Michele Sisani

Immunologic Checkpoints Blockade in Renal Cell, Prostate, and Urothelial Malignancies

Genitourinary (GU) tumors, and in particular renal cell and prostate cancer, represent one of the most dynamic areas in oncology from the scientific point of view. One of the most recent treatment approaches for GU tumors has focused on a series of molecules known as immune checkpoints and the possibility of manipulating immune responses against tumor cells by blocking these molecules with monoclonal antibodies (mAbs). Cytotoxic T lymphocyte antigen-4 (CTLA-4), and the immune checkpoint inhibitor mAbs ipilimumab and tremelimumab, represent the prototypes of this new growing class of agents called immunomodulating antibodies, while programmed death/ligand 1 (PD-1/PD-L1) also has garnered a significant interest as a new immune checkpoints to target in urothelial cancer, with the anti-PD-1/PD-L1 inhibitor mAbs nivolumab, MPDL-3280, and BMS-936559 as the first agents tested. Here we report the encouraging initial data observed in GU cancers with this new class of agents, which have reinforced the interest of investigating the therapeutic potential of the immune checkpoint modulators in large controlled trials.

Clinical implications for a treatment algorithm and differential indication to hormone therapy and chemotherapy options in metastatic castrate-resistant prostate cancer: a personal view

Although docetaxel is still considered a mainstay of treatment in metastatic castrate-resistant prostate cancer (mCRPC), in the last few years, new agents have been developed to improve survival in this setting and reach a possible optimal personalized treatment strategy. In this paper, we provide a personal view and an algorithm for mCRPC patients, according to available evidence, personal opinion and experience. Abiratone acetate, cabazitaxel, radium-223, sipuleucel-T and enzalutamide, together with docetaxel, have demonstrated a survival benefit in these patients. The use of rechallenge with docetaxel in mCRPC patients with disease progression after a first response has been considered. These new agents complicated the scenario and posed the challenge to move from the old sequential to a new algorithm-based approach. At this stage, the algorithm is necessarily based on experts’ opinion, since the efficacy of a single agent in a specific setting has not been validated by sequential trials.

Axitinib safety in metastatic renal cell carcinoma: suggestions for daily clinical practice based on case studies

Introduction: Axitinib, a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine. We review data for axitinib and discuss strategies to manage or prevent adverse events (AEs) and maximize clinical benefit. Areas covered: A literature search identified key advanced RCC trials of axitinib and other targeted therapies. Each author also contributed a clinical case study to illustrate management approaches in patients who received axitinib following sunitinib in the AXIS Phase III trial. Axitinib has demonstrated a predictable and manageable AE profile in clinical trials; most commonly reported treatment-related events are diarrhea, hypertension, fatigue, nausea, vomiting and dysphonia. Case studies demonstrate that successful management requires patient awareness of potential AEs, regular monitoring and dose modification for specific AEs. Expert opinion: Improvement in progression-free survival with axitinib versus sorafenib in a Phase III trial supports preferred selection of axitinib in the second-line setting. The safety profile of axitinib versus mammalian target of rapamycin inhibitors and sorafenib also provides the opportunity to personalize treatment in advanced RCC based on the likelihood for specific AEs to occur and on prior toxicities in the first-line setting.

Docetaxel rechallenge in metastatic castration-resistant prostate cancer: any place in the modern treatment scenario? An intention to treat evaluation

BACKGROUND We evaluated the possible advantages of a docetaxel (DCT) rechallenge strategy in metastatic castration-resistant prostate cancer (mCRPC) patients, also given the possible earlier positioning of this treatment option in the modern scenario. PATIENTS & METHODS All mCRPC patients planned for DCT chemotherapy rechallenge in our institutions were evaluated. RESULTS Of 128 patients, 98 achieved disease control on the initial DCT round. After a treatment holiday of 8.3 months, the 98 responsive patients underwent a second DCT round, with 56 cases achieving again disease control. After a 5.7-month off-treatment period, 32 of these cases underwent a third DCT round, and 16 responded. Lastly, after a further 4.2-month treatment holiday, eight patients underwent a fourth DCT round and two responded. Median time to definitive disease progression for the whole population was 16.4 months. CONCLUSIONS Rechallenge with DCT may be considered a suitable treatment option for mCRPC patients recurring after a successful DCT chemotherapy. The interest in this strategy may be increased because of the showed efficacy of early DCT chemotherapy in patients with bulky disease (CHAARTED study) and the potential lower efficacy of the new hormonal agents abiraterone acetate and enzalutamide when used in a immediate sequencing.

Preliminary safety results of an Italian early-access program (EAP) with cabazitaxel plus prednisone (CbzP) in patients with docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC).

253 Background: A significant number of docetaxel (D) refractory mCRPC patients (pts) have a life expectancy of > 15 months and ask for additional efficacious treatments. In the phase 3 TROPIC trial treatment of mCRPC patients with CbzP who progressed during or after docetaxel resulted in a statistically significant overall survival benefit compared with mitoxantrone / prednisone (Lancet 2010). This survival benefit supported establishment of a global early access program (EAP), allowing pts with mCRPC to have access to the drug prior to its commercial availability. Here we describe preliminary safety results from the EAP in Italy. METHODS We report here the data of the first 16 mCRPC patients (out of the 123 enrolled by 19 Italian centers until Sept 2011 in EAP) treated with Cbz (25mg/m2 Q3W) plus P(10mg bid). RESULTS Pts were median age 73.5 years (>75 years 38%), ECOG PS-0 81.3% and had received a median of 7 prior cycles of D (median cumulative D dose 562.5mg). Median time from last D dose to inclusion was 7.1 months. Overall, 62.5% (10 Pts) had 2 or more metastatic sites (bone 94%, regional/distant lymph nodes 25% and 44%, lung 12.5%, other sites 19%). A limited number of relevant adverse events (AE) were observed. All grade AEs were seen in 14/16 pts (81.3%), with 4/16 pts experiencing grade 3/4 leukopenia, 8/16 pts grade 3 - 4 neutropenia, one patient with febrile neutropenia and one with hypertransaminasaemia. Grade 1-2 asthenia and fatigue were experienced respectively by 2 pts. No grade 3 / 4 diarrhea, vomiting or constipation were observed and no AEs results in death. All pts received at least 2 cycles of CbzP (2÷5) and only one patient permanently discontinued treatment (disease progression). CONCLUSIONS This preliminary analysis of Italian pts enrolled in the EAP provides real world safety data and suggests a good safety profile of cabazitaxel even in heavily pretreated pts, which is in agreement with Italian experience in TROPIC. Results of the entire Italian cohort with a longer follow-up will be presented.

Biologic tools to personalize treatment in genitourinary cancers

BACKGROUND Genitourinary (GU) cancers are a major healthcare issue in modern oncology. In the last decade many efforts have been made to develop new treatment options but with the possible exception of renal cell carcinoma, very few steps ahead have been taken. At the same time, a wide variety of molecular markers, potentially helpful in identifying patient subpopulation most likely to benefit from a specific treatment have been identified. Our goal is to clarify if biomarkers could be used at present to personalize treatment for GU cancers. MATERIALS AND METHODS Literature was search using PubMed and EMBASE using different terms and combinations regarding possible prognostic and predictive markers in renal, prostate and urothelial cancers. RESULTS 3546 articles were retrieved. After excluding duplications, preclinical studies and factors without possible predictive value 654 publications remain. N-telopeptide, HER2/neu, EGFR, and p53 in prostate cancer, sVEGF-A for RCC and EMMPRIN and Survivin in urothelial cancer were among those identified. After a careful examination of published data, none of them reached a sufficient evidence to be suggested for use outside of clinical trials. CONCLUSIONS To date any reliable biomarkers has been validated for tailored treatments approaches in GU cancer. Future studies focusing on this issue are urgently needed.

Retrospective analysis of sorafenib as first- or second-line targeted therapy in patients with mRCC: Three-year Italian experience.

415 Background: The Retrospective analysis of Sorafenib (So) as the first- or second- target therapy (RESET) study in metastatic renal cell carcinoma (mRCC) patients assessed the use and safety of sorafenib under daily-life treatment conditions in a community-based patient population in Italian centers. METHODS RESET was a retrospective, observational, non-interventional field study in mRCC patients. Treatment decisions were determined by each physician according to local prescribing guidelines and clinical practice. Patients for whom a decision to treat with sorafenib single agent as first- or second- target therapy (TT) for mRCC has been made, were eligible for inclusion. Patients that started So treatment between January 1, 2008 and December 31, 2010 were included. Data collection started retrospectively in 2012, in order to have a period of observation of at least 1 year up to 31st Dec 2011. Endpoints included safety, overall survival (OS), progression-free survival (PFS), response rate (RR), and treatment duration. Subgroup analyses included age, Eastern Cooperative Oncology Group performance status, prior therapy, number of metastases, and line of TT with So. RESULTS From February to Jululy 2012, 358 pts from 37 Italian centers were enrolled. The most common ≥ grade 3 drug-related adverse events were hand-foot skin reaction (6.3%), rash (2.3%), hypertension, fatigue, and diarrhea (1.7% each). In the overall population, median OS was 17.2 months (mos) (95% CI 15.5 - 19.6 mos) and median PFS was 5.9 mos (95% CI 5.0-6.8 mos). Median duration of treatment with So was 5.09 mos. Complete response was observed in 3 (0.8%) pts, partial response in 53(15.0%) pts and stable disease in 139(39.4%) pts. In pts receiving So as first- or second- TT, median OS was 19.9 mos (95% CI 15.4-25.3 mos) and 16.6 mos (95% CI 13.1-18.4 mos) respectively, and median PFS was 6.6 mos (95% CI 4.9-9.3 mos) and 5.3 mos (95% CI 4.4-6.2 mos) respectively. CONCLUSIONS The efficacy and safety of So under routine clinical practice conditions in the setting of community-based practice in Italy were similar to that reported in prospective clinical trials. The efficacy of So was observed in the subgroup of pts receiving So as either the first or second TT for mRCC.