Safety and Efficacy of Tivozanib in First-Line mRCC: A Multicenter Compassionate-Use Study (Meet-Uro 16).

INTRODUCTION: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, and VEGFR-3, recently approved in Europe for the first-line treatment of metastatic renal cell carcinoma (mRCC). METHODS: Retrospective analysis of safety and activity of tivozanib administered at 1.34 mg daily (3 weeks on, 1 week off) within a compassionate-use program to patients with mRCC with no prior systemic treatment in Italy. RESULTS: From August 2018 to April 2019, 64 patients have started tivozanib in 9 oncology units. The median age was 67.5 years (range 40-85), 62.5% males. According to International Metastatic Renal Cell Carcinoma Database Consortium criteria, 27.1% of patients were good prognosis, 57.6% intermediate, and 15.3% poor. Primary tumor had been removed in 71.9% of patients. Histology was clear cell 89%, papillary 4.7%, and unclassified 6.3%. The response rate was 34.4%, stable disease 40.6%, and progression 15.6%. Grade 3-4 toxicities were 7.8% hypertension, 4.7% anemia, 3.1% mucositis, 3.1% asthenia, 1.6% diarrhea, 1.6% anorexia, 1.6% worsening of renal function, and 3.1% cardiac events. Dose reduction to 0.89 mg was applied to 17.2% of patients, and the discontinuation rate due to toxicity was 5.8%. Median progression-free survival was 12.4 months, with 68.7% of patients alive at 12 months. The developing of hypertension predicted increased progression-free survival at multivariate analysis (HR, 0.128; 95% CI, 0.03-0.59; p = 0.008). CONCLUSIONS: Tivozanib showed good activity and favorable safety profile in a real-world cohort of unselected patients with mRCC. Predictive biomarkers of response to antiangiogenic therapy are urgently needed in order to identify RCC patients who could still receive a monotherapy with VEGFR inhibitors in the first line.

Renal Cell Carcinoma: the Oncologist Asks, Can PSMA PET/CT Answer?

PURPOSE OF REVIEW: To critically review the potential clinical applications of prostate-specific membrane antigen (PSMA) radioactive ligands in renal cell carcinoma (RCC). RECENT FINDINGS: Radioactive probes targeting PSMA hold promise in several malignancies in addition to prostate cancer, owing to the expression of PSMA by tumor neovasculature. The majority of clear cell RCCs (ccRCC), the most malignant RCC subtype, express PSMA on tumor-associated neovasculature. The endothelium of less aggressive RCC subtypes is PSMA positive in a lower, but still significant percentage of cases. PSMA might therefore represent an interesting theragnostic target in RCC. The preliminary data available suggest a potential role for PSMA-targeting radiopharmaceuticals in complementing conventional imaging for staging ccRCC patients at risk of nodal involvement and oligometastatic disease. Additional applications of PSMA imaging may be the selection and the response assessment of patients receiving anti-angiogenic treatments. The effectiveness of PSMA-targeting radionuclide therapy should also be investigated.

Duration of response to first androgen deprivation therapy, time to castration resistance prostate cancer, and outcome of metastatic castration resistance prostate cancer patients treated with abiraterone acetate.

Abiraterone acetate (AA) demonstrated its efficacy in the treatment of patients with metastatic castration resistance prostate cancer (mCRPC) in predocetaxel and postdocetaxel setting. However, we learn from pivotal studies that forms of primary and acquired resistance to this drug exist. Patient selection becomes so crucial to optimize treatment results. Potential predictive biomarkers have been identified but are not yet validated. In this scenario, clinical features and disease characteristics may still be of value in selecting patients for different treatments. The objective of this retrospective study was to assess whether or not a correlation between duration of response to first androgen deprivation therapy (ADT), time to castration-resistant prostate cancer (TTCRPC), and outcome of AA therapy exists. A retrospective analysis of clinical data of mCRPC patients treated with AA at two Italian cancer centers was carried out. The Kaplan-Meier method and Cox proportional hazard model were used to analyze survival data. Correlation between median duration of response to first ADT or median TTCRPC and the outcome of patients treated with AA was analyzed. From January 2015 to November 2015, data of 59 patients with mCRPC were collected. We observed no differences in patient's median progression-free survival (PFS) and biochemical progression-free survival (bPFS), according to both median duration of response to first-line ADT (duration of first ADT<13 months: median PFS and bPFS were 11 and 5 months, respectively; duration of ADT≥13 months: median PFS and bPFS were 9 and 6 months, respectively) and median TTCRPC (TTCRPC<28 months: median PFS and bPFS were 8 and 5 months, respectively; TTCRPC≥28 months: median PFS and bPFS were 10 and 9 months, respectively). Overall survival, in the same group, did not differ between patients with a duration of response to first ADT over or under 13 months (P=0.90) but in patients with a TTCRPC of 28 months or more, there was a trend toward longer survival than patients with TTCRPC less than 28 months (5-year overall survival was 74 vs. 50%; P=0.14). The duration of response to first-line ADT and the TTCRPC showed no significant association with outcome of AA therapy in patients with mCRPC. However, large prospective trials are desirable to confirm these data.

Evaluation of 5-fluorouracil degradation rate and Pharmacogenetic profiling to predict toxicity following adjuvant Capecitabine.

BACKGROUND: On account of the lack of predictive biomarkers of toxicity, we investigated whether polymorphisms of genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with outcomes of adjuvant capecitabine in patients with early stage gastrointestinal cancers. METHODS: Genotyping of DPYD GIVS14A, MTHFR C677T and A1298C SNPs were performed by pyro-sequencing technology. PCR analysis was used for genotyping TYMS-TSER. We also evaluated the 5-FU degradation rate, which determines the amount of drug consumed by PBMC in a time unit. Association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis. RESULTS: One hundred forty-two patients with early stage colon (39%), rectal (28%), stomach (20%) and pancreatic (13%) cancer, treated with adjuvant capecitabine, were included in this retrospective analysis. Seventy and 20% of the patients suffered from at least one G1-4 and G3-4 adverse events, respectively. According to the 5-FU degradation rate, three and 13 patients were assigned as poor (<0.86 ng/mL/106 cells/min) and ultra-rapid (>2.1 ng/mL/106 cells/min) metabolizers, respectively. At a multivariate logistic regression analysis, an altered 5-FU degradation rate (values <0.86 or >2.10 ng/mL/106 cells/min) was associated with grade 3-4 adverse events (OR = 2.09, 95% CI: 1.14-3.82, P = 0.01). No correlation was reported between toxicity and gene polymorphisms except for hand-foot syndrome that was more frequent in the MTHFR 1298CC homozygous variant genotype (OR = 2.03, 95% CI 1.04-3.96, P = 0.03). CONCLUSIONS: 5-FU degradation rate may be regarded as possible predictive biomarker of capecitabine toxicity in early stage gastrointestinal cancer.

Real World Analysis of Peritoneal Metastasis From Renal Cell Carcinoma. Meet-Uro27.

BACKGROUND: Peritoneal metastases (PM) have been reported in approximately 1% of patients with metastatic Renal Cell Carcinoma (mRCC). Outcome data are limited due to the rarity of this metastatic site. Therefore, the aim of our study is to describe renal cell carcinoma (RCC) patients with PM treated as per clinical practice. MATERIALS AND METHODS: Baseline characteristics and outcome data of patients with PM from RCC were retrospectively collected from 18 Italian oncological referral centers adhering to the Meet-Uro group, from January 2016 to January 2023. RESULTS: We collect 81 RCC patients with PM. 78/81 received systemic treatment, 3/81 only best supportive care. First line treatment included tyrosine-kinase inhibitors (TKI) (46/78), ImmuneOncology (IO)-TKI (26/78) and IO-IO (6/78), with different Objective Response Rate (ORR) (43.4% in TKI monotherapy group vs 50% in IO-TKI group, respectively) and Disease Control Rate (DCR) (60.8% in TKI treated patients vs. 76.9% in IO-TKI treated patients). Median PFS was 6.4 months (95%CI 4.18-14.8) in patients treated with TKI monotherapy vs 23.7 months (95%CI 11.1-NR) in patients treated with IO-TKI (p < 0.015). The median OS (mOS) was 22.7 months (95%CI 13.32 - 64.7) in the TKI monotherapy group vs 34.5 mo (95%CI NR-NR) in the IO-TKI group with 53.8% of patients alive at 1 years in the latter group, (p < 0.16). Primary refractory patients were 36.9% for TKI and 15.3% for IO-TKI. According to International Metastatic renal cell carcinoma Database Consortium (IMDC) score, mPFS and mOS were consistent among risk categories. Median PFS was 36.6 months (95%CI 10.9-NR) for good risk patients compared to 10 months (95%CI 7.5-29.8) for intermediate risk and 2.96 months (95%CI 2.43-11.28) for poor risk population (p < 0.0005) whereas mOS was NR (95%CI 28.65-NR) for good risk patients compared to 35.3 months (95%CI 24.6-NA) and 12.4 months (95%CI 3.52-NR) for intermediate and poor risk population, respectively, (p < 0.0002). Only 34/78 (43.5%) received a second line treatment that was TKI (ORR 8.3% and DCR 41.6%) or IO (ORR 18.1% and DCR 40.9%). CONCLUSION: We report one of the largest case series regarding PM from RCC. Characteristics of patients suggest a more aggressive behavior of PM from mRCC. Outcome data suggest that TKI-IO as first line treatment, and TKI as second line, confirm their activity for these patients with dismal prognosis.

Clinical Outcomes and Prognostic Factors in Patients With Penile Carcinoma: A Sub-Analysis From Meet-URO 23 (I-RARE) Registry Study.

INTRODUCTION: Penile squamous cell carcinoma (PSCC) is a rare tumor with an aggressive behavior. The Meet-URO 23/I-RARE registry includes rare genitourinary malignancies. We extracted patients with PSCC to conduct a retrospective study aimed at assessing clinical outcomes and prognostic factors. PATIENTS AND METHODS: Primary endpoints were overall survival and progression-free survival. Prognostic factors for OS and PFS were analyzed using univariate and multivariate analysis. From the Meet-URO 23/I-RARE database, we extracted 128 patients with diagnosis of PSCC. About 48% of patients underwent first-line of therapy. RESULTS: In the overall population, median OS from diagnosis was 34.6 months. Significant differences in median OS were observed according to ECOG PS at diagnosis (57.3 months vs. 8.3 months; P < .001), and median age (≤77y 88.8 months vs. >77y 26 months; P = .013). At multivariate analysis, ECOG PS 2-4 at diagnosis (HR 3.04) and lymph node metastases (HR 2.49) were independently associated with a higher risk of death. Among patients undergoing first-line therapy (n = 61), median OS was 12.3 months, and a statistically significant difference was found according to type of response to first-line (DCR 24.4 months vs. PD 7.1 months; P < .001). Multivariate analysis showed that only age >77 years was associated with a worse OS (HR 2.16). A statistically significant difference in PFS was found according to platinum plus 5-fluorouracil versus platinum plus taxane (4.9 vs. 3.4 months; P = .036) and regimens with 2 versus 3 drugs (3.4 vs. 8.6 months; P = .019). At the multivariate analysis only regimens with platinum plus taxane were associated with worse PFS (HR 2.83). CONCLUSION: In our registry study, PSCC is confirmed to be an aggressive disease. Poor ECOG PS, presence of lymph node metastases, and higher age at diagnosis appear to be associated with worse survival outcomes.

Real-world Outcome of Patients with Advanced Renal Cell Carcinoma and Intermediate- or Poor-risk International Metastatic Renal Cell Carcinoma Database Consortium Criteria Treated by Immune-oncology Combinations: Differential Effectiveness by Risk Group?

BACKGROUND: Renal c carcinoma (RCC) is one of the most common urinary cancers worldwide, with a predicted increase in incidence in the coming years. Immunotherapy, as a single agent, in doublets, or in combination with anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), has rapidly become a cornerstone of the RCC therapeutic scenario, but no head-to-head comparisons have been made. In this setting, real-world evidence emerges as a cornerstone to guide clinical decisions. OBJECTIVE: The objective of this retrospective study was to assess the outcome of patients treated with first-line immune combinations or immune oncology (IO)-TKIs for advanced RCC. DESIGN, SETTING, AND PARTICIPANTS: Data from 930 patients, 654 intermediate risk and 276 poor risk, were collected retrospectively from 58 centers in 20 countries. Special data such as sarcomatoid differentiation, body mass index, prior nephrectomy, and metastatic localization, in addition to biochemical data such as hemoglobin, platelets, calcium, lactate dehydrogenase, neutrophils, and radiological response by investigator's criteria, were collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. The median follow-up was calculated by the inverse Kaplan-Meier method. RESULTS AND LIMITATIONS: The median follow-up time was 18.7 mo. In the 654 intermediate-risk patients, the median OS and PFS were significantly longer in patients with the intermediate than in those with the poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (38.9 vs 17.3 mo, 95% confidence interval [CI] p < 0.001, and 17.3 vs 11.6 mo, 95% CI p < 0.001, respectively). In the intermediate-risk subgroup, the OS was 55.7 mo (95% CI 31.4-55.7) and 40.2 mo (95% CI 29.6-51.6) in patients treated with IO + TKI and IO + IO combinations, respectively (p = 0.047). PFS was 30.7 mo (95% CI 16.5-55.7) and 13.2 mo (95% CI 29.6-51.6) in intermediate-risk patients treated with IO + TKI and IO + IO combinations, respectively (p < 0.001). In the poor-risk subgroup, the median OS and PFS did not show a statistically significant difference between IO + IO and IO + TKI. Our study presents several limitations, mainly due to its retrospective nature. CONCLUSIONS: Our results showed differences between the IO + TKI and IO + IO combinations in intermediate-risk patients. A clear association with longer PFS and OS in favor of patients who received the IO + TKI combinations compared with the IO-IO combination was observed. Instead, in the poor-risk group, we observed no significant difference in PFS or OS between patients who received different combinations. PATIENT SUMMARY: Renal cancer is one of the most frequent genitourinary tumors. Treatment is currently based on immunotherapy combinations or immunotherapy with tyrosine kinase inhibitors, but there are no comparisons between these.In this study, we have analyzed the clinical course of 930 patients from 58 centers in 20 countries around the world. We aimed to analyze the differences between the two main treatment strategies, combination of two immunotherapies versus immunotherapy + antiangiogenic therapy, and found in real-life data that intermediate-risk patients (approximately 60% of patients with metastatic renal cancer) seem to benefit more from the combination of immunotherapy + antiangiogenic therapy than from double immunotherapy. No such differences were found in poor-risk patients. This may have important implications in daily practice decision-making for these patients.

Geographical differences in the management of metastatic de novo renal cell carcinoma in the era of immune-combinations.

BACKGROUND: The upfront treatment of metastatic renal cell carcinoma (mRCC) has been revolutionized by the introduction of immune-based combinations. The role of cytoreductive nephrectomy (CN) in these patients is still debated. The ARON-1 study (NCT05287464) was designed to globally analyze real-world data of mRCC patients receiving first-line immuno-oncology combinations. This sub-analysis is focused on the role of upfront or delayed partial or radical CN in three geographical areas (Western Europe, Eastern Europe, America/Asia). METHODS: We conducted a multicenter retrospective observational study in mRCC patients treated with first-line immune combinations from 55 centers in 19 countries. From 1152 patients in the ARON-1 dataset, we selected 651 patients with de novo mRCC. 255 patients (39%) had undergone CN, partial in 14% and radical in 86% of cases; 396 patients (61%) received first-line immune-combinations without previous nephrectomy. RESULTS: Median overall survival (OS) from the diagnosis of de novo mRCC was 41.6 months and not reached (NR) in the CN subgroup and 24.0 months in the no CN subgroup, respectively (P<0.001). Median OS from the start of first-line therapy was NR in patients who underwent CN and 22.4 months in the no CN subgroup (P<0.001). Patients who underwent CN reported longer OS compared to no CN in all the three geographical areas. CONCLUSIONS: No significant differences in terms of patients' outcome seem to clearly emerge, even if the rate CN and the choice of the type of first-line immune-based combination varies across the different Cancer Centers participating in the ARON-1 project.

Global Real-World Outcomes of Patients Receiving Immuno-Oncology Combinations for Advanced Renal Cell Carcinoma: The ARON-1 Study.

BACKGROUND: Immuno-oncology combinations have achieved survival benefits in patients with metastatic renal cell carcinoma (mRCC). OBJECTIVE: The ARON-1 study (NCT05287464) was designed to globally collect real-world data on the use of immuno-combinations as first-line therapy for mRCC patients. PATIENTS AND METHODS: Patients aged ≥ 18 years with a cytologically and/or histologically confirmed diagnosis of mRCC treated with first-line immuno-combination therapies were retrospectively included from 47 International Institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit (OCB). RESULTS: A total of 729 patients were included; tumor histology was clear-cell RCC in 86% of cases; 313 patients received dual immuno-oncology (IO + IO) therapy while 416 were treated with IO-tyrosine kinase inhibitor (IO + TKI) combinations. In the overall study population, the median OS and PFS were 36.5 and 15.0 months, respectively. The median OS was longer with IO+TKI compared with IO+IO therapy in the 616 patients with intermediate/poor International mRCC Database Consortium (IMDC) risk criteria (55.7 vs 29.7 months; p = 0.045). OCB was 84% for IO+TKI and 72% for IO + IO combination (p < 0.001). CONCLUSIONS: Our study may suggest that immuno-oncology combinations are effective as first-line therapy in the mRCC real-world context, showing outcome differences between IO + IO and IO + TKI combinations in mRCC subpopulations. CLINICAL TRIAL REGISTRATION: NCT05287464.

Clinico-Pathological Features Influencing the Prognostic Role of Body Mass Index in Patients With Advanced Renal Cell Carcinoma Treated by Immuno-Oncology Combinations (ARON-1).

BACKGROUND: Obesity has been associated with improved response to immunotherapy in cancer patients. We investigated the role of body mass index (BMI) in patients from the ARON-1 study (NCT05287464) treated by dual immuno-oncology agents (IO+IO) or a combination of immuno-oncology drug and a tyrosine kinase inhibitors (TKI) as first-line therapy for metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Medical records of patients with documented mRCC treated by immuno-oncology combinations were reviewed at 47 institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (OS), and overall clinical benefit (OCB), defined as the sum of the rate of partial/complete responses and stable disease. Univariate and multivariate analyses were used to explore the association of variables of interest with survival. RESULTS: A total of 675 patients were included; BMI was >25 kg/m2 in 345 patients (51%) and was associated with improved OS (55.7 vs. 28.4 months, P < .001). The OCB of patients with BMI >25 kg/m2 versus those with BMI ≤25 kg/m2 was significantly higher only in patients with nonclear cell histology (81% vs. 65%, P = .011), and patients with liver metastases (76% vs. 58%, P = .007), Neutrophil to lymphocyte ratio >4 (77% vs 62%, P = .022) or treated by nivolumab plus ipilimumab (77% vs. 64%, P = .044). In the BMI ≤25 kg/m2 subgroup, significant differences were found between patients with NLR >4 versus ≤4 (62% vs. 82%, P = .002) and patients treated by IO+IO versus IO+TKIs combinations (64% vs. 83%, P = .002). CONCLUSION: Our study suggests that the prognostic significance and the association of BMI with treatment outcome varies across clinico-pathological mRCC subgroups.

Radiotherapy and Immunotherapy: The Power of the Teamwork for the Treatment of NSCLC.

Immune checkpoint inhibitors (ICPi) targeting programmed cell death 1(PD-1)/programmed cell death ligand-1 (PD-L1) have revolutionized the treatment of patients with advanced non-small cell lung cancer (NSCLC). Despite impressive success, only a small proportion of patients benefit from PD1/PDL1 inhibitors. Radiotherapy (RT) can induce a systemic anti-tumor immune response on local and distant tumors. Some preclinical and clinical evidence showed a critical role of RT to overcome acquired resistance to immunotherapy. Currently, durvalumab consolidation represents the new standard treatment for unresectable stage III NSCLC patients whose tumors express PDL1 on ≥1% of tumor cells (TC), and whose disease has not progressed following platinum-based chemoradiotherapy (CRT). In this review, we focus on the synergic effect of RT with ICPi and the new role that different RT schedules can play in combination with immunotherapy for early-stage NSCLC.

Systemic effect of radiotherapy before or after nivolumab in lung cancer: an observational, retrospective, multicenter study.

BACKGROUND: The combination of radiotherapy (RT) and programmed death 1 inhibitors seems to increase antitumor immune responses. OBJECTIVE: To assess the outcome and the role of the best combination sequence, i.e. immunotherapy given before, during, and/or after RT, in patients with non-small cell lung cancer (NSCLC). METHODS: We conducted an observational, retrospective analysis of 95 consecutive patients with advanced NSCLC who received any radiotherapy treatment and nivolumab, as clinically indicated. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan-Meier method. Cox model was used to obtain hazard ratio (HR) and associated 95% CI with statistical inference by log-rank statistic. RESULTS: Median OS was 11.9 months (95% CI, 6.6-17.2). Patients who received radiotherapy during an immune checkpoint inhibitor treatment started more than 60 days before showed a better outcome than patients who started immunotherapy over 60 days after RT ending (HR, 2.90 [1.37-6.12], p = 0.005; median OS, 22.4 months vs 8.6 months, p = 0.005). Median progression-free survival was 6.3 months (95% CI, 4.6-8.0). CONCLUSIONS: This study shows that combining irradiation with nivolumab for the treatment of advanced NSCLC leads to improved OS. The optimal time window for the combination of RT and immunotherapy seems to play a critical role for therapeutic antitumor response derived by abscopal effect.

Concomitant Use of Statins, Metformin, or Proton Pump Inhibitors in Patients with Advanced Renal Cell Carcinoma Treated with First-Line Combination Therapies.

BACKGROUND: Drug-drug interactions are a major concern in oncology and may potentially affect the outcome of patients with cancer. OBJECTIVE: In this study, we aimed to determine whether the concomitant use of statins, metformin, or proton pump inhibitors affects survival in patients with metastatic renal cell carcinoma treated with first-line combination therapies. METHODS: Medical records of patients with documented metastatic renal cell carcinoma between January 2016 and November 2021 were reviewed at 17 participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. Patients were assessed for overall survival, progression-free survival, and overall clinical benefit. Univariate and multivariate analyses were conducted to explore the association of variables of interest with overall survival and progression-free survival. RESULTS: A total of 304 patients receiving dual immunotherapy (51%) or immunotherapy/vascular endothelial growth factor-tyrosine kinase inhibitor (49%) combinations were eligible for inclusion in this retrospective study. Statin use was a significant prognostic factor for longer overall survival in a univariate analysis (hazard ratio 0.48, 95% confidence interval 0.26-0.87; p = 0.016) and a multivariate analysis (hazard ratio 0.48, 95% confidence interval 0.31-0.74; p < 0.001) and was significantly associated with an overall clinical benefit (83% in statin users vs 71% in non-users; p = 0.045). Otherwise, the use of metformin or proton pump inhibitors did not affect the outcome of these patients. CONCLUSIONS: Our study suggests a prognostic impact of statin use in patients receiving first-line immuno-oncology combinations. The mechanism of this interaction warrants further elucidation.

A 17-Gene Expression Signature for Early Identification of Poor Prognosis in Clear Cell Renal Cell Carcinoma.

The Identification of reliable Biomarkers able to predict the outcome after nephrectomy of patients with clear cell renal cell carcinoma (ccRCC) is an unmet need. The gene expression analysis in tumor tissues represents a promising tool for better stratification of ccRCC subtypes and patients' evaluation. METHODS: In our study we retrospectively analyzed using Next-Generation expression analysis (NanoString), the expression of a gene panel in tumor tissue from 46 consecutive patients treated with nephrectomy for non-metastatic ccRCC at two Italian Oncological Centres. Significant differences in expression levels of selected genes was sought. Additionally, we performed a univariate and a multivariate analysis on overall survival according to Cox regression model. RESULTS: A 17-gene expression signature of patients with a recurrence-free survival (RFS) < 1 year (unfavorable genomic signature (UGS)) and of patients with a RFS > 5 years (favorable genomic signature (FGS)) was identified and resulted in being significantly correlated with overall survival of the patients included in this analysis (HR 51.37, p < 0.0001). CONCLUSIONS: The identified Genomic Signatures may serve as potential biomarkers for prognosis prediction of non-metastatic RCC and could drive both follow-up and treatment personalization in RCC management.

[Pharmacogenomics and chemotherapy]. / Farmacogenomica e chemioterapia: attuali conoscenze.

Genetic factors could alter drug metabolism and activity and could predict drug toxicity and/or efficacy. Several chemotherapy agents are administered in different schedules for the treatment of different cancer histotypes. The most used drug in the treatment of gastro-intestinal, head and neck and breast neoplasms is the 5-fluorouracil (5-FU). Capecitabine is a prodrug of 5-FU. Cisplatin based chemotherapy is administered in the treatment of lung, genitourinary tract, head and neck, occult neoplasms, mesothelioma and melanoma. Taxanes are used in lung, breast, head and neck, genitourinary tract neoplasms and sarcomas. Determination of polymorphisms in metabolizing enzymes before the administration of chemotherapy could offer new strategies for optimizing the treatment of individual patients.

Safety and Efficacy of Nivolumab in Patients With Advanced Non-small-cell Lung Cancer Treated Beyond Progression.

INTRODUCTION: Treatment with immune checkpoint inhibitors beyond progression is associated with improved survival in patients with melanoma and clear-cell renal carcinoma. Whether this association exists for patients with non-small-cell lung cancer (NSCLC) is currently still unclear. PATIENTS AND METHODS: We performed a multi-institutional retrospective study based on landmark and multivariable analyses to evaluate the safety and efficacy of treatment with nivolumab beyond Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 progression in patients with advanced NSCLC. Criteria for receiving nivolumab beyond progression were investigator-assessed clinical benefit, stable performance status, tolerance of treatment, and no need of immediate intervention to prevent serious complication of progression. RESULTS: Of 176 patients progressed to nivolumab according to RECIST v1.1, 60 (34.1%) were treated beyond progression (TBP) and 116 (65.9%) were not-TBP (NTBP). The median overall survival was significantly longer in the TBP group compared with the NTBP group (17.8 vs. 3.7 months; hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.21-0.46; P < .0001). In a landmark analysis of evaluable patients beginning 6 weeks from first progression, the median overall survival for patients TBP was 10.7 months and for those NTBP, 3.4 months (HR, 0.48; 95% CI, 0.30-0.77; P = .002). Discontinuation of nivolumab at first progression was associated with shorter survival in multivariable analysis (HR, 2.98; 95% CI, 1.95-4.54; P < .001). No safety concerns emerged in patients who were in the TBP group. CONCLUSION: A subset of patients with NSCLC and progressive disease may continue to benefit from nivolumab beyond progression. Discontinuation of immunotherapy based only on RECIST v1.1 may be premature.

Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: long-term outcomes from a multi-institutional analysis.

PURPOSE: Immune-checkpoint inhibitors (ICIs) represent the standard of care for platinum-pretreated advanced non-small cell lung cancer patients. Patients treated with ICIs may experience immune-related adverse events (irAEs), that might reflect antitumor responses. Here we evaluated nivolumab efficacy according to the development of irAEs. METHODS: We conducted a multicenter retrospective study of patients with advanced NSCLC treated with nivolumab between October 2013 and September 2017. IrAEs were defined as AEs having immunological basis that required intensive monitoring and interventions. RESULTS: Among 195 patients [median (range) age, 63 (30-84) years; 128 men (65.6%), 67 women (34.4%)], irAEs were observed in 85 patients (43.6%), including 15 patients (7.6%) with grade 3 or 4 events. Median PFS was 5.7 months in irAEs group compared to 2.0 months of no-irAEs group [HR: 0.41 (95% CI 0.3-0.57), P < 0.0001]. Median OS was 17.8 months compared to 4.0 months of no-irAEs group [HR: 0.33 (95% CI 0.23-0.47), P < 0.0001]. IrAEs were significantly associated with improved clinical outcome in 12- and 6-week landmark analysis. Patients who developed ≥ 2 irAEs during treatment (n: 37) had a significantly longer median PFS and OS compared to those with one (n: 48) or none AEs (n: 110) (PFS: 8.5 months vs. 4.6 vs. 2.0, P < 0.0001; OS: 26.8 months vs. 11.9 vs. 4.0, P < 0.0001). Multivariable analysis revealed that irAEs were positively associated with PFS [HR: 0.48 (95% CI 0.34-0.67), P < 0.0001] and OS [HR: 0.38 (95% CI 0.26-0.56), P < 0.0001]. CONCLUSION: In this study we confirmed that the development of irAEs was a strong predictor of survival outcomes in NSCLC patients treated with nivolumab monotherapy in landmark and multivariable models. Patients who experienced ≥ 2 irAEs had a more pronounced survival benefit compared to those with 1 irAE further suggesting a mechanistic association between irAEs and immunotherapy efficacy.

Castration-resistance prostate cancer: what is in the pipeline?

INTRODUCTION: To evaluate the available evidence on the standard diagnosis and management of men with metastatic castration resistant prostate cancer (mCRPC), and providing the timely update on new pharmacological treatments. EVIDENCE ACQUISITION: A systematic literature search from from January 2000 until March 2017 was performed by combining the following MESH terms: castrate resistant prostate cancer, abiraterone, enzalutamide, 223radium, sipuleucel-T, docetaxel, cabazitaxel, resistance mechanisms, resistance to androgen deprivation, androgen receptor (AR) mutations, amplifications, splice variants, and AR alterations. We followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). EVIDENCE SYNTHESIS: In the few last years the introduction of new treatment modalities as abiraterone or enzalutamide have significantly change our prospective in mCRPC management increasing patients survival and quality of life. The standard imaging modalities to define the presence of regional or distant metastasis or the different resistant mechanisms to the available treatments are still an issue of debate, however several studies are ongoing to define the standard of care and to reduce treatments' resistance. Data from ongoing phase III trials are awaited to introduce in clinical new effective treatments that can be used in patients resistant to abiraterone/enzalutamide or more probably in a different phase of the disease. CONCLUSIONS: Castration resistant prostate cancer is now the key issue in prostate cancer management and research. Our challenge in the near future will be to identify the right treatment or better the right combination and sequencing of treatments that should be used in patients with mCRPC or even with advanced prostate cancer.

Heterogeneity of PD-L1 Expression and Relationship with Biology of NSCLC.

Immunotherapy with monoclonal antibodies against programmed cell death (PD-1), such as nivolumab and pembrolizumab, has significantly improved the survival of patients with metastatic non-small cell lung cancer (NSCLC). In order to determine the subset of patients that can benefit most from these therapies, biomarkers such as programmed death ligand-1 (PD-L1) have been proposed. However, the predictive and prognostic role of the use of PD-L1 is controversial. Anti-PD-L1 immunohistochemistry may not represent the actual status of the tumour because of individual variability and tumour heterogeneity. Additionally, there may be analytical variability due to the use of different assays and antibodies to detect PD-L1. Moreover PD-L1 expression is also regulated by oncogenic drivers in NSCLC, such as epidermal growth factor receptor (EGFR), echinoderm microtubule-associated protein-like 4 (EML4) fusion with anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS). Preclinical studies have shown the potential role of targeted therapy in immune escape mechanisms in NSCLC cells. This review summarizes current literature data on the heterogeneity of PD-L1 expression and the relationship with such factors and with clinicopathological features of NSCLC.

Molecular Basis of Drug Resistance and Insights for New Treatment Approaches in mCRPC.

Inhibiting androgen receptor (AR) signaling with androgen deprivation therapy (ADT) represents the mainstay of therapy for advanced and metastatic prostate cancer. However, about 20-60% of patients receiving first-line treatment for prostate cancer will relapse, evolving in a more aggressive and lethal form of the disease, the castration-resistant prostate cancer (CRPC), despite the use of ADT. Multiple approved systemic therapies able to prolong survival of patients with metastatic CRPC (mCRPC) exist, but almost invariably, patients treated with these drugs develop primary or acquired resistance. Multiple factors are involved in CRPC treatment resistance and elucidating the mechanisms of action of these factors is a key question and an active area of research. Due to such a complex scenario, treatment personalization is necessary to improve treatment effectiveness and reduce relapse rates in CRPC. In this review, current evidence about the major mechanisms of resistance to the available prostate cancer treatments were examined by introducing insights on new and future therapeutic approaches.