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Background: AU-007 is a computationally designed, monoclonal antibody that binds to IL-2 on its CD25 binding epitope. AU-007 bound IL-2 (A/IL-2) cannot bind to high affinity trimeric IL-2 receptors (IL-2R) consisting of CD25, CD122, and CD132 expressed on Tregs and vascular endothelium, but its binding to low affinity dimeric IL-2Rs (CD122 and CD132) expressed on T effector and NK cells is unhindered. Thus, AU-007 redirects endogenously produced or exogenous IL-2 (aldesleukin) towards activation of immune stimulating T effector and NK cells, while diminishing Treg activation and expansion. AU-007 will also bind and redirect newly secreted endogenous IL-2 resulting from A/IL-2 driven T cell expansion in the tumor, converting a Treg mediated autoinhibitory loop into an immune stimulating loop. AU-007 is unique in the IL-2 therapeutic field as engineered exogenous, recombinant "non-CD25" IL-2s in development cannot address the autoinhibitory effect of endogenous IL-2. Preclinically, AU-007 has been demonstrated to capture endogenous human IL-2 in vivo. AU-007 with a single low dose of IL-2 has demonstrated efficacy in multiple cancer models and has an excellent safety profile in non-human primates. Method(s): This first-in-human, multicenter, open label Phase 1- 2 study evaluates the safety, tolerability, and initial efficacy of AU-007 +/- aldesleukin in patients with advanced solid tumors (CT-2021-CTN-03938-1). Phase 1 consists of 3 escalation arms each starting with a single 1+2 escalation cohort followed by 3+3 escalation cohorts to define the recommended Phase 2 dose (RP2D) or maximum tolerated dose (MTD). Patients with melanoma, renal cell carcinoma (RCC) and 17 selected solid tumors are eligible. Prior treatment with check point inhibitors is allowed. In Arm A, escalating doses of Q2w AU-007 are evaluated in sequential escalation cohorts. In Arm B, a single dose of aldesleukin is given with the initial AU-007 dose. AU-007 is given at a fixed dose Q2w with an esca

Background: Elderly men (>/=75yo) comprise 25% of patients with prostate cancer. However, they are typically underrepresented in pivotal trials. Limited data suggest these patients receive less intensive treatment with greater toxicity, despite comparable response rates. Our retrospective study examined treatment patterns and outcomes in a real-world population with castration-resistant prostate cancer (CRPC). Method(s): Using the multi-centre electronic CRPC Australian Database (ePAD), we extracted clinicopathologic, treatment and outcome data. Descriptive statistics were used to report data in patients aged >/=75yo and <75yo. Comparisons between these groups were analysed using T-tests and Fisher's exact tests. Time-to-event analyses were performed using the Kaplan-Meier method. Result(s): We identified 753 men with CRPC, with 327 (43%) aged >/=75yo. Elderly patients had higher rates of ischemic heart disease (33% vs 16% in younger patients, p=0.004) and stroke (11% vs 5%, p=0.007). They were more likely to receive only one line of systemic therapy (67% vs 40%, p<0.001), and androgen receptor signalling inhibitors (ARSIs) were most commonly prescribed as initial therapy (78% vs 48%, p<0.001). Enrolment in clinical trials was less frequent (5% vs 15%, p<0.001). There was no statistical difference in treatment duration or PSA50 response rates with ARSIs or docetaxel (Table). Overall, serious adverse events (SAEs) leading to hospitalisation, dose delays or modifications occurred in more elderly men (24% vs 16%, p=0.003), with a trend towards greater SAEs in those receiving docetaxel or ARSIs. Elderly patients were more likely to stop docetaxel due to toxicity (39% vs 21%, p=0.02). [Formula presented]. Conclusion(s): In our real-world cohort, elderly men had greater comorbidities and received fewer lines of systemic therapy. Although there was no difference in treatment response or duration, elderly patients experienced higher SAE rates. Prospective studies are requir

Background: There is no prospective data to guide optimal selection of treatment for first line (1L) mCRPC after D and androgen deprivation therapy (ADT) is given in the hormone sensitive setting. We explored efficacy of 1L treatment in this group. Method(s): Pts with mCRPC treated with D for hormone sensitive disease were identified from a prospectively maintained multi-site mCRPC database (ePAD) of patients treated in a community and academic setting in Australia. 1L treatment, clinicopathologic and outcome data were extracted. Result(s): We identified 93 pts, median age 65y (range 43-85), who received median 6 cycles of D-ADT and developed mCRPC between May 2013 and Jun 2019. 58% had Gleason > 8, median PSA at diagnosis was 53 ng/mL (range 0.67-7086), 65% had de-novo metastatic disease. Median time to mCRPC was 14.8mo (range 1.3 to 56.9) with median time to 1L 16.3mo (range 2.1-57.2). Eighty-five patients (91%) received at least one further active treatment for mCRPC with outcomes below. Conclusion(s): Abiraterone, enzalutamide, and cabazitaxel all demonstrate activity for 1L mCRPC following progression on D-ADT. Compared to historical controls, PSA responses appear less than pre-docetaxel, but greater than the post-docetaxel setting.

Aim: Targeted therapy (TT) has improved survival for metastatic renal cell carcinoma (mRCC). However, survival is usually limited if brain metastases (BMs) develop. We aimed to evaluate survival outcomes in mRCC patients based on timing of BM diagnosis. Method(s): We conducted a multicenter, retrospective study of mRCC patients with BM who received TT at any point between 2005 and 2014. We determined overall survival (OS) from stage IV diagnosis, TT initiation and BM diagnosis, and prognostic factors. Patients were grouped into three categories: synchronous-BM, metachronous-BM diagnosed while conservatively managed (metachronous-BM before TT) and metachronous-BM diagnosed during TT. Survival was calculated by Kaplan-Meier method and predictors were calculated using Cox hazards regression. Result(s): Incidence of BM was 17% in mRCC patients treated with TT (two centers). Fifty-four mRCC-BM patients were identified from five tertiary centers. Twenty-eight percentage (15/54) had synchronous-BM, 28% (15/54) had metachranous-BM before TT and 44% (24/54) had metachronous-BM during TT. Most had central nervous system (CNS) symptoms at BM diagnosis (78%; 42/54). Median OS from stage IV diagnosis, TT commencement and BM diagnosis was 28 months (95% confidence interval [CI] 16-43), 19 months (95% CI 9-26) and 9 months (95% CI 5-16), respectively. Synchronous-BM group trended toward poorer survival from TT commencement (P = 0.06). Metachronous-BM during TT group had lower survival from BM diagnosis than synchronous-BM and metachronous-BM before TT group (P < 0.001). Eight of 50 deaths (16%) were from neurological complications. The presence of CNS symptoms did not predict worse survival from stage IV diagnosis (P = 0.73). Conclusion(s): In patients with mRCC, the development of BM while on TT portends shorter prognosis compared with synchronous diagnosis of BM at stage IV disease or metachronous BM developed prior to commencing TT. The presence of CNS symptoms does not predict

Contains fulltext : 154417pub.pdf (publisher's version ) (Closed access), BACKGROUND: Bevacizumab prolongs progression-free survival (PFS) in patients with metastatic colorectal cancer. We analysed the protein expression levels of vascular endothelial growth factor (VEGF) ligands and receptors to determine their prognostic and predictive effects. METHODS: We graded expression of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-R1, and VEGF-R2 to assess whether overexpression predicted bevacizumab resistance in samples from 268 of 471 patients randomised to capecitabine (C), capecitabine and bevacizumab (CB), or CB and mitomycin (CBM) in the MAX trial and extended the analysis to the CAIRO-2 population. RESULTS: Patients with low expression of VEGF-D (0, 1thorn) benefited from bevacizumab treatment (PFS hazard ratio (HR) (C vs CBthornCBM), 0.21; 95% CI, 0.08-0.55; overall survival (OS) HR, 0.35; 95% CI, 0.13-0.90). Patients with higher VEGF-D expression received less benefit (VEGF-D 2thorn PFS HR, 0.67; 95% CI, 0.45-1.00; OS HR, 0.82; 95% CI, 0.52-1.30; VEGF-D 3thorn PFS HR, 0.77; 95% CI, 0.50-1.17; OS HR, 1.28; 95% CI, 0.79-2.09) (P interaction o0.05). In CAIRO-2, there was no difference in PFS or OS according to VEGF-D expression. CONCLUSIONS: The predictive value of VEGF-D expression for bevacizumab may depend on the chemotherapy backbone used. Further evaluation is required before clinical utilisation.