Sharma, Vidit

458 Background: Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 axis has revolutionized the therapeutic landscape of patients with advanced and locally advanced renal cell carcinoma (RCC). However, complete response rates remain low and there is a need for novel therapeutic options for ICI-resistant and refractory RCC. Our group has generated a novel humanized anti-PD-L1 antibody, called H1A, that induces PD-L1 degradation preventing not only its interaction with PD-1 but also inhibiting pro-tumorigenic intracellular signaling. In this study, we compared the antitumor activity of H1A with FDA-approved ICI using patient-derived immune cells and humanized mouse tumor models. Methods: In vivo antitumor activity of H1A and atezolizumab (ATZ) was compared in three humanized PD-1/PD-L1 mouse tumor models with different immunogenicity (E0771:high, MC38:moderate, B16-F10:poor). Peripheral blood mononuclear cells (PBMC) were isolated from 14 RCC patients undergoing with nephrectomy. PBMC were treated with H1A, nivolumab (NIV), atezolizumab (ATZ) and pembrolizumab (PEM) to evaluate their efficacy in inducing tumor cell death in an ex-vivo cytotoxicity assay. Mass cytometry was employed to determine the impact of H1A and atezolizumab on the PBMC profile. Results: MC38 tumors showed moderate response to both H1A and ATZ which was abrogated by CD8 T cell depletion. In E0771 tumors, higher percentage of complete responders was observed with H1A compared to ATZ and E0771 rechallenge revealed memory antitumor immunity with complete rejection of tumors. Patient-derived PBMC treated with H1A showed superior tumor cell killing compared to NIV, PEM and ATZ (p<0.01). While H1A treatment of PBMC induced expansion of effector NK and CD8 T cells (GZMB+ T-bet+), ATZ treatment led to enrichment of Tregs (CD25+,Foxp3+) expressing inhibitory markers PD-1 and LAG-3. Conclusions: H1A demonstrated superior antitumor activity compared to FDA-approved ICI which lays the ground for clinical testing of H1A as a next-generation immune checkpoint inhibitor for the treatment of renal cell carcinoma.

Abstract Background The Surgery in Early Metastatic Seminoma (SEMS) trial examined retroperitoneal lymph node dissection as first-line treatment for patients with isolated 1-3 cm retroperitoneal lymphadenopathy. To date, the standard of care for these patients has been either chemotherapy or radiotherapy. Herein, we evaluated the relative cost-effectiveness of these management strategies. Methods A microsimulation model assessed the cost-effectiveness of retroperitoneal lymph node dissection, chemotherapy, and radiotherapy for stage IIA seminoma. Sensitivity analyses were performed to evaluate model robustness. Retroperitoneal lymph node dissection recurrence probabilities were obtained from the SEMS trial. All other probability and utility values were obtained from published literature. Primary outcomes included costs from a commercial insurer’s perspective, effectiveness (quality adjusted life-years [QALYs]), and incremental cost-effectiveness ratios using a willingness-to-pay threshold of $100 000/QALY. Results At a lifetime horizon, the mean costs per patient for retroperitoneal lymph node dissection, radiotherapy, and chemotherapy were $58 469, $98 783, and $104 096, and the mean QALYs were 40.61, 40.70, and 39.15, respectively. Retroperitoneal lymph node dissection was found to be the most cost-effective approach because of high costs and accrued disutility of chronic toxicities associated with radiotherapy (cost-effectiveness ratios = $433 845/QALY) and chemotherapy (dominated). On 1-way sensitivity analyses, retroperitoneal lymph node dissection was no longer cost-effective if the probabilities of infertility and cardiovascular toxicity after radiotherapy were less than 13% and 16%, respectively, or if the 2-year probability of progression after retroperitoneal lymph node dissection was more than 26%. Conclusions Retroperitoneal lymph node dissection was the most cost-effective treatment approach for stage IIA seminoma. These findings support clinical guideline consideration of including retroperitoneal lymph node dissection as a treatment option for well-selected patients with stage IIA seminoma.

482 Background: Population-based studies evaluating outcomes exclusively for metastatic upper tract urothelial carcinoma (mUTUC) are sparse and often only capture patients with de novo (synchronous) metastases as opposed to those who progress to metastatic disease (metachronous). We sought to evaluate the outcomes and costs associated with mUTUC and employ a novel methodology to identify both synchronous and metachronous mUTUC patients using claims data. Additionally, we created a guideline-based quality score to improve quality of care in this space. Methods: Using the SEER-Medicare database we identified patients aged 66 years and older diagnosed with mUTUC between 2004 and 2012. Achievement of the following quality criteria was assessed: 1) cancer-specific survival greater than 12 months; 2) receipt of systemic therapy; 3) receipt of hospice/palliative care. Kaplan-Meier survival curves and Cox proportional hazard models were used to compare overall survival between quality scores (0 vs. ≥1) and synchronous vs. metachronous mUTUC. Total healthcare and Medicare Part D out-of-pocket costs within two years of diagnosis were evaluated. Regression analyses were performed to assess characteristics associated with quality criteria and total healthcare costs. Results: Of the 1,223 patients identified, 381 (31.2%) and 842 (68.8%) had synchronous and metachronous mUTUC, respectively. At least one quality criterion was met in 40.2% of patients. Notably, only 54 patients (4.4%) received palliative care services. On multivariable analysis, patients with synchronous mUTUC (OR:0.55, 95%CI:0.41–0.72), and at least 3 comorbidities (OR:0.68, 95%CI:0.47–0.98), were less likely to achieve at least one quality criterion. Patients meeting quality criteria had longer survival compared with patients who did not meet criteria (HR:0.52, 95%CI: 0.46–0.59). Meeting at least one quality criterion was independently associated with increased costs ($94,677, 95%CI: 87702–101652 vs. $63575, 95%CI: 59598–67552) on multivariable regression analysis. Conclusions: Less than half of mUTUC patients met at least one quality criterion. Quality score achievement was associated with longer overall survival at a modest increase in total healthcare spending. These findings not only provide guidance for future study of rare diseases using secondary data, but also highlight inadequacies in the current management of mUTUC.