the histological types and the proportion of azoo- and oligozoospermia. The parameters of testicular cancer and non-Hodgkin lymphoma patients were worse compared to the normal population. Sperm cryopreservation prior to initiating life-saving cancer treatment offers men the best chance to father children and should be offered to all men with testicular cancer before chemotherapy, since cytostatic therapy may lead to infertility.

Real-world safety and efficacy of nivolumab for ≥ 2nd line treatment of metastatic renal cell carcinoma: A retrospective cohort study in Croatia, Hungary, and Malta.

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.

Real-World Safety and Efficacy of Nivolumab in Advanced Squamous and Nonsquamous Non-Small-Cell Lung Cancer: A Retrospective Cohort Study in Croatia, Hungary, and Malta.

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.

[Therapeutic sequences in the treatment of advanced/metastatic prostate cancer]. / Terápiás szekvenciák az elorehaladott/ áttétes prosztatadaganatok gyógyszeres kezelésében.

The unprecedented development of prostate cancer therapy is a challenge for the proper sequential use of modern medicines. Patients' life expectancies improve when we use treatment lines, one after the other. There is no evidence- based guideline regarding the optimal sequence, but a number of data are available to help the physician selecting the best individualized therapeutic option. The basic treatment for advanced prostate cancer is still androgenic deprivation (ADT), to which we can add additional therapeutic agents. New types of hormonal (androgen receptor targeted, ARTA) agents are being used in an increasingly early line. Chemotherapy (CT) is the first choice in case of metastatic, hormone-sensitive disease especially in high volume cases that are causing symptoms or visceral crisis. CT is otherwise applied after ARTA. We have little but encouraging data about the early, sequential use of ARTAs with different mechanisms of action. In later lines, cross-resistance may develop between ARTA treatments, in which cases CT is the right decision. In this paper, we summarize the results of clinical trials that may help in therapeutic decision making, maximizing the benefits for patients.

Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

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 < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier. Conclusions and Relevance: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.