Cora N. Sternberg

Background The Italian Renal Cell Cancer Early Access Program was an expanded access program that allowed access to nivolumab, for patients (pts) with metastatic renal cell carcinoma (mRCC) prior to regulatory approval. Methods Pts with previously treated advanced or mRCC were eligible to receive nivolumab 3 mg/kg every 2 weeks. Pts included in the analysis had received ≥1 dose of nivolumab and were monitored for drug-related adverse events (drAEs) using CTCAE v.4.0. Immune-related (ir) AEs were defined as AEs displaying a certain, likely or possible correlation with immunotherapy (cutaneous, endocrine, hepatic, gastro-intestinal and pulmonary). The association between overall survival (OS) and irAEs was assessed, and associations between variables were evaluated with a logistic regression model. Results A total of 389 pts were enrolled between July 2015 and April 2016. Overall, the objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% CI 3.7–6.2) and the 12-month overall survival rate was 63%. Any grade and grade 3–4 drAEs were reported in 124 (32%) and 27 (7%) of pts, respectively, and there were no treatment-related deaths. Any grade irAEs occurred in 76 (20%) of patients, 8% cutaneous, 4% endocrine, 2% hepatic, 5% gastro-intestinal and 1% pulmonary. Of the 22 drAEs inducing treatment discontinuation, 10 (45%) were irAEs. Pts with drAEs had a significantly longer survival than those without drAEs (median OS 22.5 versus 16.4 months, p = 0.01). Pts with irAEs versus without irAEs had a more significant survival benefit (median OS not reached versus 16.8 months, p = 0.002), confirmed at the landmark analysis at 6 weeks. The occurrence of irAEs displayed a strong association with OS in univariable (HR 0.48, p = 0.003) and multivariable (HR 0.57, p = 0.02) analysis. Conclusions The appearance of irAEs strongly correlates with survival benefit in a real-life population of mRCC pts treated with nivolumab.

138 Background: Prognostic models require updating to reflect contemporary medical practice. In a post hoc analysis of the phase 3 PREVAIL trial (enzalutamide vs placebo), we identified prognostic factors for overall survival (OS) in chemotherapy-naïve men with mCRPC. Methods: Patients were randomly divided 2:1 into training (n = 1159) and testing (n = 550) sets. Using the training set, 23 predefined candidate prognostic factors (including treatment) were analyzed in a multivariable Cox model with stepwise procedures and in a penalized Cox proportional hazards model using the adaptive least absolute shrinkage and selection operator (LASSO) penalty (data cutoff June 1, 2014). A multivariable model predicting OS was developed using the training set; the predictive accuracy was assessed in the testing set using time-dependent area under the curve (tAUC). The testing set was stratified based on risk score tertiles (low, intermediate, high), and OS was analyzed using Kaplan-Meier methodology. Results: Demographics, disease characteristics, and OS were balanced between the training and testing sets; median OS was 32.7 months for both datasets. There were no enzalutamide treatment-prognostic factor interactions (predictors). The final multivariable model included 11 prognostic factors: prostate-specific antigen, treatment, hemoglobin, neutrophil-lymphocyte ratio, liver metastases, time from diagnosis to randomization, lactate dehydrogenase, ≥ 10 bone metastases, pain, albumin, and alkaline phosphatase. The tAUC was 0.74 in the testing set. Median (95% confidence interval [CI]) OS for the low-, intermediate-, and high-risk groups (testing set) were not yet reached (NYR) (NYR–NYR), 34.2 months (31.5–NYR), and 21.1 months (17.5–25.0). The hazard ratios (95% CI) for OS in the low- and intermediate-risk groups vs the high-risk group were 0.20 (0.14–0.29) and 0.40 (0.30–0.53), respectively. Conclusions: Our validated prognostic model incorporates factors routinely collected in chemotherapy-naïve men with mCRPC treated with enzalutamide and identifies subsets of men with widely differing survival times.

499 Background: Cabozantinib (C) inhibits tyrosine kinases including VEGFRs, MET, and AXL. The METEOR phase 3 trial (NCT01865747) met its primary endpoint of significant improvement in PFS with C versus everolimus (E) in pts with advanced clear cell RCC and prior exposure to VEGFR TKIs (7.4 mo median PFS [C] vs 3.8 mo [E], HR = 0.58, 95% CI, 0.45 to 0.75; p < 0.001). The improvement in PFS was accompanied by a significant improvement in ORR and a trend for improved OS at an interim analysis. Safety profiles of C and E in this trial were similar to prior experience with each drug in this pt population. This analysis further evaluates PFS and ORR across pt subgroups. Methods: Pts had advanced RCC with clear cell component, measurable disease per RECIST 1.1, KPS ≥ 70%, and were stratified by MSKCC prognostic criteria and number of prior VEGFR TKIs. Pts must have progressed during treatment or within 6 months of the last dose of their most recent VEGFR TKI. 658 pts were randomized 1:1 to receive C (60 mg QD) or E (10 mg QD). The primary endpoint was PFS among the first 375 pts randomized. ORR was a secondary endpoint. Results: In the PFS group, 187 pts were randomized to C and 188 to E. 73% pts had 1 and 27% pts ≥ 2 prior VEGFR TKIs; 43% pts had favorable, 41% intermediate, and 15% poor risk by MSKCC criteria. Across multiple subgroups defined by baseline characteristics, PFS HRs favored C over E. PFS HRs were similar for subgroups defined by prior number of TKIs (HR = 0.56 [1 prior] and 0.67 [ ≥ 2 prior]), and showed higher activity of C over E in pts with fewer MSKCC risk factors (HR = 0.54 [0 factors], 0.56 [1 factor], 0.84 [ ≥ 2 factors]) or with metastases in various organs (HR = 0.47 [lung mets], 0.53 [liver mets], 0.50 [bone mets]). Detailed analysis of the clinical activity of C and E (PFS and ORR) across pt subgroups will be presented, including treatment duration with first VEGFR TKI ( < or ≥ 6mo), receipt of prior anti-PD1/PDL1 agents, time to progression after most recent TKI ( < or ≥ 3mo), and frequency/location of metastases. Conclusions: The METEOR trial met its primary endpoint of improved PFS, and subgroup analyses of the endpoints PFS and ORR generally favored C over E in patients with advanced RCC. Clinical trial information: NCT01865747.

A 70-year-old man affected by bone metastases from castration resistant prostate cancer underwent Alpharadin (²²³Ra-dichloride) therapy (6 administrations of 50 kBq per kg i.v., once every 4 weeks). The inter-fraction variability of the absorbed dose to lesions was evaluated for four injections. Dosimetric assessments were performed following the MIRD approach and a recently published methodology. The mean absorbed dose and standard deviation for 4 lesions [mean (σ %)] were: 434 mGy (15 %) and 516 mGy (21 %) for the right and left humeral head, 1205 mGy (14 %) and 781 mGy (8 %) for the right and left glenoid. The estimated total absorbed dose after the whole treatment, considering also the relative-biological effectiveness of alpha particles (RBE = 5), yielded a D _RBE range of 13–36 Gy. A good correlation between ^99mTc and ²²³Ra uptake was obtained (R ² = 0.7613). The tumour–non-tumour (TNT) ratio of 8 lesions (those above, plus 4 additional), monitored by six ^99mTc-MDP bone scans over a period of about 10 months, evidenced a TNT reduction in two lesions (−42 and −48 %), but in most lesions the TNT remained fairly constant, evidencing that ²²³Ra-dichloride therapy tends to prevent further progression of osseous disease, leading to chronicity of the metastatic status.

301 Background: PFS6 was identified to be a robust intermediate endpoint in the setting of second-line therapy for advanced UC (Sonpavde, ESMO Congress, 2012) We studied the impact of second-line prognostic factors (Sonpavde, ESMO Congress 2012) (liver metastasis [LM], anemia [Hb

Introduction: The toxicities of cisplatin, that is, nephrotoxicity, neurotoxicity and emesis, provided the impetus for the development of more tolerable platinum analogs. Satraplatin is an investigational third-generation orally available lipophilic platinum, which has demonstrated safety and antitumor activity in multiple settings. Areas covered: The clinical activity of satraplatin in metastatic castrate-resistant prostate cancer (mCRPC), breast, lung and other advanced solid tumors is discussed with a focus on its pharmacokinetic properties. The article was formulated using publications found through PubMed search in addition to presentations given at major conferences. Expert opinion: Satraplatin was associated with dose-limiting myelosuppression, but no significant ototoxicity, neurotoxicity or nephrotoxicity. Despite the activity of satraplatin in mCRPC, survival was not extended in an unselected population included in a Phase III trial. While further development of satraplatin in large Phase III trials is not planned at this time, efforts are ongoing to develop tailored therapy in mCRPC based on excision repair cross-complementing group 1 expression or BRCAness. Moreover, based on potentially better central nervous system penetration due to lipophilicity, evaluation in patients with brain tumors is ongoing. Given the favorable toxicity profile and convenient oral administration, satraplatin may warrant development in settings that preclude cisplatin, for example, underlying renal dysfunction, elderly age and poor performance status.

Neoadjuvant cisplatin‐based combined chemotherapy is an established standard for muscle‐invasive bladder cancer and pathological complete remission is an excellent intermediate surrogate endpoint for survival. Phase III trials are ongoing to elucidate the role of neoadjuvant combined androgen deprivation and docetaxel‐based chemotherapy for localized high‐risk prostate cancer. Neoadjuvant therapy with biological agents targeting angiogenesis preceding cytoreductive nephrectomy for metastatic renal cell carcinoma is a novel approach, although ongoing randomized trials are validating this paradigm and attempting to establish the timing and necessity of cytoreductive nephrectomy. Neoadjuvant trials provide a window of opportunity to evaluate and screen novel agents for biological activity by using brief therapy preceding surgery and provide a rationale to further develop the most promising agents in larger trials. The neoadjuvant therapy approach followed by surgery is acceptable and feasible with a wide array of agents in urological cancers and provides a paradigm for evaluating the activity, mechanism of action and resistance to new treatments. Urological cancers are initially characterized by localized presentation in the vast majority of cases, coupled with a substantial risk of distant relapses following surgical resection. Therefore, the paradigm of neoadjuvant therapy preceding surgery may expedite the development of novel systemic agents and improve outcomes.

Docetaxel based chemotherapy has been shown to modestly extend life, relieve pain and improve the quality of life in patients with metastatic castration-resistant prostate cancer. Current trials are attempting to build on the backbone of docetaxel by combining it with novel biological agents. Trials are also investigating the role of docetaxel for earlier stages of prostate cancer. No standard second-line systemic therapy exists and such patients are candidates for clinical trials. The increased understanding of the mechanisms of progressive castration-resistant prostate cancer is being translated into an increasing pipeline of novel therapies.