A comparison of combined immune checkpoint inhibitors (IO) versus vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) in the treatment of advanced clear cell renal cell carcinoma.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 692-692
Author(s):  
Abigail Sy Chan ◽  
Gregory Russell Pond ◽  
Guru Sonpavde ◽  
Ajjai Shivaram Alva
Keyword(s):  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Small Sample ◽  
Adverse Event Rate ◽  
Comparable Efficacy ◽  
Published Data ◽  
Efficacy And Safety ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc

692 Background: IO and VEGFR/TKI are approved treatment options, either alone or combination, in advanced clear cell RCC. Currently, there is a lack of evidence comparing efficacy and safety outcomes amongst these therapies. We sought to compare the published data for the various options with respect to efficacy and safety. Methods: A literature search using PubMed, clinicaltrials.gov, ASCO and ESMO meeting abstract databases from January 1, 2015 to June 30, 2019 to identify eligible clinical trials in advanced clear cell RCC involving at least one immunotherapy agent was performed. Due to small sample sizes in the various cohorts, descriptive statistics were provided. Weighting of estimates was based on sample size of the intervention arms. Results: 14 studies involving 6,197 pts were identified. The median age was 62 years (54.8, 64), men constituting median of 75%, and prior TKI receipt in 63%. There were 7 studies in each treatment arm. The efficacy outcomes did not demonstrate statistical differences. In the safety analyses, IO + VEGFR/TKI demonstrated the highest serious adverse event rate, correlating with treatment discontinuation rates. Conclusions: IO + IO and IO + VEGFR/TKI showed comparable efficacy and toxicity outcomes in the treatment of advanced clear cell RCC. There is a non-significant trend towards increased efficacy in some outcomes with IO + VEGFR/TKI, with possibly increased adverse events. Further studies with patient level data, cross-comparative trials, and predictive biomarkers are needed to establish a therapeutic matrix for RCC pts.[Table: see text]

Efficacy and safety of sorafenib in patients with advanced clear-cell renal cell carcinoma (RCC) with diabetes: Results from the phase III TARGET study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16099-e16099
Author(s):  
S. Oudard ◽  
T. Eisen ◽  
C. Szczylik ◽  
M. Siebels ◽  
S. Negrier ◽  
...  
Keyword(s):  
Clear Cell ◽  
Formal Analysis ◽  
Phase Iii ◽  
Controlled Study ◽  
Efficacy And Safety ◽  
Cell Renal Cell Carcinoma ◽  
Double Blind ◽  
Diabetes Status ◽  
Study Population ◽  
Clear Cell Rcc

e16099 Background: Results of the phase III TARGET trial, a randomized, double-blind, placebo-controlled study of sorafenib (SOR) treatment in pts with clear-cell RCC in whom 1 prior systemic therapy had failed, indicated that SOR is effective and safe for pts with advanced RCC, leading to the approval of SOR for the treatment of advanced RCC. Diabetes can be associated with increased morbidity during treatment in a variety of malignancies. Therefore, an exploratory subset analysis was performed to evaluate the efficacy and safety of SOR in pts enrolled in TARGET with or without diabetes at baseline. Methods: Pts (N=903) with advanced clear-cell RCC, ECOG PS 0–2, and low- or intermediate-risk MSKCC score were randomized 1:1 to SOR 400 mg BID or placebo (PBO). End points included OS, PFS, and safety. A planned independently-assessed formal analysis of PFS showed significant benefit for SOR over PBO; consequently, pts assigned to PBO were able to cross over to SOR. Results: Pt demographics were similar for all subsets. Pre- crossover data by subset are shown in the table . The incidence of drug-related adverse events (AEs) across subgroups was consistent with that for the overall population. In pts with vs without diabetes, treatment with SOR was not associated with increased hyperglycemia (1 pt/arm in the without diabetes subgroups only) or hypertension. Conclusions: The safety profile of SOR in pts with diabetes was comparable with that for the overall study population. SOR was well tolerated and AEs were manageable. Trends in improved PFS were observed for SOR regardless of baseline diabetes status; however, the small diabetic subset limits interpretation of a SOR OS benefit in this subpopulation. *Final PFS of overall study population based on independent review from Jan 2005; all other data from May 2005 database [Table: see text] [Table: see text]

scholarly journals Renal Cell Carcinoma in the Era of Precision Medicine: From Molecular Pathology to Tissue-Based Biomarkers

2018 ◽  
Vol 36 (36) ◽  
pp. 3553-3559 ◽  
Author(s):  
Sabina Signoretti ◽  
Abdallah Flaifel ◽  
Ying-Bei Chen ◽  
Victor E. Reuter
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Molecular Features ◽  
Pathologic Features ◽  
Clear Cell Rcc ◽  
Metastatic Rcc

Renal cell carcinoma (RCC) is not a single entity but includes various tumor subtypes that have been identified on the basis of either characteristic pathologic features or distinctive molecular changes. Clear cell RCC is the most common type of RCC and is characterized by dysregulation of the von Hippel Lindau/hypoxia-inducible factor pathway. Non–clear cell RCC represents a more heterogeneous group of tumors with diverse histopathologic and molecular features. In the past two decades, the improved understanding of the molecular landscape of RCC has led to the development of more effective therapies for metastatic RCC, which include both targeted agents and immune checkpoint inhibitors. Because only subsets of patients with metastatic RCC respond to a given treatment, predictive biomarkers are needed to guide treatment selection and sequence. In this review, we describe the key histologic features and molecular alterations of RCC subtypes and discuss emerging tissue-based biomarkers of response to currently available therapies for metastatic disease.

scholarly journals Tumor Microenvironment Features as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors (ICI) in Metastatic Clear Cell Renal Cell Carcinoma (mccRCC)

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 231
Author(s):  
Audrey Simonaggio ◽  
Nicolas Epaillard ◽  
Cédric Pobel ◽  
Marco Moreira ◽  
Stéphane Oudard ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Cell Renal Cell Carcinoma ◽  
Genomic Signatures

Renal cell carcinoma (RCC) is the seventh most frequently diagnosed malignancy with an increasing incidence in developed countries. Despite a greater understanding of the cancer biology, which has led to an increase of therapeutic options, metastatic clear cell renal cell carcinoma (mccRCC) still have a poor prognosis with a median five-years survival rate lower than 10%. The standard of care for mccRCC has changed dramatically over the past decades with the emergence of new treatments: anti-VEGFR tyrosine kinase inhibitors, mTOR Inhibitors and immune checkpoint inhibitors (ICI) such as anti-Programmed cell-Death 1 (PD-1) and anti-anti-Programmed Death Ligand-1 (PD-L1) used as monotherapy or as a combination with anti CTLA-4 or anti angiogenic therapies. In the face of these rising therapeutic options, the question of the therapeutic sequences is crucial. Predictive biomarkers are urgently required to provide a personalized treatment for each patient. Disappointingly, the usual ICI biomarkers, PD-L1 expression and Tumor Mutational Burden, approved in melanoma or non-small cell lung cancer (NSCLC) have failed to distinguish good and poor mccRCC responders to ICI. The tumor microenvironment is known to be involved in ICI response. Innovative technologies can be used to explore the immune contexture of tumors and to find predictive and prognostic biomarkers. Recent comprehensive molecular characterization of RCC has led to the development of robust genomic signatures, which could be used as predictive biomarkers. This review will provide an overview of the components of the RCC tumor microenvironment and discuss their role in disease progression and resistance to ICI. We will then highlight the current and future ICI predictive biomarkers assessed in mccRCC with a major focus on immunohistochemistry markers and genomic signatures.

scholarly journals Emerging Therapies for Advanced Clear Cell Renal Cell Carcinoma

2020 ◽  
Vol 7 (4) ◽  
pp. 17-26
Author(s):  
Alexander T. Toth ◽  
Daniel Cho
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Small Subset ◽  
Front Line ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc

Multiple combinational regimens have recently been approved and are now considered the standard of care for patients with advanced clear cell renal cell carcinoma (RCC). Several additional combinational regimens are deep in clinical assessment and are likely to soon join the crowded front-line therapeutic landscape. Most of these regimens are combinations of agents already approved as single-agents in RCC including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors. While these new front-line regimens are associated with reliably high response rates and prolonged survival, complete and durable remissions remain limited to a small subset of patients and the vast majority of patients continue to require subsequent therapy. The need for the continued development of novel agents in RCC persists and efforts have focused on agents targeting the molecular biology of clear cell RCC and novel immunotherapies including cytokines. In this review, we discuss the progress in the development of these novel therapies in the context of the evolving standard of care for patients with advanced clear cell RCC.

scholarly journals Emerging Therapies for Advanced Clear Cell Renal Cell Carcinoma

2020 ◽  
Vol 7 (4) ◽  
pp. 17-26
Author(s):  
Alexander T. Toth ◽  
Daniel C. Cho
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Small Subset ◽  
Front Line ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc

Multiple combinational regimens have recently been approved and are now considered the standard of care for patients with advanced clear cell renal cell carcinoma (RCC). Several additional combinational regimens are deep in clinical assessment and are likely to soon join the crowded front-line therapeutic landscape. Most of these regimens are combinations of agents already approved as single-agents in RCC including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors. While these new front-line regimens are associated with reliably high response rates and prolonged survival, complete and durable remissions remain limited to a small subset of patients and the vast majority of patients continue to require subsequent therapy. The need for the continued development of novel agents in RCC persists and efforts have focused on agents targeting the molecular biology of clear cell RCC and novel immunotherapies including cytokines. In this review, we discuss the progress in the development of these novel therapies in the context of the evolving standard of care for patients with advanced clear cell RCC.

scholarly journals Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3652
Author(s):  
Kevin Zarrabi ◽  
Emily Walzer ◽  
Matthew Zibelman
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Rapid Development ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc

Renal cell carcinoma (RCC) is a histologically heterogeneous disease with multiple subtypes. Clear cell RCC (ccRCC) represents the most common histology and has thus been easiest to study in clinical trials. Non-clear cell RCC (nccRCC) represents about 25% of RCC tumors, with fewer treatment options available, compared to ccRCC, and with poorer outcomes. Non-clear cell RCC tumors are histologically diverse, with each subtype having distinct molecular and clinical characteristics. Our understanding of nccRCC is evolving, with a gradual shift from treating nccRCC as a single entity to approaching each subtype as its own disease with unique features. Due to the scarcity of patients for study development, trials have predominantly combined all nccRCC subtypes and re-purposed drugs already approved for ccRCC, despite the decreased efficacy. We are now in the early stages of a potential paradigm shift in the treatment of nccRCC, with a rapid development of clinical studies with a focus on this subset of tumors. Investigators have launched trials focused on the molecular drivers of tumorigenesis using targeted therapies. Harboring the immunogenicity of some nccRCC subtypes, and based on promising retrospective studies, clinicians have also devised multiple trials using immune checkpoint inhibitors (ICIs), both alone or in combination with targeted therapies, for nccRCC subtypes. We highlight the promising completed and ongoing studies employing ICIs that will likely continue to improve outcomes in patients with nccRCC and propose future potential immunotherapeutic avenues.

scholarly journals Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3807
Author(s):  
Pierangela Sepe ◽  
Arianna Ottini ◽  
Chiara Carlotta Pircher ◽  
Andrea Franza ◽  
Melanie Claps ◽  
...  
Keyword(s):  
Renal Cell ◽  
Kinase Inhibitors ◽  
Clear Cell ◽  
Case Reports ◽  
Treatment Options ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Mtor Inhibitors ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc

Non-clear cell renal cell carcinomas (RCC) comprise several rare and poorly described diseases, often characterized by bad prognosis and with no standard treatments available. The gap in their clinical management is linked to the poor molecular characterization in handling the treatment of non clear-cell RCC with untailored therapies. Due to their rarity, non-clear RCC are in fact under-represented in prospective randomized trials. Thus, treatment choices are based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. Over the last two decades, various options have been considered as the mainstay for the treatment of metastatic RCC (mRCC), including angiogenesis inhibitors, vascular endothelial growth factor receptor inhibitors, other tyrosine kinase inhibitors (TKIs), as well as MET inhibitors and mammalian targeting of rapamycin (mTOR) inhibitors. More recently, the therapeutic armamentarium has been enriched with immunotherapy, alone or in combination with targeted agents that have been shown to significantly improve outcomes of mRCC patients, if compared to TKI single-agent. It has been widely proven that non-clear cell RCC is a morphologically and clinically distinct entity from its clear cell counterpart but more knowledge about its biology is certainly needed. Histology-specific collaborative trials are in fact now emerging to investigate different treatments for non-clear cell RCC. This review summarizes pathogenetic mechanisms of non-clear cell RCC, the evolution of treatment paradigms over the last few decades, with a focus on immunotherapy-based trials, and future potential treatment options.

scholarly journals MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Brian Shuch ◽  
Ryan Falbo ◽  
Fabio Parisi ◽  
Adebowale Adeniran ◽  
Yuval Kluger ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Predictive Biomarkers ◽  
Cell Renal Cell Carcinoma ◽  
Primary Tumors ◽  
Distant Tissue ◽  
Significant Expression ◽  
Metastatic Sites

Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available.Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P=0.1). MET expression weakly correlated between primary and matched metastatic sites (R=0.5) and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P=0.39).Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents.

Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: Results of a phase 2 trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4509-4509
Author(s):  
Chung-Han Lee ◽  
Martin H Voss ◽  
Maria Isabel Carlo ◽  
Ying-Bei Chen ◽  
Eduard Reznik ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Clear Cell ◽  
Phase 2 ◽  
Phase 3 ◽  
Cell Renal Cell Carcinoma ◽  
Stage Design ◽  
Phase 2 Trial ◽  
Clear Cell Rcc ◽  
Grade 3

4509 Background: Cabozantinib plus nivolumab (CaboNivo) improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) over sunitinib in a phase 3 trial for metastatic clear cell renal cell carcinoma (RCC). (Choueiri, abstract 6960, ESMO 2020) We report the results of a phase 2 trial of CaboNivo in patients (pts) with non-clear cell RCC. Methods: Pts had advanced non-clear cell RCC, 0 or 1 prior systemic therapies excluding prior immune checkpoint inhibitors, and measurable disease by RECIST. Cabo 40 mg/day plus Nivo 240 mg every 2 weeks or 480 mg every 4 weeks was given across two cohorts. Cohort 1: papillary, unclassified, or translocation associated RCC; Cohort 2: chromophobe RCC. The primary endpoint was ORR by RECIST; secondary endpoints included PFS, OS, and safety. Cohort 1 was a single stage design that met its primary endpoint and was expanded to produce more precise estimates of ORR. Cohort 2 was a Simon two-stage design that closed early for lack of efficacy. Correlative analyses by next generation sequencing were performed and to be presented. Results: A total of 40 pts were treated in Cohort 1, and 7 pts were treated in Cohort 2 (data cutoff: Jan 20, 2021). Median follow up time was 13.1 months (range 2.2 – 28.6). In Cohort 1, 26 (65%) pts were previously untreated, and 14 (35%) pts had 1 prior line: 10 (25%) received prior VEGF-targeted therapy and 8 (20%) received prior mTOR-targeted therapy. ORR for Cohort 1 was 48% (95% CI 31.5–63.9; Table). Median PFS was 12.5 months (95% CI 6.3–16.4) and median OS was 28 months (95% CI 16.3–NE). No responses were seen among 7 patients in Cohort 2 with chromophobe histology (Table). Grade 3/4 treatment emergent adverse events were consistent with that reported in the phase 3 trial; Grade 3/4 AST and ALT were 9% and 15%, respectively. Cabozantinib and nivolumab were discontinued due to toxicity in 17% and 19% of pts, respectively. Conclusions: CaboNivo had an acceptable safety profile and showed promising efficacy in metastatic non-clear cell RCC pts with papillary, unclassified, or translocation associated histologies whereas activity in patients with chromophobe RCC was limited. Clinical trial information: NCT03635892. [Table: see text]

scholarly journals 413 Toripalimab in combination with concurrent chemoradiation in patients with advanced/metastatic esophageal carcinoma: protocol for a single-arm, prospective, open-label, phase II clinical trial

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A444-A444
Author(s):  
Lei Wu ◽  
Yi Wang ◽  
Gang Wan ◽  
Jiahua Lv ◽  
Qifeng Wang ◽  
...  
Keyword(s):  
Esophageal Carcinoma ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Stage Iv ◽  
Predictive Biomarkers ◽  
Primary Objective ◽  
High Morbidity ◽  
Efficacy And Safety ◽  
Open Label ◽  
Carboplatin Auc

BackgroundEsophageal carcinoma is a disease with high morbidity and mortality in China and, recently, Immune checkpoint inhibitors(ICIs) combined with chemotherapy have shown good efficacy and safety for treatment; however, some patients still suffer from tumor progression or metastasis after treatment. Clinical studies have confirmed that immunotherapy combined with chemoradiotherapy can significantly improve the prognosis of patients with advanced esophageal cancer, but the efficacy and safety of adding radiotherapy to immunotherapy and chemotherapy have been less reported.MethodsThis is an open-label, single-arm, and single-center phase ll trial.Patients with unresectable stage IV esophageal squamous cell carcinoma(ESCC) who had not received prior systemic therapy were enrolled. The patients were treated with two cycles of toripalimab (240 mg d1, Q3W) combined with induction chemotherapy (paclitaxel 135–175 mg/m2, d1+carboplatin AUC=4–6, d1, Q3W), sequentially combined with concurrent chemoradiotherapy (30–50 Gy in 15–25 fractions, paclitaxel 135–175 mg/m2, d1+carboplatin AUC=4–6 d1, Q3W), followed by maintenance treatment with toripalimab (240 mg d1, Q3W) for 1 year. The primary objective of this trial is to evaluate the progression-free survival (PFS) of this combination therapy;and the secondary objective is related to the assessment of objective response rate (ORR), the disease control rate (DCR), the duration of remission (DOR), the 1- and 2-year overall survival(OS) rates, the safety and tolerability of patients to treatment, and the identification of the changes in the health-related quality of life (HRQoL) of patients. Furthermore, we aimed to identify predictive biomarkers (such as the expression of PD-L1 ctDNA and cytokines) and to explore the relationship between these biomarkers and tumor response to the study treatment.AcknowledgementsWe thank all the participants and their advisors involving in this study. We owe thanks to the patients in our study and their family members.Trial RegistrationChiCTR(ChiCTR2100046715). Registered on the 27th of May 2021.Ethics ApprovalThe study protocol is approved by Ethics Committee of Sichuan Cancer Hospital (SCCHEC-02-2021-021).Changes to the protocol will be communicated via protocol amendment by the study principal investigators. Written informed consent will be obtained from all participants.

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