Raffaele Ratta

Nivolumab in the treatment of advanced renal cell carcinoma: clinical trial evidence and experience.

Renal cell carcinoma (RCC) is considered an immunogenic tumor with a prominent dysfunctional immune cell infiltrate, unable to control tumor growth. Cytokine-based immunotherapies, including interferon-α and interleukin-2, have been used for the treatment of metastatic RCC (mRCC). Long-term responses and complete remissions were observed, but durable clinical benefit efficacy in the overall population was limited and associated with significant toxicity. As a consequence, new generation agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways replaced interferon alpha (IFN-α). Strategies of tumor immune evasion include T-cell suppression by negative signals deriving from the interaction between programmed death-1 (PD-1) on the T cell and its ligand (PDL-1) on the tumor cells. Nivolumab, a programmed death 1 checkpoint inhibitor, blocks this pathway, thus reversing T-cell suppression and activating antitumor responses. The aim of this review is to summarize the safety and efficacy data of nivolumab in mRCC. Objective responses and safety profile of single-agent nivolumab are favorable in both previously treated and treatment-naïve mRCC patients. Despite toxic effects, combination therapies with nivolumab have shown promising results, indicating a potential role in the treatment of mRCC. Tailoring immunotherapy on a patient-to-patient basis represents a major challenge for the future.

safety and clinical outcomes of patients treated with abiraterone acetate after docetaxel: results of the Italian Named Patient Programme

To assess the safety and efficacy of abiraterone acetate (AA) in patients with metastatic castration‐resistant prostate cancer (mCRPC) treated in a compassionate named patient programme (NPP).

Dicer and Drosha expression and response to Bevacizumab-based therapy in advanced colorectal cancer patients

PURPOSE The miRNA-regulating enzymes Dicer and Drosha exhibit aberrant expression in several cancer types. Dicer and Drosha play a crucial role during the angiogenetic process in vitro and, for Dicer, in vivo. We aimed to investigate the potential role of Dicer and Drosha in predicting response to Bevacizumab-based therapy in advanced colorectal cancer (CRC) patients. METHODS Dicer and Drosha mRNA levels were analysed in formalin-fixed paraffin-embedded specimens from patients affected by advanced CRC treated with or without Bevacizumab-containing regimens (n=116 and n=50, respectively) and from patients with diverticulosis as control group (n=20). The experimental data were obtained using qRT-PCR, analysed comparing Dicer and Drosha expression levels in tumour samples versus normal mucosa and then compared to clinical outcome. RESULTS The tumour samples from Bevacizumab-treated patients showed a significantly higher Drosha expression (P<.001) versus normal mucosa, while Dicer levels did not differ. Intriguingly, we found that low Dicer levels predicted a longer progression-free survival (PFS) (P<.0001) and overall survival (OS) (P=.009). In addition, low Dicer levels were associated with better response to Bevacizumab-based treatments versus high Dicer levels (1.7% complete responses and 53.4% partial responses versus 0% and 32.7%, respectively; P=.0067). Multivariate analysis identified three independent predictors of improved OS: high performance status (PS) (relative risk (RR) 1.45; P=.011), lower organs involvement (RR 0.79; P=.034) and low Dicer expression (RR 0.71; P=.008). Conversely, Drosha levels were not associated with prognosis and outcome associated with treatment. In non-Bevacizumab-treated patients, Dicer and Drosha expression did not correlate with outcome. CONCLUSION These findings suggest that low Dicer mRNA levels seem to be independent predictors of favourable outcome and response in patients affected by advanced CRCs treated with Bevacizumab-based therapy.

Immunotherapy advances in uro-genital malignancies.

Immunotherapy for the treatment of cancer has made significant progresses over the last 20 years. Multiple efforts have been attempted to restore immune-mediated tumor elimination, leading to the development of several targeted immunotherapies. Data from recent clinical trials suggest that these agents might improve the prognosis of patients with advanced genito-urinary (GU) malignancies. Nivolumab has been the first immune checkpoint-inhibitor approved for pre-treated patients with metastatic renal cell carcinoma. Pembrolizumab and atezolizumab have shown promising results in both phase I and II trials in urothelial carcinoma. Brentuximab vedotin has demonstrated early signals of clinical activity and immunomodulatory effects in highly pre-treated patients with testicular germ cell tumors. In this review, we have summarized the major clinical achievements of immunotherapy in GU cancers, focusing on immune checkpoint blockade as well as the new immunomodulatory monoclonal antibodies (mAbs) under clinical evaluation for these malignancies.

Cabozantinib in the treatment of advanced renal cell carcinoma: design, development, and potential place in the therapy

The treatment of metastatic renal cell carcinoma (mRCC) has markedly improved over the last few years with the introduction of several targeted agents in clinical practice. Nevertheless, either primary or secondary resistance to inhibition of VEGF and mTOR pathways has limited the clinical benefit of these systemic treatments. Recently, a better understanding of the involvement of MET and its ligand HGF in many biological processes made this signaling pathway an attractive therapeutic target in oncology, particularly in mRCC. Herein, we review the development of cabozantinib, a recently approved inhibitor of multiple tyrosine kinase receptors, including MET, VEGFRs, and AXL, which has proven to increase progression-free survival and overall survival when compared to everolimus in mRCC patients who had progressed after VEGFR-targeted therapy. Finally, we discuss the potential role of cabozantinib within the current treatment landscape for mRCC.

Safety of long-term exposure to abiraterone acetate in patients with castration-resistant prostate cancer and concomitant cardiovascular risk factors:

Background: We aimed to evaluate the long-term safety profile of abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) with controlled cardiovascular comorbidities or risk factors. Methods: We retrospectively analysed the clinical charts of consecutive mCRPC patients with cardiac disorders/risk factors who had been treated with abiraterone 1000 mg once daily plus prednisone 5 mg twice daily for a median duration of 16 months at an oncology referral centre between April 2011 and July 2015. Patients underwent an electrocardiogram (ECG) and echocardiographic assessments, including measurement of left ventricular ejection fraction (LVEF) at baseline and at the end of treatment. Blood pressure (BP) was measured daily at home. During follow up (median 24 months), all adverse events were recorded. Cardiac events (CEs) were defined, according to Common Terminology Criteria for Adverse Events version 4.0, as the appearance of a symptomatic CE that required medical intervention. Results: A total of 51 patients (median age 71 years) were evaluated. Pre-existing cardiovascular conditions included hypertension (41%), cardiac ischaemia (12%), stroke (9%), dyslipidaemia (18%) and type 2 diabetes mellitus (12%). No CEs were recorded and no changes in LVEF were observed. The most frequently reported adverse events were Grade 1–2 fluid retention (18%), hypertension (16%) and asthenia (16%). No patients permanently discontinued abiraterone due to cardiac events. Conclusions: Long-term abiraterone treatment was well tolerated in mCRPC patients with controlled cardiovascular comorbidities/risk factors, with no apparent worsening of cardiovascular conditions from baseline over an extended observation period.

Safety and Clinical Outcomes of Abiraterone Acetate after Docetaxel in Octogenarians with Metastatic Castration-Resistant Prostate Cancer: Results of the Italian Compassionate Use Named Patient Programme

UNLABELLED Metastatic castration-resistant prostate cancer mainly affects older men, opening issues about the efficacy and safety of therapies in this population. We have demonstrated that abiraterone, a selective androgen biosynthesis inhibitor, is a safe and active therapeutic option in a subgroup of 47 very elderly adults (aged > 80 years) enrolled in the Italian named patient program, with a tolerability profile and clinical outcomes comparable to those of younger population. BACKGROUND Prostate cancer mainly affects elderly men, who are often frail and whose reduced physiological reserves and multiple comorbidities increase the risk of side effects. The availability of new drugs has improved the overall survival (OS) of patients with castration-resistant prostate cancer (CRPC) but has increased the number of very elderly CRPC patients receiving anticancer drugs, raising questions about their efficacy and safety in this population. PATIENTS AND METHODS We assessed the tolerability of abiraterone (AA) in a cohort of very elderly adults with metastatic CRPC (mCRPC) enrolled in the Italian AA named patient program and analyzed their clinical outcomes. We retrospectively reviewed the clinical records of 47 mCRPC patients aged > 80 years who had received AA after docetaxel. The Kaplan-Meier method was used to calculate OS and progression-free survival (PFS). Safety and clinical outcomes were also analyzed by age group (< 80 and > 80 years). Cox regression analysis was used to calculate the differences in PFS and OS between the groups according to the stratification variables. RESULTS In very elderly men, the prostate-specific antigen response rate was 48.9%, and the median PFS and OS were 8 and 18 months, respectively. The differences in toxicities between the older and younger age groups were not major. The limitation of the present study was mainly its retrospective nature. CONCLUSION Our data show that AA is active and safe in very elderly patients and leads to outcomes similar to those observed in younger patients, thus confirming that AA is a manageable therapeutic option for this patient population.

Impact of visceral metastases on outcome to abiraterone after docetaxel in castration-resistant prostate cancer patients

BACKGROUND The objective of this study was to analyze the impact of visceral metastases in castration-resistant prostate cancer (CRPC) treated with abiraterone. MATERIALS & METHODS All CRPC patients received abiraterone 1000 mg daily plus prednisone 10 mg orally daily. Liver and lung metastases were considered as visceral metastases. RESULTS Of 265 CRPC patients, 49 had visceral metastases. Results on progression-free survival were not significantly different in patients with or without visceral metastases. Conversely, the median overall survival between the two groups was 12.4 and 18.5 months (p = 0.01), respectively, and median overall survival of patients with liver-only disease versus other sites was 10.5 versus 18.5 months (p = 0.006), respectively. CONCLUSION Visceral disease appears to be an important predictor of clinical outcome in CRPC patients treated with abiraterone.

Safety and Efficacy of Cabozantinib in Metastatic Renal-Cell Carcinoma: Real-World Data From an Italian Managed Access Program

Micro‐Abstract The aim of this analysis was to evaluate the safety and activity of cabozantinib in a large unselected population of patients with metastatic renal‐cell carcinoma (mRCC) progressing after prior treatments. Our data showed that cabozantinib is effective in a large unselected population of mRCC patients treated in everyday clinical practice. Cabozantinib was also safe and its toxicity profile was feasible and manageable. Background: The randomized phase 3 METEOR study confirmed a survival benefit of cabozantinib over everolimus in patients with metastatic renal‐cell carcinoma (mRCC) with disease that progressed after treatment with at least one previous antiangiogenic inhibitor. The aim of this analysis was to evaluate the safety and activity of cabozantinib in an unselected population. Methods: Data were collected across 24 Italian centers. Cabozantinib therapy was initiated at physician request between September and December 2016. Patients with mRCC with disease that progressed after one or more prior systemic treatment were evaluated. Cabozantinib 60 mg was administered orally once daily. Doses were reduced to 40 mg or 20 mg in patients experiencing grade 3 or intolerable grade 2 adverse events (AEs). Results: Data from 96 patients were evaluated. Cabozantinib was administered as second‐line therapy in 28 patients (29%) and as third‐line therapy in 18 patients (19%), while the remaining 50 patients (52%) received cabozantinib in further treatment lines. Sixty‐six patients began therapy with the full dose of 60 mg. Because of poor performance status, 29 patients began therapy with a reduced dose of 40 mg and 1 patient with 20 mg. At the time of our analysis, grade 3/4 AEs were observed in 35 patients (36%). Only 5 patients discontinued treatment as a result of AEs. Partial response was observed in 35 patients (36%), whereas 33 (34%) had stable disease and 28 (30%) progressive disease. Median progression‐free survival was 8.0 months. Conclusion: Cabozantinib showed acceptable tolerability and activity in a large unselected population treated according to everyday clinical practice.

Exposure to multiple lines of treatment and survival of patients with metastatic renal cell carcinoma: a real-world analysis.

Micro‐Abstract The aim of the present retrospective analysis was to describe trends in exposure to multiple lines of treatment and survival among 500 metastatic renal cell carcinoma patients who started first‐line therapy in 2 different periods (2004‐2010 and 2011‐2017) in daily practice. Patients who started treatment during the past 5 years received a greater number of treatment lines with an improvement in overall survival. Background: The purpose of the present retrospective analysis was to describe the trends in exposure to multiple lines of treatment and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) who started therapy in 2 different periods (period 1, 2004‐2010; and period 2, 2011‐2017). Patients and Methods: The proportion of patients who received subsequent lines of treatment after disease progression was compared between the 2 groups. OS was measured from the start of first‐line treatment for metastatic disease to death or the last follow‐up examination. Both univariate and multivariate analyses were performed. Results: A total of 500 patients were included in the study; 274 started treatment in period 1 and 226 in period 2. Of those patients who stopped first‐line treatment because of disease progression, the patients in period 2 had a greater conditional probability to receive second‐ and third‐line treatment compared with patients in period 1 (77.2% vs. 63.7%; odds ratio [OR], 1.93; 95% confidence interval [CI], 1.20‐3.11; P = .0065; and 69.6% vs. 48.1%; OR, 2.48; 95% CI, 1.40‐4.40; P = .002, respectively). The median OS improved from 22.8 months for patients in period 1 to 38.2 months for patients in period 2 (univariate analysis: hazard ratio, 0.65; 95% CI, 0.50‐0.83; P = .001). Conclusion: Patients who started treatment during the past 5 years were exposed to a greater number of treatment lines compared with patients treated before 2011. Our data suggest that the increase of treatment options available and clinician expertise could be associated with better outcomes.