The genomic landscape of metastatic clear cell renal cell carcinoma (ccRCC) after treatment with systemic therapy.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 675-675
Author(s):  
Johannes Van Der Mijn ◽  
Kenneth Eng ◽  
Evan Fernandez ◽  
Clara Oromendia ◽  
Tuo Zhang ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Systemic Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Vegf Inhibitors ◽  
Cell Renal Cell Carcinoma ◽  
Primary Tumors ◽  
Anti Vegf ◽  
Genomic Landscape

675 Background: The most frequent genomic alterations in patients (pts) with ccRCC have been identified in primary tumors. Here we investigated the genomic landscape of ccRCC in a cohort enriched for metastatic tumors after treatment with systemic therapy. Methods: We prospectively enrolled pts with ccRCC in a clinical study in which Whole-Exome Sequencing (WES) of normal and tumor tissue was performed. Clinical features, treatment outcome and survival were evaluated. Results: Forty-five pts with ccRCC with a median age of 65 years (range 38–86) were enrolled. According to the Heng risk criteria, 15 pts (33.3%) were classified as favorable-risk 23 pts (51.1%) were intermediate-risk and 7 pts (15.6%) were poor-risk. Pts received a median number of 3 lines (range 0–9) of therapy including cytokines (n=7), anti-VEGF (n=36), mTOR inhibitors (n=10) and/or immune checkpoint inhibitors (n=23). The median progression free survival (PFS) after treatment was 3.5 months (0.7-13.1), 11.1 months (1.1–54.2), 2.7 months (0.7-36.2) and 4.9 months (1.4–29.2) after cytokines, VEGF-, mTOR- and immune checkpoint inhibitors, respectively. The median overall survival (OS) from start of treatment to last follow up was 2.2 years (range 0.2–14.9 years). A total of 68 samples were sequenced. These included 9 (12.5%) primary tumors, 38 (55.9%) collected after treatment with anti-VEGF, 16 (23.5%) after mTOR- and 8 (11.8%) after immune checkpoint inhibitor. VHL, KDM5C, SETD2 and PBRM1 were the most frequent somatic mutations detected in this cohort. In two cases with a short and long response to VEGF targeted therapy (PFS 2.8 versus 50.3 months) rapid autopsies were performed which allowed multiregional (n=7, n=4) sampling. The multiregional sequencing in the rapid autopsy case with a prolonged response to VEGF targeted therapy revealed recurrent KDM5C mutations. Conclusions: We present the genomic landscape of metastatic ccRCC after treatment with systemic therapy. We report an increased frequency of KDM5C mutations, previously described to be associated with a favorable response to VEGF-inhibitors.

scholarly journals A Contemporary Review of Immune Checkpoint Inhibitors in Advanced Clear Cell Renal Cell Carcinoma

Vaccines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 919
Author(s):  
Eun-mi Yu ◽  
Laura Linville ◽  
Matthew Rosenthal ◽  
Jeanny B. Aragon-Ching
Keyword(s):  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Vascular Endothelial ◽  
Vegf Inhibitors ◽  
Cell Renal Cell Carcinoma ◽  
Improved Outcomes ◽  
Immune Oncology ◽  
Endothelial Growth Factor

The use of checkpoint inhibitors in advanced and metastatic renal cell carcinomas (RCCs) has rapidly evolved over the past several years. While immune-oncology (IO) drug therapy has been successful at resulting in improved responses and survival, combination therapies with immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) inhibitors have further improved outcomes. This article reviews the landmark trials that have led to the approval of IO therapies, including the Checkmate 214 trial and combination IO/VEGF TKI therapies with Checkmate 9ER, CLEAR, and Keynote-426, and it includes a discussion on promising therapies moving in the future.

Effectiveness of first-line immune checkpoint inhibitors (ICI) in advanced non-clear cell renal cell carcinoma (ccRCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 316-316
Author(s):  
Jeffrey Graham ◽  
Connor Wells ◽  
Shaan Dudani ◽  
Chun Loo Gan ◽  
Frede Donskov ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
First Line ◽  
Cell Renal Cell Carcinoma

316 Background: Immune checkpoint inhibitors (ICI) have demonstrated impressive activity in metastatic clear-cell renal cell carcinoma (ccRCC) and have become standard treatment options in this setting. Data supporting the effectiveness of ICI based therapy in non-clear cell RCC (nccRCC) is more limited. Methods: We performed a retrospective analysis using the International Metastatic RCC Database Consortium (IMDC). Patients with nccRCC were classified into 3 groups based on first-line therapy: ICI based therapy (in monotherapy or in combination), vascular endothelial growth factor targeted therapy (VEGF-TT) monotherapy, or mammalian target of rapamycin (mTOR) inhibitor monotherapy. Primary outcome was overall survival (OS). Secondary outcomes were time to treatment failure (TTF) and objective response rate (ORR). We used Kaplan-Meier method to compare OS and TTF between treatment groups and Cox proportional hazards models to adjust for prognostic covariates. Results: We identified 1181 patients with nccRCC. In first-line, 78.2% received VEGF-TT, 15.8% mTOR inhibitors, and 5.5% ICI based therapy, of which 41.5% in monotherapy, 30.8% doublet-ICIs and 27.7% an ICI combined with VEGF-TT. Median OS in the ICI group was 28.6 months, compared to 19.2 and 12.6 in the VEGF-TT and mTOR groups, respectively. Median TTF was 6.9 months vs. 5.1 and 3.9 and ORR was 25% vs. 17.8% and 5.8% in the ICI, VEGF-TT and mTOR groups, respectively. After adjusting for IMDC risk group, histological subtype, and age, the hazard ratio (HR) for OS was 0.58 (95% CI 0.35-0.94, p=0.03) for ICI vs. VEGF-TT and 0.48 (95% CI 0.29-0.80, p=0.005) for ICI vs. mTOR. Conclusions: In advanced nccRCC, first-line ICI based treatment appears to be associated with improved OS compared to VEGF and mTOR targeted therapy. These results need to be confirmed in prospective randomized trials. [Table: see text]

scholarly journals Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors

2020 ◽  
Vol 38 (27) ◽  
pp. 3088-3094 ◽  
Author(s):  
Anita Gul ◽  
Tyler F. Stewart ◽  
Charlene M. Mantia ◽  
Neil J. Shah ◽  
Emily Stern Gatof ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Free Survival ◽  
Metastatic Rcc

PURPOSE Immune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti–PD-1 pathway–targeted therapy. PATIENTS AND METHODS Patients with metastatic RCC who received prior anti–PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed. RESULTS Forty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients. CONCLUSION Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.

Human leukocyte antigen expression in paired primary lung lesions and brain metastases in non-small cell lung cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 43-43
Author(s):  
Jarrett Failing ◽  
Marie-Christine Aubry ◽  
Aaron Scott Mansfield
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Human Leukocyte ◽  
Small Cell ◽  
Small Cell Lung ◽  
Primary Tumors ◽  
Primary Nsclc

43 Background: Human leukocyte antigens (HLA) are crucial for cytotoxic T cell responses to cancer. Loss of HLA expression is a mechanism of tumor immune escape and may contribute to resistance to immunotherapy. In patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors we have observed discordant responses between brain metastases and extracranial disease and reported on differential PD-L1 expression and clonal T cell infiltration between paired primary lung lesions and brain metastases. In this project we sought to evaluate whether HLA expression was retained in metastatic NSCLC. Methods: Adult patients with paired primary NSCLC and brain metastases were identified from our institution’s tissue registry. HLA-A cell membrane expression on tumor cells was determined by immunohistochemistry with an anti-HLA-A antibody. Tumors with greater than 10% HLA expression were considered positive. Agreement statistics (κ) and Fisher’s exact test were used for analysis. Results: 51 patients with paired primary NSCLC and brain lesions were identified. The median HLA expression was 20% in the primary tumors (IQR 0-65%) and 10% in the brain metastases (IQR 5-40%). 27 primary tumors and 24 brain metastases were positive for HLA expression. There was disagreement in HLA positivity between paired lesions in 11 patients (22%, 95% CI 12-35%)(κ = 0.57, 95% CI 0.35-0.79)(p = 0.0001). There was no significant difference in the time between the primary tumor and brain metastasis resections in patients with HLA expression disagreement compared to those with HLA expression agreement. None of the patients received immune checkpoint inhibitors for treatment of these lesions. Conclusions: We found significant differences in HLA-A expression on tumor cells in nearly one quarter of paired primary lung cancers and brain metastases. Differences in HLA expression may help explain the discrepancies in response to immune checkpoint inhibitors at different sites of disease and warrants further study.

scholarly journals Antiangiogenic antibody BD0801 combined with immune checkpoint inhibitors achieves synergistic antitumor activity and affects the tumor microenvironment

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Liting Xue ◽  
Xingyuan Gao ◽  
Haoyu Zhang ◽  
Jianxing Tang ◽  
Qian Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Clinical Development ◽  
Cell Mediated Immunity ◽  
Tumor Models ◽  
Anti Vegf

Abstract Background Signaling through VEGF/VEGFR induces cancer angiogenesis and affects immune cells. An increasing number of studies have recently focused on combining anti-VEGF/VEGFR agents and immune checkpoint inhibitors (ICIs) to treat cancer in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody in the clinical development stage. Methods In this study, the anti-cancer activities of BD0801 and its potential synergistic anti-tumor effects when combined with different immunotherapies were assessed by using in vitro assays and in vivo tumor models. Ex vivo studies were conducted to reveal the possible mechanisms of actions (MOA) underlying the tumor microenvironment modification. Results BD0801 showed more potent antitumor activity than bevacizumab, reflected by stronger blockade of VEGF/VEGFR binding and enhanced inhibitory effects on human umbilical vein endothelial cells (HUVECs). BD0801 exhibited dose-dependent tumor growth inhibitory activities in xenograft and murine syngeneic tumor models. Notably, combining BD0801 with either anti-PD-1 or anti-PD-L1 antibodies showed synergistic antitumor efficacy in both lung and colorectal cancer mouse models. Furthermore, the mechanistic studies suggested that the MOA of the antitumor synergy involves improved tumor vasculature normalization and enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells and reduced double-positive CD8+PD-1+ T cells. Conclusions These data provide a solid rationale for combining antiangiogenic agents with immunotherapy for cancer treatment and support further clinical development of BD0801 in combination with ICIs.

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