Pessoa, Rodrigo Rodrigues

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions for patients with prostate cancer across the disease spectrum. The Guidelines sections included in this article focus on metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). For patients with mCSPC, disease characteristics, such as whether metastases arose synchronously or metachronously and the degree of metastatic burden, impact therapy decisions, including how much treatment intensification is appropriate and when prostate-directed and/or metastasis-directed therapy should be considered. In the mCRPC setting, androgen deprivation therapy is continued with the sequential or concurrent addition of certain androgen receptor pathway inhibitors, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, biomarkers, the extent and location of metastases, symptoms, and potential side effects.

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.

381 Background: Venous tumor thrombus (VTT) is associated with worse oncologic outcomes in clear cell renal cell carcinoma (ccRCC). It is unknown if VTT and pulmonary embolism (PE) predispose patients to pulmonary metastasis. Methods: We queried our institutional registry for ccRCC patients undergoing radical nephrectomy (1970-2019). Cox proportional hazards regression models, adjusting for factors associated with ccRCC progression, were used to determine if VTT and PE were associated with pulmonary metastasis. Results: Of 3,410 patients studied, 1,025 (30%) had VTT, and patients with VTT were more likely to present with pulmonary metastasis at nephrectomy (20% vs 7%, p<0.001). Within the VTT subset, level of VTT was not significantly associated with pulmonary metastasis at nephrectomy (p=0.3). For all patients who had metastatic disease at nephrectomy (n=643), pulmonary metastasis was more common in those with VTT versus those without VTT (68% vs 51%, p<0.001). Excluding patients with pulmonary metastasis at nephrectomy, on multivariable analysis, VTT remained associated with post-nephrectomy pulmonary metastasis (hazard ratio (HR) 1.31, p<0.001) without a notable difference in HRs between renal vein (1.27) and caval (1.38) VTT. Presence of PE in the setting of VTT was associated with increased pulmonary metastasis post-nephrectomy (HR 2.31, p<0.001). Conclusions: VTT is associated with disproportionately increased pulmonary metastasis at presentation and post-nephrectomy in ccRCC patients. Further, the presence of PE at nephrectomy for VTT was associated with increased pulmonary metastasis post-nephrectomy. These results support a metastatic predilection of ccRCC with VTT to the lungs.

Background: Approximately 30% of renal cell carcinoma (RCC) cases present with de novo metastatic disease, while 20% to 30% of those with localized disease will develop metastases following surgical resection. Various drug classes have been investigated to treat RCC, including cytokine-based therapies, small molecule Vascular Endothelial Growth Factor (VEGF) tyrosine kinase inhibitors (TKIs) and antibody-based therapies. Up to 58% of patients fail to respond to primary immune checkpoint inhibitor (ICI) therapy, and nearly all initial responders experience disease progression due to the development of secondary resistance. Consequently, novel treatment options are being investigated. Objective: Review the rapidly evolving ADC therapeutic landscape in metastatic RCC including recent trials, emerging ADCs targets, and future directions for ADCs in the treatment of advanced RCC. Methods: Literature review using the MEDLINE database on important trials and presentations from the American Society of Clinical Oncology (ASCO), and the European Society for Medical Oncology (ESMO) conferences. Key words used included “renal cell carcinoma,” “RCC,” “metastatic RCC,” “advanced RCC,” “antibody-based therapies,” “immunotherapy,” “clinical trials,” and “emerging drugs.” Specifically for review of ADCs in RCC, the following search string was used with additional review of bibliographies from retrieved papers: “((antibody drug conjugate) OR (antibody-dependent cellular cytotoxicity) OR (chimeric antigen receptor)) AND ((kidney cancer) OR (renal cell carcinoma))”. Results: Several promising targets including MMP14, EGFR, MCT4, CA9, MET, CDH13, B7-H3, and PSMA were identified with relevant preclinical and clinical studies reviewed. Conclusions: While ADCs therapeutics have not shown benefit to date for renal cell carcinoma, there are ample promising candidates and targets for future research.

Abstract The intrinsic and acquired resistance to PD-1/PD-L1 immune checkpoint blockade is an important challenge for patients and clinicians because no reliable tool has been developed to predict individualized response to immunotherapy. In this study, we demonstrate the translational relevance of an ex vivo functional assay that measures the tumor cell killing ability of patient-derived CD8 T and NK cells (referred to as “cytotoxic lymphocytes,” or CLs) isolated from the peripheral blood of patients with renal cell carcinoma. Patient-derived PBMCs were isolated before and after nephrectomy from patients with renal cell carcinoma. We compared the efficacy of U.S. Food and Drug Administration (FDA)-approved PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, atezolizumab) and a newly developed PD-L1 inhibitor (H1A Ab) in eliciting cytotoxic function. CL activity was improved at 3 mo after radical nephrectomy compared with baseline, and it was associated with higher circulating levels of tumor-reactive effector CD8 T cells (CD11ahighCX3CR1+GZMB+). Treatment of PBMCs with FDA-approved PD-1/PD-L1 inhibitors enhanced tumor cell killing activity of CLs, but a differential response was observed at the individual-patient level. H1A demonstrated superior efficacy in promoting CL activity compared with FDA-approved PD-1/PD-L1 inhibitors. PBMC immunophenotyping by mass cytometry revealed enrichment of effector CD8 T and NK cells in H1A-treated PBMCs and immunosuppressive regulatory T cells in atezolizumab-treated samples. Our study lays the ground for future investigation of the therapeutic value of H1A as a next-generation immune checkpoint inhibitor and the potential of measuring CTL activity in PBMCs as a tool to predict individual response to immune checkpoint inhibitors in patients with advanced renal cell carcinoma.

239 Background: In part, TMB guides therapeutic decisions on the use of immune checkpoint inhibitors (ICIs) in aPC. Most patients (pts) with aPC do not have high TMB (TMB-H) at the time of initial assessment. However, TMB changes over time (from treatment pressure) as pts progress through lines of therapy (LOT) has not been extensively explored in aPC. We describe real world data on changes to blood TMB (bTMB) in pts with aPC exposed to several LOT. Methods: Genomic results from pts with aPC who had ≥1 ctDNA test(s) with TMB analyzed (Guardant360, Guardant Health, Inc) as part of clinical care from Oct 2020 – Jun 2022 were retrospectively queried. Clinical factors were extracted from test requisition forms; pts from Mayo Clinic had additional factors, including intervening treatment, extracted from medical records. High bTMB (TMB-H) was defined as ≥13.4 mut/Mb, as previously reported. Proportions were compared using Fisher’s Exact Test. Results: 316 patients with a median age of 72 (range: 44-91) were analyzed. Initial median TMB for the entire cohort was 8.18 mut/Mb (range: 0.01-268.3). On subsequent test, TMB decreased in 122(40%), increased in 173(55%), of whom 29 (17%) became TMB-H; 21 (7%) had unchanged TMB. Median time between tests was 182 days (range: 21-578). 101 patients with 262 tests and a median age of 71 years (range: 46-87) were clinically annotated in the Mayo cohort of whom 58 had >2 consecutive TMB scores: 25 (43%) had TMB increase, of whom 4 (16%) became TMB-H, 23 (40%) had TMB decrease, 10 (17%) had dynamic changes with increases and decreases. Numeric but not statistically significant differences in clinical factors were observed between groups (p>0.05). Conclusions: In this real world cohort, variation in TMB is seen with increasing LOT. Importantly, nearly 1 in 5 patients with increasing tumor mutational burden develop TMB-H, which may be a clinically actionable finding as these pts become eligible for ICI. Findings underscore the importance of repeat genetic testing with time and LOT. [Table: see text]

AbstractRenal cell carcinoma (RCC) is among the top 10 most common cancers in both men and women with an estimated 75 000 cases each year in the US. Over the last decade, the therapeutic landscape for patients with metastatic RCC has significantly evolved, with immunotherapy emerging as the new front-line therapy. Despite significant improvement in toxicity profile and survival outcomes, key concerns such as patient selection, treatment sequencing, and intrinsic and acquired resistance remain unresolved. Emerging options such as antibody-based therapeutics (eg, anti-CD70, anti-CA9, and anti-ENPP3) are being explored in clinical trials for patients with cancer resistant or refractory to current immunotherapies. Despite positive results for hematological cancers, breast cancer, and more recently bladder cancer, most antibody-based therapies failed to improve the outcomes in patients with advanced RCC. This underscores the need to understand the underlying causes of failed responses to this treatment class, which will ultimately support the rational design of more effective and tolerable treatments. In this review, we summarize the evolving landscape of RCC therapeutics and describe recent clinical trials with emerging antibody-based therapeutics. We also describe the challenges that need to be overcome for the successful creation of therapeutic antibodies for treating RCC.