Predictors of early progressive disease and antitumor effects by metastatic site in renal cell carcinoma treated with ipilimumab plus nivolumab.

Redefining early vs late progressive disease (PD) in chronic lymphocytic leukemia: A pooled analysis of fixed-duration therapies

327 Background: This phase 2 randomized discontinuation trial evaluated tivozanib, a potent and selective vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3 kinase inhibitor. Median progression-free survival (PFS) in all pts was 11.8 mo, and the objective response rate (ORR) was 27%. Methods: Pts received 1.5 mg/d tivozanib (3 wk on, 1 wk off = 1 cycle). A retrospective analysis evaluated efficacy and safety by histologic subtype. Response was evaluated by independent radiology review using standard RECIST criteria. Results: 272 pts were enrolled: 70% were male; median age was 56 y (range, 26–79). 226 (83%) pts had clear cell (CC) RCC; 46 had non–clear cell (NCC) RCC, including 11 with papillary RCC. Of pts with CC RCC, 176 (78%) had undergone nephrectomy; of pts with NCC RCC, 23 (50%) had undergone nephrectomy. Median treatment duration was 8.5 mo (range, 0.03– 23.8) as of the data cutoff. Median PFS was 12.5 mo (range, 9.9–17.7) for pts with CC RCC, not yet reached for pts with papillary RCC, and 5.4 mo (range, 3.7–12.0) for pts with other NCC subtypes. ORR and disease control rate (DCR; ORR + stable disease), respectively, were 29% and 85% for pts with CC RCC, 18% and 100% for pts with papillary RCC, and 17% and 74% for pts with other NCC subtypes. For pts with CC RCC, median PFS, ORR, and DCR, respectively, were 14.8 mo, 32%, and 88% for those who had undergone nephrectomy and 8.9 mo, 18%, and 76% for those who had not. Among pts with NCC RCC, median PFS was 6.6 mo for pts who had undergone nephrectomy and 7.2 mo for pts without nephrectomy; ORR was 17% for both NCC subgroups, with a DCR of 78% for pts who had undergone nephrectomy and 83% for pts who had not. Common drug- related adverse events (AEs) for pts with CC and NCC RCC, respectively, included hypertension (49% and 48%), dysphonia (22% and 22%), asthenia (12% and 13%), and diarrhea (13% and 9%). The most common grade ≥3 drug-related AE was hypertension (CC, 8%; NCC, 4%). Conclusions: Disease control was observed for pts with all RCC histologic subtypes. The rate of AEs was similar among patients with CC and NCC RCC and consistent with that of a selective VEGFR inhibitor with minimal off-target toxicities. Tivozanib is currently being tested in a phase 3 trial in pts with CC RCC. [Table: see text]

Renal cell carcinoma (RCC) is a renal cortical tumor with high clinical incidence. The effect of glutathione peroxidases (GPXs) on RCC and the possible mechanism are still unclear. This study aims to explore the expression level of GPXs gene in RCC and its effect on the clinical prognosis of patients with RCC via bioinformatics analysis. The mRNA expressions of GPXs family genes were obtained from the public data of The Cancer Genome Atlas (TCGA) database. The Kruskal-Wails test was used to analyze the differences in mRNA expression of GPXs family genes between samples from patients with RCC and the normal population. UALAN databases were used to analyze the differences in protein expression of GPXs family genes between samples from patients with renal clear cell carcinoma and the normal population, and to evaluate the role of GPXs family genes in RCC. The Kaplan-Meier Plotter was used to analyze the correlation between different types of RCC and overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and progression-free survival (PFS). Kaplan-Meier survival curve was drawn based on the GPX8 gene expression to study the relationship between GPX8 gene expression and prognosis of RCC patients. Based on the results of multivariate Cox regression analysis, a Nomogram scoring model for RCC prediction was established by introducing GPX8 gene. The mRNA expressions of GPX1 and GPX4 were higher in the sample of renal chromophobe cell carcinoma, renal clear cell carcinoma, and renal papillary cell carcinoma than those in the normal population (all P<0.01), and GPX7 and GPX8 were significantly over-expressed in patients with renal papillary cell carcinoma and renal clear cell carcinoma (all P<0.01). Compared with the normal group, the protein expressions of GPX1, GPX2, GPX7, and GPX8 were increased significantly in renal clear cell carcinoma (all P<0.01), while GPX3 and GPX4 expressions were decreased significantly (both P<0.01). The protein expressions of GPX1, GPX2, GPX7, and GPX8 were increased significantly in patients with renal clear cell carcinoma at different tumor grades (all P<0.01), while GPX3 and GPX4 expressions were decreased significantly (both P<0.01). Survival analysis showed that OS, DFS, DSS, and PFS were all decreased in patients with clear cell carcinoma compared with patients with papillary cell carcinoma and chromophobe cell carcinoma. According to the GPX8 level, patients were assigned into the low, medium, and high expression groups. Compared with the low GPX8 level group, the OS (P<0.01), DFS (P=0.03), DSS (P<0.01), and PFS (P=3.18×10-7) were significantly decreased in the high level group. Univariate Cox proportional regression analysis showed that the high level of GPX8 was associated with poor OS of 3 different types of renal cancer. Multifactorial analysis showed that GPX8 was an independent factor affecting the OS of patients with renal papillary cell carcinoma. Race and post tumor node metastasis (pTNM) typing were independent factors influencing the OS of patients with renal clear cell carcinoma. GPX8 and pTMN were independent factors influencing the OS of patients with renal chromophobe cell carcinoma. Based on these variables, the Nomogram risk models of 3 types of cell carcinoma were established, and the discrimination and calibration of the models were evaluated using the Consistency index (C-index) and calibration curves. The C-index of the risk model of renal papillary cell carcinoma was 0.62 (95% CI 0.51 to 1.00, P=0.03). The results of receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) was 0.88. The C-index of the risk model of renal clear cell carcinoma was 0.72 (95% CI 0.52 to 1.00, P=0.03). The results of ROC curve showed that the AUC was 0.90. The C-index of the risk model of chromophobe cell carcinoma of kidney was 0.90 (95% CI 0.85 to 1.00, P<0.01). The results of ROC curve showed that the AUC was 0.59. GPXs family genes, especially GPX8, are potential markers for poor prognosis of RCC, and the occurrence and development of RCC can be predicted in clinical practice based on the expressions of GPXs family genes.

Tailored immunotherapy approach with nivolumab with or without nivolumab plus ipilimumab as immunotherapeutic boost in patients with metastatic renal cell carcinoma (TITAN-RCC): a multicentre, single-arm, phase 2 trial

ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma

629 Background: Cytoreductive nephrectomy (CRN) is an important treatment modality in patients (pts) with advanced RCC, however the role and timing in the context of VEGF-TT remains under investigation. The aim of this study is to determine the efficacy of VEGF-TT to induce primary tumor shrinkage in advanced RCC. Methods: We conducted a pooled analysis of 12 Pfizer-sponsored trials in pts with metastatic RCC treated with sunitinib, sorafenib, axitinib, bevacizumab, termsirolimus or interferon-α. Primary endpoint was the primary tumor objective response rate (ORR) by RECIST in pts who have not undergone prior nephrectomy. Kaplan-Meier method was used to estimate median overall survival (OS) of responders (PR or CR) v. non-responders. Cox regression adjusting for demographics, histology type, prior therapy, metastasis sites, IMDC risk factors and neutrophil-to-lymphocyte ratio was used to compare OS between pts with and without primary tumor ORR. Results: 565 (12%) out of 4736 pts included had their primary tumors intact, of which 360 (8%) received VEGF-TT. In pts with primary tumor intact, 87% had clear-cell RCC and IMDC risk group were 4% favourable, 33% intermediate, 39% poor, 24% unknown. 35% had bone metastasis and 32% had liver metastases. 65% had ECOG performance status ≥1. Compared to pts with prior nephrectomy, primary tumor intact pts were more likely to have bone or liver metastases or to be IMDC poor risk. Primary tumor ORR was 17% (95% exact CI, 14, 20) in all pts, 19% (95% exact CI, 16, 23) in first line treated pts and 23% (95% Exact CI, 19, 28) in pts treated with VEGF-TT (any line). Primary tumor ORR was 20% (95% exact CI, 15, 26) in IMDC intermediate risk pts and 9% (95% exact CI, 5 – 13) in the poor risk. No pts had PD as best response in their primary tumor at the time they stopped systemic therapy. Median OS was 33.98 months in pts with primary tumor ORR and 9.8 months in pts without ORR, adjusted HR 0.42 [95%CI, 0.28, 0.6; p &lt; 0.0001]. Conclusions: VEGF-TT resulted in primary tumor shrinkage in 23% of pts with IMDC intermediate and poor risk advanced RCC who have not undergone CRN. VEGF-TT may potentially facilitate future CRN in select pts. Trials assessing the utility of CRN are underway.

The MRC Randomised-controlled Trial of Interferon-α, Interleukin-2 and 5-Fluorouracil vs Interferon-α Alone in Patients with Advanced Renal cell Carcinoma (RE04): Rationale and Progress

Low Immunoglobulin G and Low Lymphocyte-Monocyte Ratio at the End of Treatment Predict Early Progression in Diffuse Large B-Cell Lymphoma

Renal Cell Carcinoma: Diagnosis Based on Metastatic Manifestations

Background: Immune checkpoint inhibitors (ICIs) as monotherapy (ICI-mono) or with chemotherapy (ICI-chemo) are standard first-line treatment in NSCLC patients lacking targetable driver mutations. Biomarkers to identify patients at risk for early progression on ICI-mono or those who would maximally benefit from upfront ICI-chemo have not been defined. Methods: We queried the GEMINI database to identify metastatic NSCLC patients without targetable EGFR/ALK alterations who were treated with ICI-mono or ICI-chemo. Mutational profiling was performed on tissue or blood using targeted NGS. Outcome measures were defined as clinical progression free survival (PFS) or early progressive disease (PD) rate (defined as rate of 3-month progression), and their association with variables was assessed via Cox Proportional Hazards regression (PFS) or logistic regression (early PD). Predictive deep learning models were used to integrate clinicopathological factors and genomic profile. Results: 735 patients were included in this study, 269 treated with ICI-chemo and 466 with ICI-mono; 446 were treated in the first-line setting. TP53 was the most frequently altered gene (60%), followed by KRAS (37%), AR (21%), and STK11 (19%). In ICI-mono patients, alterations in STK11, ERBB2, ARID1A and CDK6 were associated with a higher likelihood of early PD; only STK11 was associated with early PD (29% vs 17%, P = 0.04) on ICI-chemo. In all patients, low PD-L1 expression and high disease burden (stage IVb and liver metastases) associated with early PD, but there were borderline significant treatment effects in favor of ICI-chemo in never smokers and patients with liver metastases and stage IVb. Shorter PFS was observed in the ICI-chemo group who had CDKN2A alterations vs wild type (median PFS: 5.1 vs 9.0 months; HR: 1.72; P = 0.01). A subgroup analysis of patients with CDKN2A alterations demonstrated preferentially worse outcomes in ICI-chemo compared to ICI-mono, with the best PFS achieved in the ICI-mono treated patients with CDKN2A point mutation. Integration of clinicogenomic features into a multivariate model with feature selection to predict early PD demonstrated a predictive performance of AUC 0.73 (vs PD-L1 alone, AUC 0.60) in the ICI-mono group, driven by liver metastases, stage IVb disease, PD-L1 expression, and STK11 alterations. These features were less predictive in ICI-chemo-treated patients, indicating a protective effect against early PD in these patients from combination chemoimmunotherapy. Conclusions: Low PD-L1, high disease burden, and STK11 alterations are markers of early PD on ICI-mono, and patients with these features may particularly benefit from upfront combination treatment with ICI-chemo to protect against early progression. Citation Format: Lingzhi Hong, Muhammad Aminu, Xuetao Lu, Maliazurina B. Saad, Pingjun Chen, Waree Rinsurongkawong, Amy Spelman, Yasir Y. Elamin, Marcelo V. Negrao, Ferdinandos Skoulidis, Carl M. Gay, Tina Cascone, Mara B. Antonoff, Boris Sepesi, Jeff Lewis, Don L. Gibbons, Ara A. Vaporciyan, Xiuning Le, J.Jack Lee, Sinchita Roy-Chowdhuri, Mark J. Routbort, John V. Heymach, Jia Wu, Jianjun Zhang, Natalie I. Vokes. Genomic and clinical predictors of early disease progression and chemoimmunotherapy benefit in advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 964.

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Early Relapse Of Follicular Lymphoma After R-CHOP Uniquely Defines Patients At High Risk For Death: An Analysis From The National Lymphocare Study

Renal cell carcinoma (RCC) is the third leading cause of death among urological tumours, annually afflicts about 150, 000 people globally and causes nearly 78, 000 deaths (Jemal et al., 2008; Zbar et al., 2003). RCC is an epithelial tumour consisting of several different histological subtypes of which clear cell RCC is the prototypical. Traditionally treatment has been via surgery and immunotherapy. Surgical resection is appropriate for some patient cohorts including those with isolated metastases. However, recurrence is common even when the primary and metastatic sites have been aggressively resected (Couillard & deVere White, 1993). RCC is highly unresponsive to standard chemotherapy and the use of cytokine therapy with interleukin (IL)-2 or interferon (IFN)-┙ is associated with low rates of response and high rates of toxicity (Oudard et al., 2007). Thus, development of new therapies continues to be crucial to improve outcomes in patients with RCC. The increased understanding of the molecular structure and aberrant activity of signalling pathways in RCC has lead to a flurry of research activity in the arena of targeted therapies namely anti-angiogenic vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR), both of which are involved in the pathogenesis of RCC (Mulders, 2009). These advancements in an obvious therapeutic gap have significantly improved the progression free survival (PFS) of patients with RCC. Despite the explosion in drug development during the past five years, however, PFS for patients with metastatic RCC (mRCC) still remains poor as none of the current targeted therapies possess the capacity to induce remission. In addition these drugs provide dose-limiting toxic side effects and so we are still faced with a considerable task in developing newer safer therapeutics for use as either first line agents or in combination with existing ones.

486 Background: The VEGFR inhibitor sunitinib is a standard tx for metastatic clear cell RCC. Data on the activity of sunitinib in metastatic non clear cell RCC, is limited by small or heterogeneous (mixed histology or targeted therapies) studies, that revealed a lower antitumor activity than in patients with clear cell histology. We aimed to analyze the activity of sunitinib in a large international cohort of patients with metastatic papillary RCC, and to characterize patients who may benefit for this therapy. Methods: Records from metastatic papillary RCC patients treated with sunitinib in 10 centers across 3 countries were retrospectively reviewed. Univariate and multivariate analyses of association between clinicopathologic factors and clinical outcome were performed using Cox regression. Results: Between 2004-2013, 74 patients (median age 60, 68% male) with metastatic papillary RCC were treated with sunitinib. 78% had a prior nephrectomy. HENG risk was good 11%, intermediate 56%, and poor 33%. 21% were active smokers, and 31% users of angiotensin system inhibitors. 24% and 41% had liver and bone metastases, respectively. 55% had a pre-treatment neutrophil to lymphocyte ratio (NLR) &gt;3. 40% had dose reduction/treatment interruption. Sunitinib induced hypothyroidism and hypertension (HTN) occurred in 30% and 43%, respectively. 70% achieved a clinical benefit (partial response + stable disease), while 30% had disease progression within the first 3 months of therapy. Median progression free survival (PFS) and overall survival (OS) were 5 and 12 months, respectively. 27% had a PFS ≥ 1 year, and 26% survived ≥ 2 years. Factors associated with PFS were sunitinib induced HTN (HR 0.31, p=0.002), pre-treatment NLR &gt;3 (HR 5.3, p=0.001), and active smoking (HR 2.5, p=0.01). Factors associated with OS were sunitinib induced hypothyroidism (HR 0.4, p=0.024), past nephrectomy (HR 0.41, p=0.02), pre-treatment NLR &gt;3 (HR 2.25, p=0.036), and active smoking (HR 2.3, p=0.027). Conclusions: Clinicopathologic factors may be used to identify patients with metastatic papillary RCC who may benefit from sunitinib tx. A prolonged PFS and OS were noted in 26-27% of patients.

Early Progression of Disease (< 2 Years) Is a Negative Predictor of Survival in Patients (Pts) with Chronic Lymphocytic Leukemia (CLL): An Analysis from the Connect® CLL Registry