No abstract

9508 Background: Nivolumab (nivo) and the combination of nivo + ipilimumab (ipi) improve response rates (RR) and progression-free survival (PFS) compared with ipi alone in clinical trials of metastatic melanoma pts, but pts with untreated brain mets were excluded. Brain mets are a major cause of morbidity and mortality in melanoma and their management is critical. We sought to determine the antitumour activity and safety of nivo and nivo+ipi in pts with active melanoma brain mets (NCT02374242). Methods: This open-label, ph II trial enrolled 3 cohorts of pts naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014 - Feb 2017. Pts with asymptomatic melanoma brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3W x4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets 1) that failed local therapy (new +/- progressed in previously treated met), 2) were neurologically symptomatic and/or 3) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥ wk12. Secondary endpoints were best extracranial response (ECR), best overall response (OR), IC PFS, EC PFS, overall PFS, OS, and safety. Results: A total of 66 pts (med f/u 14 mo) were included in this analysis of total 76 planned; median age 60y, 77% male. For cohorts A, B and C: elevated LDH 48%, 58% and 19%; V600BRAF 44%, 56% and 81%; prior BRAFi 24%, 24%, 75%. Table shows RR, PFS and OS. ICR in cohort A treatment naïve vs prior BRAFi was 53% vs 16%. Treatment-related gd 3/4 toxicity in cohorts A, B and C were 68%, 40% and 56%, respectively. There were no treatment-related deaths. Conclusions:Nivo monotherapy and ipi+nivo and are active in melanoma brain mets. Ipi+nivo had reduced activity in pts who progressed on BRAFi. Pts with symptomatic brain mets, leptomeningeal mets or previous local therapy responded poorly to nivo alone. Clinical trial information: NCT02374242. [Table: see text]

5500 Background: LuPSMA is a radiolabeled small molecule that delivers therapeutic β-radiation to PSMA-expressing tumors. Encouraging efficacy and safety has been shown in non-randomized studies of mCRPC. TheraP is a randomized phase II trial comparing LuPSMA vs cabazitaxel in men with mCRPC progressing after docetaxel. Methods: Men with mCRPC, and imaging with 68Ga-PSMA-11 and 18F-FDG PET/CT that confirmed high PSMA-expression and no sites of FDG-positive/PSMA-negative disease, were randomly assigned (1:1) to LuPSMA (6-8GBq q6weeks up to 6 cycles) vs cabazitaxel (20mg/m2 q3weeks up to 10 cycles); stratified by disease burden (>20 vs ≤20 sites), prior novel antiandrogens (NAA; abiraterone or enzalutamide), and study site. The primary endpoint was PSA response rate (PSA50-RR) defined by ≥50% reduction. Secondary efficacy endpoints included PSA-progression-free survival (PSA-PFS) and overall survival (OS). Data cut-off was 31DEC19 at this first pre-specified analysis. Results: 200 (median age 72 y, prior NAA 91%, >20 lesions 78%) of 291 PET screened men were randomised to LuPSMA (N=99) or cabazitaxel (N=101). 17 patients withdrew or died before receiving study treatment (1 LuPSMA vs 16 cabazitaxel). The PSA50-RR was higher in those assigned LuPSMA than cabazitaxel (65/99 [66%; 95%CI 56-75] vs 37/101 [37%; 95%CI 27-46]; P<0.001). At a median follow-up of 11.3 months, LuPSMA significantly improved PSA-PFS (HR 0.63, 95%CI 0.45-0.88, P=0.007; 143 events with next pre-specified analysis planned after 170 events). Efficacy results were similar when analyses were restricted to per-protocol treated men. OS data remains immature (57 deaths). Grade III-IV adverse events (AEs) occurred in 31/98 (32%) LuPSMA-treated men vs 42/85 (49%) in cabazitaxel-treated men. Discontinuations for toxicity occurred in 1/98 (1%) LuPSMA vs 3/85 (4%) cabazitaxel-treated. There were no treatment-related deaths. Conclusions: In men with docetaxel-treated mCRPC, LuPSMA was more active (PSA50-RR) than cabazitaxel with relatively fewer G3-4 AEs and PSA-PFS favoring LuPSMA. Clinical trial information: NCT03392428 .

BackgroundMulti-parametric magnetic resonance imaging (mpMRI) is validated for the diagnosis of clinically significant prostate cancer (csPCa). 68 Ga-PSMA -11 PET/CT (PSMA-PET/CT) combined with mpMRI has improved negative predictive value over mpMRI alone for csPCa. The aim of this post-hoc analysis of the PRIMARY study was to evaluate the clinical significance of patterns of intra-prostatic PSMA activity, proposing a 5-point PRIMARY score to optimise accuracy of PSMA-PET/CT for csPCa in a low prevalence population. MethodsThe PRIMARY trial is a prospective multi-centre phase II imaging trial that enrolled biopsy-naïve men with suspected PCa, no prior biopsy, recent mpMRI (6 months) and planned for prostate biopsy. 291 men underwent mpMRI, PSMA-PET/CT and systematic +/-targeted biopsy. The mpMRI was read separately using PI-RADS (V2).PSMA-PET/CT (pelvic only) was acquired a minimum 60 minutes post injection. PSMA-PET/CT was centrally read for pattern (diffuse transition zone (TZ), symmetrical central zone (CZ), focal TZ or peripheral zone (PZ), and intensity (SUVmax). In this post-hoc analysis, a 5-level PRIMARY score was assigned based on analysis of the central read: 1. No pattern, 2. Diffuse TZ or CZ (no focal), 3. Focal TZ, 4. Focal PZ or 5. SUVmax ≥ 12. Two further readers independently assigned a PRIMARY score to 118 scans for inter-rater agreement. Associations between PRIMARY score and csPCa (ISUP≥2) were evaluated. ResultsOf 291 men enrolled, 162 (56%) had csPCa. PRIMARY score-1 was present in 16% (47), score-2 in 19% (55), score-3 in 10% (29), score-4 in 40% (117) and score-5 in 15% (43). The proportion of patients with csPCa and PRIMARY score 1 to 5 was 8.5% (4/47), 27% (15/55), 38% (11/29), 76% (89/117) and 100% (43/43) respectively. Sensitivity, specificity, PPV and NPV for PRIMARY score 1,2 (low-risk patterns) vs PRIMARY score 3-5 (high-risk patterns) was 88%, 64%, 76% and 81%, compared to 83%, 53%, 69% and 72% for PI-RADS (2 vs 3-5) on mpMRI. The inter-rater agreements for PRIMARY score 1,2 vs. PRIMARY score 3-5 was 0.76 (CI: 0.64-0.88) and 0.64 (CI: 0.49-0.78). ConclusionA PRIMARY score incorporating intra-prostatic pattern and intensity on PSMA-PET/CT shows potential with high diagnostic accuracy for csPCa. Further validation is warranted prior to implementation.