NIVOREN GETUG-AFU 26 translational study: Association of PD-1, AXL, and PBRM-1 with outcomes in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) treated with nivolumab (N).

Vano, Yann-Alexandre; Rioux‐Leclercq, Nathalie; Dalban, Cécile; Sautès-Fridman, Catheriné; Bougoüin, Antoine; Chaput, Nathalie; Chouaı̈b, Salem; Beuselinck, Benoît; Chevreau, Christine; Gross‐Goupil, Marine; Négrier, Sylvie; Laguerre, Brigitte; Borchiellini, Delphine; Colina-Moreno, Irelka; Chabaud, Sylvie; Tantot, Florence; Monteiro, Janice; Escudier, Bernard; Albigès, Laurence

doi:10.1200/jco.2020.38.6_suppl.618

Cited by 10 publications

(11 citation statements)

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“…Macrophage reprogramming is another promising approach nowadays, as diverse therapeutic strategies have been suggested to suppress tumor-associated macrophage recruitment, switching them back to the antitumor M1 phenotype [ 121 ]. Nevertheless, several studies have reported that high M2 macrophage tumor infiltration is associated with a more durable response to anti-PD-1 therapy [ 116 , 168 ]. This association was not found in patients treated with TKIs.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of Resistance to Immunotherapy and Antiangiogenic Treatments in Clear Cell Renal Cell Carcinoma

Ballesteros

Chamorro

Román-Gil

et al. 2021

Cancers

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Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype arising from renal cell carcinomas. This tumor is characterized by a predominant angiogenic and immunogenic microenvironment that interplay with stromal, immune cells, and tumoral cells. Despite the obscure prognosis traditionally related to this entity, strategies including angiogenesis inhibition with tyrosine kinase inhibitors (TKIs), as well as the enhancement of the immune system with the inhibition of immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. This approach has achieved a substantial improvement in life expectancy and quality of life from patients with advanced ccRCC. Unfortunately, not all patients benefit from this success as most patients will finally progress to these therapies and, even worse, approximately 5 to 30% of patients will primarily progress. In the last few years, preclinical and clinical research have been conducted to decode the biological basis underlying the resistance mechanisms regarding angiogenic and immune-based therapy. In this review, we summarize the insights of these molecular alterations to understand the resistance pathways related to the treatment with TKI and immune checkpoint inhibitors (ICIs). Moreover, we include additional information on novel approaches that are currently under research to overcome these resistance alterations in preclinical studies and early phase clinical trials.

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Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of Resistance to Immunotherapy and Antiangiogenic Treatments in Clear Cell Renal Cell Carcinoma

Ballesteros

Chamorro

Román-Gil

et al. 2021

Cancers

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“…Studies evaluating only the second-and later lines of treatment were those reported by Dizman et al [30] and Vano et al [29]. All other articles included patients in the first-line, second-line or beyond.…”

Section: Discussionmentioning

confidence: 99%

“…In only 3 studies (Braun et al [26,27] and Vano et al [29]) and in the primary cohort of Miao et al, patients received nivolumab as a single therapy. In the validation cohort of the study by Miao et al and in all others, the therapies were as follows: antiPD1/ L1 + anti-CTLA-4, anti-PD1/L1 + anti-VEGF-TKI, anti-PD1/L1 + another drug or anti-CTLA-4 alone.…”

Section: Discussionmentioning

confidence: 99%

“…The tumor samples of the patients were collected, reviewed and analyzed by IHC with a total of 13 markers, including PBRM-1, which was considered mutated when there was protein loss (absence of IHC staining). PBRM-1 loss was detected in 15% of the 324 patients included in the ancillary cohort and showed a trend in PFS and statistically improvement in OS [29].…”

Section: Genomic Alterations Beyond First-line Treatmentmentioning

confidence: 98%

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PBRM1 Mutations as a Predictive Biomarker for Immunotherapy in Metastatic Renal Cell Carcinoma: A Systematic Review

Carneiro

Monteiro²,

Soares

2021

KCA

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Introduction: Genomic features linked to prediction of response to immunotherapy in metastatic renal cell carcinoma (mRCC) are still lacking. Protein polybromo-1 (PBRM1) mutations have been studied as a potential biomarker of clinical benefit, with conflicting published data so far. Material and Methods: This systematic review was guided by the standards of the PRISMA statement to identify studies involving mRCC, immunotherapy and mutations in PBRM1. The main objective was to assess the relationship between PBRM1 mutations and response to immune checkpoint inhibitors (ICI) in patients with mRCC. Results: After an initial search that identified 422 studies, 8 studies met the eligibility criteria and were selected for the final analysis. Data are included from 2 trials in the first-line treatment setting, and 6 trials in second- or later treatment lines evaluating the relationship between the presence of PBRM1 mutations and clinical benefit (CB) with ICI treatment. Regarding the first-line treatment setting, the analysis of both studies failed to show any CB in patients with PBRM1 mutations treated with ICI. However, for the second- and later treatment lines, the results were mixed. Conclusions: PBRM1 mutations may be a potential genomic biomarker to predict response to ICI treatment in patients with mRCC, mainly in second- and later treatment lines, but the existence of conflicting data in the literature highlights an important bias in the studies and the need for additional clinical validation in large, prospective trials.

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“…A retrospective study from an institutional cohort of patients at MSKCC (n = 105) that included 24% patients with BAP1 mutations showed a shorter time to treatment failure for patients with mutated BAP1 in response to VEGF-TKIs (median 6.4 months vs 11.0 months; p = 0.01) as well as a shorter overall survival (median 28.7 months vs. not reached; p = 0.02)[53].iii) Response to immunotherapy-based therapy:Even though data from larger clinical trials using immune checkpoint inhibitors is lacking, smaller studies have tried to dissect this relationship. The NIVOREN GETUG-AFU 26 study included 324 patients who had received the programmed death-1 (PD-1) inhibitor nivolumab[54]. The investigators reported no association of BAP-1 loss with PFS or OS (p = 0.6 and 0.9 respectively).…”

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confidence: 99%

BRCA1-Associated Protein 1 (BAP-1) as a Prognostic and Predictive Biomarker in Clear Cell Renal Cell Carcinoma: A Systematic Review

Gulati

Previtera

Czyzyk-Krzeska

et al. 2022

KCA

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BACKGROUND: The gene that encodes BRCA1-associated protein 1 (BAP1) has been reported to be dysregulated in several human cancers such as uveal melanoma, malignant pleural mesothelioma, hepatocellular carcinoma, thymic epithelial tumors, and clear-cell renal cell carcinoma (ccRCC). The gene is located on the human chromosome 3p21.3, encoding a deubiquitinase and acts as a classic two-hit tumor suppressor gene. BAP1 predominantly resides in the nucleus, where it interacts with several chromatin-associated factors, as well as regulates calcium signaling in the cytoplasm. As newer therapies continue to evolve for the management of RCC, it is important to understand the role of BAP1 mutation as a prognostic and predictive biomarker. OBJECTIVE: We aimed to systematically evaluate the role of BAP1 mutations in patients with RCC in terms of its impact on prognosis and its role as a predictive biomarker. METHODS: Following PRISMA guidelines, we performed a systematic literature search using PubMed and Embase through March 2021. Titles and abstracts were screened to identify articles for full-text and then a descriptive review was performed. RESULTS: A total of 490 articles were initially identified. Ultimately 71 articles that met our inclusion criteria published between 2012–2021 were included in the analysis. Data were extracted and organized to reflect the role of BAP1 alterations as a marker of prognosis as well as a marker of response to treatments, such as mTOR inhibitors, VEGF tyrosine kinase inhibitors, and immune checkpoint inhibitors. CONCLUSIONS: Alterations in BAP1 appear to be uniformly associated with poor prognosis in patients with RCC. Knowledge gaps remain with regard to the predictive relevance of BAP1 alterations, especially in the context of immunotherapy. Prospective studies are required to more precisely ascertain the predictive value of BAP1 alterations in RCC.

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NIVOREN GETUG-AFU 26 translational study: Association of PD-1, AXL, and PBRM-1 with outcomes in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) treated with nivolumab (N).

Cited by 10 publications

References 0 publications

Molecular Mechanisms of Resistance to Immunotherapy and Antiangiogenic Treatments in Clear Cell Renal Cell Carcinoma

Molecular Mechanisms of Resistance to Immunotherapy and Antiangiogenic Treatments in Clear Cell Renal Cell Carcinoma

PBRM1 Mutations as a Predictive Biomarker for Immunotherapy in Metastatic Renal Cell Carcinoma: A Systematic Review

BRCA1-Associated Protein 1 (BAP-1) as a Prognostic and Predictive Biomarker in Clear Cell Renal Cell Carcinoma: A Systematic Review

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