Assessing the effectiveness and safety of lenvatinib and everolimus in advanced renal cell carcinoma: insights from the RELIEVE study's analysis of heavily pretreated patients.

Background: The treatment of heavily pretreated patients with metastatic renal cell carcinoma (mRCC) represents an unmet medical need and is still challenging. Objectives: The primary objective was to assess the effectiveness of the lenvatinib plus everolimus combination and the secondary objective was the toxicity profile of this combination. Design: We conducted a longitudinal retrospective study examining mRCC patients pre-treated with one or more lines of therapy among different cancer centers in Italy. Methods: The study included patients who received the combination of lenvatinib plus everolimus as either a second-line treatment or beyond. We assessed progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), response rate (RR), and toxicity profile. In addition, we explored the potential relationship between treatment effectiveness and clinical and laboratory parameters. Results: In all, 33 patients were assessed, the median age was 60 years, 57% had an Eastern Cooperative Oncology Group performance status of 1-2 and. 63% received ⩾ 3 prior lines of therapy. 62% were 'intermediate risk' according to the International Metastatic Renal Cell Carcinoma Database Consortium and 30% were 'poor risk'. The RR was 42% (no complete response), 18% stable disease. Median OS was 11.2 months (95% CI 6.8-19.9), median PFS was 6.7 months (95% CI 0.6-30.8), and median TTF was 6.7 months (95% CI 4.8-16.6). A shorter OS was significantly associated with lymph node metastases (p = 0.043, 95% CI), neutrophils/ lymphocytes ratio (NLR) ⩾ 3 (p = 0.007), hemoglobin/red cell distribution width ratio cutoff value <0.7 was significant (p = 0.03) while a shorter PFS was associated with lung (p = 0.048) and brain metastases (p = 0.023). The most frequent G1 toxicity was diarrhea (24%), G2 was fatigue (30%), and hypertension and skin toxicity (6%) for G3. Conclusion: Our findings suggest a clinically relevant effectiveness of lenvatinib plus everolimus combination with an acceptable toxicity profile for heavily pretreated patients with mRCC.

Analyses of tumor microenvironment in patients with advanced renal cell carcinoma receiving immunotherapy (Meet-URO 18 study).

Introduction: The Meet-URO 18 study is a multicentric study of patients with metastatic renal cell carcinoma receiving nivolumab in the second-line and beyond, categorized as responders (progression-free survival ≥ 12 months) and non-responders (progression-free survival < 3 months). Areas covered: The current study includes extensive immunohistochemical analysis of T-lineage markers (CD3, CD4, CD8, CD8/CD4 ratio), macrophages (CD68), ph-mTOR, CD15 and CD56 expression on tumor cells, and PD-L1 expression, on an increased sample size including 161 tumor samples (113 patients) compared with preliminary presented data. Responders' tumor tissue (n = 90; 55.9%) was associated with lower CD4 expression (p = 0.014), higher CD56 expression (p = 0.046) and higher CD8/CD4 ratio (p = 0.030). Expert opinion/commentary: The present work suggests the regulatory role of a subpopulation of T cells on antitumor response and identifies CD56 as a putative biomarker of immunotherapy efficacy.

Avelumab Plus Intermittent Axitinib in Previously Untreated Patients with Metastatic Renal Cell Carcinoma. The Tide-A Phase 2 Study.

BACKGROUND: Combinations of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitor (ICI) against PD1/PD-L1 are the standard first-line therapy for patients with metastatic renal cell carcinoma (mRCC), irrespective of the prognostic class. OBJECTIVE: To investigate the feasibility and safety of withdrawing VEGFR-TKI but continuing anti-PD1/PD-L1 in patients who achieve a response to their combination. DESIGN, SETTING, AND PARTICIPANTS: This was a single-arm phase 2 trial in patients with treatment-naïve mRCC with prior nephrectomy, without symptomatic/bulky disease and no liver metastases. INTERVENTION: Enrolled patients received axitinib + avelumab; after 36 wk of therapy those who achieved a tumour response interrupted axitinib and continued avelumab maintenance until disease progression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the rate of patients without progression 8 wk after the axitinib interruption. The secondary endpoints were the median value for progression-free (mPFS) and overall (mOS) survival and the safety in the overall population. RESULTS AND LIMITATIONS: Seventy-nine patients were enrolled and 75 were evaluated for efficacy. A total of 29 (38%) patients had axitinib withdrawn, as per the study design, with 72% of them having no progression after 8 wk and thus achieving the primary endpoint. The mPFS of the overall population was 24 mo, while the mOS was not reached. The objective response rate was 76% (12% complete response and 64% partial response), with 19% of patients having stable disease. In the patients who discontinued axitinib, the incidence of adverse events of any grade was 59% for grade 3 and 3% for grade 4. This study was limited by the lack of a comparative arm. CONCLUSIONS: The TIDE-A study demonstrates that the withdrawal of VEGFR-TKI with ICI maintenance is feasible for selected mRCC patients with evidence of a response to the VEGFR-TKI + ICI combination employed in first-line therapy. Axitinib interruption with avelumab maintenance leads to decreased side effects and should be investigated further as a new strategy to delay tumour progression. PATIENT SUMMARY: We evaluated whether certain patients with advanced kidney cancer treated with the fist-line combination of axitinib plus avelumab can interrupt the axitinib in case of a tumour response after 36 wk of therapy. We found that axitinib interruption improved the safety of the combination, while the maintenance with avelumab might delay tumour progression.

The Italian Rare Biliary tract Cancer initiative (IRaBiCa): A multicentric observational study of Gruppo Oncologico dell'Italia Meridionale (GOIM) in collaboration with Gruppo Italiano Colangiocarcinoma (GICO).

INTRODUCTION: About 90% of cholangiocarcinomas are adenocarcinomas with glandular or tubular structures lined by epithelial cells, with no bile production and with a variable degree of differentiation, arising in the background of desmoplastic stroma. The remaining 10% is represented by rarer histological variants of which there is little knowledge regarding the biological behavior, molecular characterization, and sensitivity to the various possible therapies, including molecular-based treatments. Such rare tumors are described only in case reports or small retrospective series because of their exclusion from clinical trials. This national initiative, here presented, aims to address the following knowledge gap: a) how much does histological diversity translate into clinical manifestation variety? b) are those chemotherapy regimens, recommended for conventional biliary tract cancers, potentially active in rare variants?Therefore, epidemiological, pathological, and clinical characterization of series of rare biliary histotypes/variants, for which therapeutic and follow-up data are available, will be collected. METHODS: An Italian task force on rare tumors of the biliary tract (IRaBiCa) has been created, whose initiative is a multicenter retrospective study involving 34 Italian cancer centers.Clinical data from approximately 100 patients will be collected and analyzed. Continuous variables will be presented as median ± standard deviation, while categorical variables will be expressed in terms of frequency. Kaplan-Maier analyses will be used to compare disease free, progression free and overall survival, according to the different histotypes. CONCLUSIONS: We expect to gather novel data on rare histotypes of biliary tract cancer that will be useful to support their molecular and immunological characterization.

Time to strategy failure and treatment beyond progression in pretreated metastatic renal cell carcinoma patients receiving nivolumab: post-hoc analysis of the Meet-URO 15 study.

Background: Immunotherapies exhibit peculiar cancer response patterns in contrast to chemotherapy and targeted therapy. Some patients experience disease response after initial progression or durable responses after treatment interruption. In clinical practice, immune checkpoint inhibitors may be continued after radiological progression if clinical benefit is observed. As a result, estimating progression-free survival (PFS) based on the first disease progression may not accurately reflect the actual benefit of immunotherapy. Methods: The Meet-URO 15 study was a multicenter retrospective analysis of 571 pretreated metastatic renal cell carcinoma (mRCC) patients receiving nivolumab. Time to strategy failure (TSF) was defined as the interval from the start of immunotherapy to definitive disease progression or death. This post-hoc analysis compared TSF to PFS and assess the response and survival outcomes between patients treatated beyond progression (TBP) and non-TBP. Moreover, we evaluated the prognostic accuracy of the Meet-URO score versus the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score based on TSF and PFS. Results: Overall, 571 mRCC patients were included in the analysis. Median TSF was 8.6 months (95% CI: 7.0 - 10.1), while mPFS was 7.0 months (95% CI: 5.7 - 8.5). TBP patients (N = 93) had significantly longer TSF (16.3 vs 5.5 months; p < 0.001) and overall survival (OS) (34.8 vs 17.9 months; p < 0.001) but similar PFS compared to non-TBP patients. In TBP patients, a median delay of 9.6 months (range: 6.7-16.3) from the first to the definitive disease progression was observed, whereas non-TBP patients had overlapped median TSF and PFS (5.5 months). Moreover, TBP patients had a trend toward a higher overall response rate (33.3% vs 24.3%; p = 0.075) and disease control rate (61.3% vs 55.5%; p = 0.31). Finally, in the whole population the Meet-URO score outperformed the IMDC score in predicting both TSF (c-index: 0.63 vs 0.59) and PFS (0.62 vs 0.59). Conclusion: We found a 2-month difference between mTSF and mPFS in mRCC patients receiving nivolumab. However, TBP patients had better outcomes, including significantly longer TSF and OS than non-TBP patients. The Meet-URO score is a reliable predictor of TSF and PFS.

Incidence and Survival of Testicular Cancers in a Province in Northern Italy and Their Association with Second Tumors.

This study investigated the incidence, mortality, and 5-year survival rates of testicular cancers diagnosed in a northern Italian province, which were eventually associated with previous or subsequent extratesticular neoplasms. Cases from 1996 to 2020 were examined by age and histotype (seminoma vs. non-seminoma). The standardized incidence rate was calculated using the European population, and the annual percent change (APC) was reported. The five-year relative survival was estimated using the Pohar Perme method. The association with the second neoplasm was also evaluated. In our study, 385 patients with testicular cancer were included, most of whom were aged between 30 and 40 years. The non-seminoma and seminoma groups accounted for 44% and 18% of younger adults, respectively. The incidence rate increased during the study period (APC 1.6*); however, it increased in seminomas (APC 2.3*) but not in non-seminomas (APC -0.1). Conversely, the mortality rate remained constantly low either overall or in each of the two groups. The overall 5-year survival rate of testicular cancer patients was 95% (99% and 88% for seminomas and non-seminomas, respectively). Primary extratesticular tumors were documented in 37 cases, 18 after and 19 before the testicular cancer diagnosis. Our study confirms that the increased incidence and excellent survival rate are the prerogative of seminomas.

[Hormone therapy, cardio-metabolic profile, and cardiotoxicity. Still a dark side of cardio-oncology - Part 2: Prostate cancer]. / Terapia ormonale, assetto cardio-metabolico e cardiotossicità. Il lato ancora oscuro della cardioncologia ­ Parte 2: Tumore della prostata.

Hormone therapies (HTs) with anti-androgenic properties are a cornerstone for the treatment of prostate cancer (PC) and have significantly improved the survival of patients, though exposing them to a higher risk of cardiovascular diseases (CVDs), which represent a major cause of morbidity and mortality. This occurs due to the high average age of patients undergoing HT for PC, an age group in which CVDs have a high prevalence and incidence, and due to the type and duration of HTs that are increasingly effective but at the same time more aggressive towards cardiovascular health. Recent evidence from the real world suggests, however, that the cardiometabolic risk is widely underestimated and undertreated with significant impact also on the oncological prognosis. In the light of the results of the PRONOUNCE study, in this review it is emphasized the need for a multidisciplinary management of patients with PC who are candidate for or treated with HT by implementing a personalized treatment program in accordance with the current European guidelines on CVD prevention.

Current practice of genomic profiling of patients with advanced solid tumours in Italy: the Italian Register of Actionable Mutations (RATIONAL) study.

BACKGROUND: The Italian Register of Actionable Mutations (RATIONAL) is a multicentric, observational study collecting next-generation sequencing (NGS)-based tumour profiling data of patients with advanced solid tumours. METHODS: The study enrols patients who had available an NGS-based tumour profiling (Pathway-A) or undergo comprehensive genomic profiling (CGP) with FoundationOne CDx assays within the trial (Pathway-B). The primary endpoint was the rate of actionable mutations identified. RESULTS: Sequencing data were available for 738 patients in Pathway-A (218) and -B (520). In Pathway-A, 154/218 (70.6%) tests were performed using NGS panels ≤52 genes, and genomic alterations (GAs) were found in 164/218 (75.2%) patients. In Pathway-B, CGP revealed GAs in 512/520 (98.5%) patients. Levels I/II/III actionable GAs according to the European Society of Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) were identified in 254/554 (45.8%) patients with non-small-cell lung cancer, cholangiocarcinoma, colorectal, gastric, pancreatic and breast cancer. The rate of patients with level I GAs was similar in Pathways A and B (69 versus 102). CGP in Pathway-B revealed a higher number of patients with level II/III GAs (99 versus 20) and potentially germline pathogenic/likely pathogenic variants (58 versus 15) as compared with standard testing in Pathway-A. In patients with cancer of unknown primary, CGP detected OncoKB levels 3B/4 GAs in 31/58 (53.4%) cases. Overall, 67/573 (11.7%) of patients received targeted therapy based on genomic testing. CONCLUSION: The Italian Register of Actionable Mutations represents the first overview of genomic profiling in Italian current clinical practice and highlights the utility of CGP for identifying therapeutic targets in selected cancer patients.

The Impact of COVID-19 on New Kidney Cancer Diagnosis: Stage and Treatment in Northern Italy.

This study aims to evaluate the impact of COVID-19 on new renal carcinoma (RC) diagnoses using data from the Reggio Emilia Cancer Registry in 2018-2020. A total of 293 RCs were registered, with roughly 100 cases yearly. The distribution by age shows a significant decrease in the 30-59 age group (33.7% in 2018, 24.8% in 2019, and 19.8% in 2020). The incidence of Stage I was 59.4%, 46.5%, and 58.2% in 2018, 2019, and 2020, respectively, whereas the Stage II rate had values of 6.9%, 7.9%, and 2.2% in the years 2018, 2019, and 2020, respectively. Slight non-significant variations were observed in Stages III and IV. Surgery was performed in 83.2% of cases in 2018, 78.2% in 2019, and 82.4% in 2020; the surgery distribution by stage showed no significant differences. Chemotherapy showed an increase in 2020, which was statistically significant only for Stage IV. The gender incidence trends over the last 25 years showed an increase in the male sex in the first period; then, a decline was documented, likely due to a decrease in cigarette consumption. In females, the trend was constant. The RC mortality trend significantly dropped in both genders over the entire study period.

A multicenter phase 2 single arm study of cabozantinib in patients with advanced or unresectable renal cell carcinoma pre-treated with one immune-checkpoint inhibitor: The BREAKPOINT trial (Meet-Uro trial 03).

BACKGROUND: First-line therapies based on immune-checkpoint inhibitors (ICIs) significantly improved survival of metastatic renal cell carcinoma (mRCC) patients. Cabozantinib was shown to target kinases involved in immune-escape and to prolong survival in patients pre-treated with tyrosine-kinase-inhibitors (TKIs). The impact of ICIs combinations in first line on subsequent therapies is still unclear. METHODS: This is an open label, multicenter, single arm, phase II study designed to assess activity, safety and efficacy of cabozantinib in mRCC patients progressed after an adjuvant or first line anti-Programmed Death (PD)-1/PD-Ligand (PD-L) 1-based therapy. Primary endpoint was progression free survival (PFS), secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. RESULTS: 31 patients were included in the analysis. After a median (m) follow-up of 11.9 months, mPFS was 8.3 months (90%CI 3.9-17.4) and mOS was 13.8 months (95%CI 7.7-29.0). ORR was 37.9% with an additional 13 patients achieving disease stability. Grade 3-4 adverse events occurred in 47% of patients, including more frequently creatine phosphokinase (CPK) serum level elevation, neutropenia, hyponatremia, diarrhea, hand-food syndrome, oral mucositis and hypertension. CONCLUSIONS: The BREAKPOINT trial met its primary endpoint showing that cabozantinib as second line therapy after ICIs was active in mRCC. Safety profile was manageable. TRIAL REGISTRATION NUMBER: NCT03463681 - A Study of CaBozantinib in Patients With Advanced or Unresectable Renal cEll cArcinoma (BREAKPOINT) - https://clinicaltrials.gov/ct2/show/NCT03463681.

Addition of Niraparib to Best Supportive Care as Maintenance Treatment in Patients with Advanced Urothelial Carcinoma Whose Disease Did Not Progress After First-line Platinum-based Chemotherapy: The Meet-URO12 Randomized Phase 2 Trial.

BACKGROUND: Platinum-based chemotherapy (PBCT) is the standard first-line treatment for advanced urothelial carcinoma (UC). Potential cross-sensitivity can be hypothesized between platinum drugs and poly-ADP ribose-polymerase (PARP) inhibitors. OBJECTIVE: To compare maintenance treatment with the PARP inhibitor niraparib plus best supportive care (BSC) versus BSC alone in patients with advanced UC without disease progression after first-line PBCT. DESIGN, SETTING, AND PARTICIPANTS: Meet-URO12 is a randomized, multicenter, open-label phase 2 trial. Patients with advanced UC, without disease progression after four to six cycles of PBCT, with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, were enrolled between August 2019 and March 2021. Randomization was stratified by ECOG performance status (0/1) and response to PBCT (objective response/stable disease). INTERVENTION: Patients were randomized (2:1) to experimental arm A (niraparib 300 or 200 mg daily according to body weight and baseline platelets, plus BSC) or control arm B (BSC alone). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was progression-free survival (PFS). The analysis was performed on an intention-to-treat basis. The secondary endpoints reported in this primary analysis are progression-free rate at 6 mo and safety (adverse event rate). RESULTS AND LIMITATIONS: Fifty-eight patients were randomized (39 in arm A and 19 in arm B). The median age was 69 yr, ECOG performance status was 0 in 66% and 1 in 34%; and the best response with chemotherapy was objective response in 55% and stable disease in 45%. The median PFS was 2.1 mo in arm A and 2.4 mo in arm B (hazard ratio 0.92; 95% confidence interval 0.49-1.75, p = 0.81). The 6-mo progression-free rates were 28.2% and 26.3%, respectively. The most common adverse events with niraparib were anemia (50%, grade [G]3 11%), thrombocytopenia (37%, G3-4 16%), neutropenia (21%, G3 5%), fatigue (32%, G3 16%), constipation (32%, G3 3%), mucositis (13%, G3 3%), and nausea (13%, G3 3%). The main limitation of the study is the small sample size: in March 2021, approval of maintenance avelumab for the same setting rendered randomization of patients in the control arm to BSC alone unethical, and accrual was stopped prematurely. CONCLUSIONS: Addition of maintenance niraparib to BSC after first-line PBCT did not demonstrate a significant improvement in PFS in patients with UC. These results do not support the conduction of a phase 3 trial with single agent niraparib in this population. PATIENT SUMMARY: In this trial, we tested the efficacy of niraparib as maintenance treatment in patients affected by advanced urothelial cancer after the completion of first-line chemotherapy. We could not demonstrate a significant improvement in progression-free survival with maintenance niraparib.

Concomitant Drugs Prognostic Score in Patients With Metastatic Renal Cell Carcinoma Receiving Ipilimumab and Nivolumab in the Compassionate Use Program in Italy: Brief Communication.

A concomitant drug-based score was developed by our group and externally validated for prognostic and predictive purposes in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). The model considers the use of three classes of drugs within a month before initiating ICI, assigning score 1 for each between proton pump inhibitor and antibiotic administration until a month before immunotherapy initiation and score 2 in case of corticosteroid intake. In the present analysis, the drug score was validated in a prospective population of 305 patients with metastatic renal cell carcinoma treated with ipilimumab plus nivolumab in the first-line setting. The value of the model in predicting overall survival and progression-free survival was statistically significant and clinically meaningful, with an overall survival rate at 12 months of 73% vs. 44% (P<0.0001), and median progression-free survival of 11.6 (95% CI: 9.1-14.1) months versus 4.8 (95% CI: 2.7-7.0) months (P=0.002), respectively, for patients belonging to the favorable group (score 0-1) versus the unfavorable (score 2-4). Further development will be represented by the gut microbiome analysis according to the drug-based model classification and to the outcome of patients to ICI therapy to demonstrate the link between drug exposure and immune sensitivity.

Trends in Incidence and Mortality of Kidney Cancer in a Northern Italian Province: An Update to 2020.

The aim of this study was to examine the incidence and mortality trends for tumors and cardiovascular disease (CVD) in a province of northern Italy. The study included kidney cancers recorded in the period 1996−2020, divided by sex, age, year of incidence and years from diagnosis. The standardized incidence rate was calculated using the European population, and the Annual Percent Change (APC) was reported. In total, 2331 patients with kidney cancers were identified, mainly males (1504 cases) aged 60−79 years (1240 cases). There were 1257 deaths; there were no differences according sex but there were differences according to age (12.1% among younger adults and 80.4% among 80+). The incidence rate increased in males between 1996 and 2011 (APC = 2.3), while the mortality rate decreased in both males (APC = −3.3%) and females (APC = −4.5%). Comparing the same periods, kidney cancer-specific mortality decreased from 81.8% to 43.7%, while in the same period there was an increasing trend for CVD mortality. Moreover, the risk of CVD mortality increased as we moved away from the diagnosis (from 6.2% to 27.5%, p < 0.01). The same trend was observed for other causes of death (from 12.6% to 32.1%, p < 0.01). Thus, a multidisciplinary approach seems necessary during the follow-up and treatments of patients with kidney cancer.

Nivolumab in Combination with Stereotactic Body Radiotherapy in Pretreated Patients with Metastatic Renal Cell Carcinoma. Results of the Phase II NIVES Study.

BACKGROUND: Nivolumab showed an overall survival (OS) benefit in pretreated metastatic renal cell carcinoma (mRCC). The role of stereotactic body radiotherapy (SBRT) in mRCC remains to be defined. OBJECTIVE: Our aim was to evaluate the efficacy and safety of SBRT in combination with nivolumab in second- and third-line mRCC patients. DESIGN, SETTING, AND PARTICIPANTS: The NIVES study was a phase II, single-arm, multicenter trial in patients with mRCC with measurable metastatic sites who progressed after antiangiogenic therapy, of whom at least one was suitable for SBRT. INTERVENTION: The patients received SBRT to a lesion at a dose of 10 Gy in three fractions for 7 d from the first infusion of nivolumab. Nivolumab was given at an initial dose of 240 mg every 14 d for 6 mo and then 480 mg q4-weekly in responding patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We hypothesized that nivolumab plus SBRT improves the objective response rate (ORR) compared with nivolumab alone from 25% (derived from historical controls) to 40%. Secondary endpoints were progression-free survival (PFS), OS, disease control rate (DCR) of irradiated and nonirradiated metastases, and safety. RESULTS AND LIMITATIONS: Sixty-nine patients were enrolled from July 2017 to March 2019. The ORR was 17% and the DCR was 55%. The median PFS was 5.6 mo (95% confidence interval [CI], 2.9-7.1) and median OS 20 mo (95% CI, 17-not reached). After 1.5 yr of follow-up, 23 patients died. The median time to treatment response was 2.8 mo and median duration of response was 14 mo. No new safety concerns arose. CONCLUSIONS: We did not find sufficient evidence to suggest that nivolumab in combination with SBRT provides an added benefit in pretreated mRCC patients; it should however be evaluated in patients with oligometastatic or oligoprogressive disease. PATIENT SUMMARY: Nivolumab in combination with stereotactic body radiotherapy does not provide evidence of increased outcomes in metastatic renal cell carcinoma patients. However this approach was safe and showed a good response of the irradiated lesions.

GU-CA-COVID: a clinical audit among Italian genitourinary oncologists during the first COVID-19 outbreak.

BACKGROUND: Considering the growing genitourinary (GU) cancer population undergoing systemic treatment with immune checkpoint inhibitors (ICIs) in the context of the COVID-19 pandemic, we planned a clinical audit in 24 Italian institutions treating GU malignancies. OBJECTIVE: The primary objective was investigating the clinical impact of COVID-19 in GU cancer patients undergoing ICI-based therapy during the first outbreak of SARS-CoV-2 contagion in Italy. DESIGN SETTING AND PARTICIPANTS: The included centers were 24 Oncology Departments. Two online forms were completed by the responsible Oncology Consultants, respectively, for metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC) patients receiving at least one administration of ICIs between 31 January 2020 and 30 June 2020. RESULTS AND LIMITATION: In total, 287 mRCC patients and 130 mUC patients were included. The COVID-19 incidence was, respectively, 3.5%, with mortality 1%, in mRCC patients and 7.7%, with mortality 3.1%, in mUC patients. In both groups, 40% of patients developing COVID-19 permanently discontinued anticancer treatment. The pre-test SARS-CoV-2 probability in the subgroup of patients who underwent nasal/pharyngeal swab ranged from 14% in mRCC to 26% in mUC. The main limitation of the work was its nature of audit: data were not recorded at the single-patient level. CONCLUSION: GU cancer patients undergoing active treatment with ICIs have meaningful risk factors for developing severe events from COVID-19 and permanent discontinuation of therapy after the infection. Treatment delays due to organizational issues during the pandemic were unlikely to affect the treatment outcome in this population.

Maintenance versus discontinuation of androgen deprivation therapy during continuous or intermittent docetaxel administration in castration-resistant prostate cancer patients: A multicentre, randomised Phase III study by the Piemonte Oncology Network.

BACKGROUND: This study was designed to demonstrate the non-inferiority (NI) in overall survival (OS) of suspension of androgen deprivation therapy (ADT) versus maintenance and intermittent versus continuous docetaxel administration in metastatic castration-resistant prostate cancer (mCRPC) patients. PATIENTS AND METHODS: mCRPC patients were randomised to first-line docetaxel with maintenance or suspension of ADT. Patients attaining a prostate-specific antigen (PSA) response after four chemotherapy cycles underwent second randomisation to receive continuous or intermittent docetaxel therapy. Six hundred patients were to be randomised to achieve 80% statistical power to demonstrate an NI hazard ratio (HR) of 1.25 of interruption versus maintenance of ADT. RESULTS: The trial was prematurely closed when 198 participants were randomised. OS was similar in patients who continued (N = 96) versus those who interrupted (n = 102) ADT during docetaxel therapy (HR 0.98, 95% confidence interval [CI] 0.72-1.33] and those on a continuous (N = 35) versus an intermittent (N = 42) docetaxel schedule (HR 0.86, 95% CI 0.55-1.43). No difference in radiological progression-free survival, PSA response, or toxicity was observed between the study arms. The actual NI hazard margins of OS in Arms A and B patients were 1.33 and 1.43, respectively. CONCLUSIONS: This trial enrolled one-third of the planned patients; this main weakness dramatically limits the interpretation of the results. ADT discontinuation and switching to an intermittent schedule did not seem to affect docetaxel efficacy. The absence of testosterone recovery in the majority of patients could have been a contributory factor. In men with mCRPC, ADT discontinuation should only be done with regular biochemical and clinical monitoring, with the option of quickly restarting ADT at disease progression.

Inflammatory indices and clinical factors in metastatic renal cell carcinoma patients treated with nivolumab: the development of a novel prognostic score (Meet-URO 15 study).

BACKGROUND: Despite the survival advantage, not all metastatic renal cell carcinoma (mRCC) patients achieve a long-term benefit from immunotherapy. Moreover, the identification of prognostic biomarkers is still an unmet clinical need. METHODS: This multicenter retrospective study investigated the prognostic role of peripheral-blood inflammatory indices and clinical factors to develop a novel prognostic score in mRCC patients receiving at least second-line nivolumab. The complete blood count before the first cycle of therapy was assessed by calculating neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and systemic inflammation response index (SIRI). Clinical factors included pre-treatment International Metastatic RCC Database Consortium (IMDC) score, line of therapy, and metastatic sites. RESULTS: From October 2015 to November 2019, 571 mRCC patients received nivolumab as second- and further-line treatment in 69% and 31% of cases. In univariable and multivariable analyses all inflammatory indices, IMDC score, and bone metastases significantly correlated with overall survival (OS). The multivariable model with NLR, IMDC score, and bone metastases had the highest c-index (0.697) and was chosen for the developing of the score (Schneeweiss scoring system). After internal validation (bootstrap re-sampling), the final index (Meet-URO score) composed by NLR, IMDC score, and bone metastases had a c-index of 0.691. It identified five categories with distinctive OSs: group 1 (median OS - mOS = not reached), group 2 (mOS = 43.9 months), group 3 (mOS = 22.4 months), group 4 (mOS = 10.3 months), and group 5 (mOS = 3.2 months). Moreover, the Meet-URO score allowed for a fine risk-stratification across all three IMDC groups. CONCLUSION: The Meet-URO score allowed for the accurate stratification of pretreated mRCC patients receiving nivolumab and is easily applicable for clinical practice at no additional cost. Future steps include its external validation, the assessment of its predictivity, and its application to first-line combinations.

Sequencing Life-Prolonging Agents in Castration-Resistant Prostate Cancer Patients: Comparison of Sequences With and Without 223Ra.

Background: The retrospective studies that have so far described the outcomes of the sequential use of life-prolonging agents (LPAs) did not include metastatic castration-resistant prostate cancer (mCRPC) patients who received radium-223 (223Ra) as part of their treatment. Consequently, it is not known whether including 223Ra in the therapeutic sequence has an impact on cumulative survival. The aim of this study was to evaluate this impact by comparing the cumulative overall survival (OS) in two series of mCRPC patients sequentially treated with two or three LPAs after first-line docetaxel (DOC), including 223Ra and not. Materials and Methods: The authors retrospectively reviewed the records of mCRPC patients with bone involvement alone who received two or three LPAs (including 223Ra) after first-line DOC. The control group was a contemporary series of mCRPC patients with bone involvement alone treated with sequences of two or three LPAs other than 223Ra after first-line DOC. Results: Median cumulative OS was 40.6 months in the 223Ra group of 78 patients and 36.2 months in the non-223Ra group of 186 patients (p = 0.08). OS outcomes were significantly influenced by the number of treatment lines, and baseline Eastern Cooperative Oncology Group performance status (PS) and prostate-specific antigen levels. Conclusions: To the best of the authors' knowledge, this is the first study designed to evaluate the impact of introducing 223Ra in the treatment sequences for mCRPC patients, and the results show that its use does not negatively affect cumulative OS.

Exceptional response to immunotherapy in association with radiotherapy in patient with breast metastasis from urothelial carcinoma: A case report.

Most common sites of metastasis of urothelial carcinoma (UC) are lungs, liver, lymph nodes and bone. Pembrolizumab, a humanized monoclonal antibody directed against programmed cell death protein-1 (PD-1), represents an effective second-line therapy for advanced UC. Radiotherapy has been shown to induce a mechanism of immunogenic cell death (ICD) resulting in immune memory and advantageous systemic effects. We present the first case of breast metastasis (BM) from a UC described in literature who had an exceptional response to second-line therapy with pembrolizumab in association with radiotherapy, showing the efficacy of combining immunotherapy and radiotherapy even in patients with atypical metastatic sites.

Incidence and outcomes of severe acute respiratory syndrome coronavirus 2 infection in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Patients with cancer are at increased risk of complicated severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, but it is still unclear if the risk of mortality is influenced by cancer type or ongoing anti-cancer treatments. An interesting debate concerning the potential relationship between androgen deprivation therapy (ADT) and SARS-CoV-2 infection has recently been opened in the case of prostate cancer (PC), and the aim of this multi-centre cohort study was to investigate the incidence and outcomes of SARS-CoV-2 infection in patients with metastatic castration-resistant prostrate cancer (mCRPC). PATIENTS AND METHODS: We retrospectively reviewed the clinical records of patients with mCRPC who developed SARS-CoV-2 infection, and recorded their baseline clinical characteristics, their history of PC and SARS-CoV-2 infection, and their oncological status and treatment at the time of infection. The primary study end point was the death rate and the possible impact of the patients' PC-related history and treatments on mortality. RESULTS: Thirty-four of the 1433 patients with mCRPC attending the participating centres (2.3%) developed SARS-CoV-2 infection, 22 (64.7%) of whom were hospitalised. Most of the patients were symptomatic, the most frequent symptoms being fever (70.6%), dyspnoea (61.8%), cough (52.9%) and fatigue (38.2%). After a median follow-up of 21 days (interquartile range: 13-41), 13 patients had died (38.2%), 17 recovered (50.0%) and four (11.7%) were still infected. The number of treatments previously administered for mCRPC had a significant impact on mortality (p = 0.004). CONCLUSIONS: Our findings contribute additional data to the current debate concerning the postulated protective role of ADT, which seems to be less in patients with metastatic PC.