Nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial

Vano, Yann-Alexandre; Elaidi, Réza; Bennamoun, Mostefa; Chevreau, Christine; Borchiellini, Delphine; Pannier, Diane; Maillet, Denis; Gross‐Goupil, Marine; Tournigand, Christophe; Laguerre, Brigitte; Barthélémy, Philippe; Coquan, Elodie; Gravis, Gwénaëlle; Houédé, Nadine; Cancel, Mathilde; Huillard, Olivier; Beuzeboc, Philippe; Fournier, Laure; Méjean, A.; Cathelineau, Xavier; Doumerc, N.; Paparel, P.; Bernhard, Jean-Christophe; Taille, Alexandre de la; Bensalah, Karim; Tricard, Thibault; Waeckel, Thibaut; Pignot, G.; Braychenko, E.; Caruso, Stefano; Sun, Chengming; Verkarre, Virginie; Lacroix, Guillaume; Moreira, Marco; Meylan, Maxime; Bougoüin, Antoine; Phan, Letuan; Thibault-Carpentier, Christelle; Zucman‐Rossi, Jessica; Fridman, Wolf Herman; Sautès-Fridman, Catheriné; Oudard, Stéphane

doi:10.1016/s1470-2045(22)00128-0

Cited by 87 publications

(42 citation statements)

References 23 publications

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“…The increased expression of PDL1 and T-effector gene signatures in these tumors relative to their non-sarcomatoid counterparts may justify the robust responses to combination CPI therapy. The results of a biomarker-driven, open-label, non-comparative, randomised phase 2 trial [ 28 ] show that a prospective patient selection based on the molecular phenotype of the tumor is possible, and has a positive effect on choosing the most effective treatment (between nivolumab, with or without ipilimumab, and a VEGFR-TKI) in the first-line treatment of metastatic clear-cell renal cell carcinoma. It is not feasible in our study to assess the molecular group determination in primary or metastatic site in all patients; however, this is a potential area of interest for future studies.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Spatial Heterogeneity of Responses in Metastatic Sites in Renal Cell Carcinoma Patients Treated with Nivolumab

et al. 2022

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Background: The purpose was to determine whether tumor response to CPI varies by organ and to characterize response patterns in a group of surgically treated metastatic RCC patients treated with Nivolumab. Methods: A retrospective analysis was undertaken between January 2016 and March 2020 on patients receiving Nivolumab for metastatic RCC, following first-line therapy and having at least one baseline and two follow-up scans. A Fisher’s exact test was used to compare categorical variables, and a Kruskal–Wallis test was used to compare continuous variables. Results: Twenty-one out of thirty patients evaluated were eligible, and they were divided into two groups: responders (n = 11) and non-responders (n = 10). According to all iRECIST standards, 18 (85.7 percent) of the 21 patients had PD (10 patients), PR (3 patients), or SD (8 patients). At baseline, 7, 15, 4, 13, 7, and 7 patients, respectively, had detectable hepatic metastasis and lung, brain, lymph node, soft tissue, and other intra-abdominal metastases; these patients were evaluated for organ-specific response. The ORRs for hepatic metastasis and lung, brain, lymph node, soft tissue, adrenals, and other intraperitoneal metastases were correspondingly 10%, 20%, 35%, 0%, and 25%. In total, 13 (61.9%) of them demonstrated varied responses to CPI therapy, with 6 (28.5%) demonstrating intra-organ differential responses. The lymph nodes (35%) had the best objective response (BOR), followed by the adrenals and peritoneum (both 25%), the brain (20%), and the lung (20%). The response rate was highest in adrenal gland lesions (2/4; 50%), followed by lymph nodes (13/19; 68.4 percent) and liver (5/10; 50%), whereas rates were lowest for lesions in the lung (9/25; 36%), intraperitoneal metastases (1/4; 25%), and brain (1/5; 20%). Conclusions: In renal cell carcinoma, checkpoint inhibitors have a variable response at different metastatic sites, with the best response occurring in lymph nodes and the least occurring in soft tissue.

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Section: Discussionmentioning

confidence: 99%

Analysis of Spatial Heterogeneity of Responses in Metastatic Sites in Renal Cell Carcinoma Patients Treated with Nivolumab

et al. 2022

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“…The size of gene panel to be tested using NGS remains controversial (tNGS versus WES and/or WGS) and clinical trials are testing this issue (NCT03163732). Inclusion of patients earlier in the disease course (less complex genomic profile and lesser risk of clinical deterioration), and with unique cancer type showed interesting results in PC [14] and bladder cancer [5], and more recently in clear-cell renal cell carcinoma [36].…”

Section: Discussionmentioning

confidence: 99%

Molecular Profiles of Advanced Urological Cancers in the PERMED-01 Precision Medicine Clinical Trial

Billon

Gravis

Guillé

et al. 2022

Cancers

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Introduction. The prognosis of advanced urological cancers (AUC) remains unfavorable, and few data are available regarding precision medicine. Methods: the PERMED-01 prospective clinical trial assessed the impact of molecular profiling in adults with refractory advanced solid cancer, in terms of number of patients with tumor actionable genetic alterations (AGA), feasibility, description of molecular alterations, treatment, and clinical outcome. We present here those results in the 64 patients enrolled with AUC. DNA extracted from a new tumor biopsy was profiled in real-time (targeted NGS, whole-genome array-comparative genomic hybridization), and the results were discussed during a weekly molecular tumor board meeting. Results: a complete molecular profile was obtained in 49 patients (77%). Thirty-eight (59%) had at least one AGA. Twelve (19%) received a matched therapy on progression, of which 42% had a PFS2/PFS1 ratio ≥ 1.3 versus 5% in the “non-matched therapy group” (n = 25). The objective response and disease control rates were higher in the “matched therapy group” (33% and 58%, respectively) than in the “non-matched therapy group” (13% and 22%), as was the 6-month OS (75% vs. 42%). Conclusion: the profiling of a newly biopsied tumor sample identified AGA in 59% of patients with AUC, led to “matched therapy” in 19%, and provided clinical benefit in 8%.

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“…To date, several targeted therapies utilizing tyrosine kinase inhibitors (TKIs) and/or anti-vascular endothelial growth factor (VEGF) antibodies are widely used as first- and second-line treatments. Recently, HIF2a targeting drugs or immune checkpoint inhibitors have been developed, and although their effects are superior to existing drugs [ 7 , 8 ], their effects are still insufficient; combination therapy to increase drug response is therefore being conducted in several studies [ 9 , 10 , 11 ]. Mammalian target of rapamycin (mTOR) inhibitors, such as temsirolimus and everolimus, are also used in this setting.…”

Section: Introductionmentioning

confidence: 99%

Synergic Effect of Metformin and Everolimus on Mitochondrial Dynamics of Renal Cell Carcinoma

Hong

Lee²,

Hwang³

et al. 2022

Genes

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Renal cell carcinoma (RCC) frequently recurs or metastasizes after surgical resection. Everolimus, an mTOR inhibitor, is used as a second-line treatment, but the response of RCC to everolimus is insufficient. Metformin is an antidiabetic drug; recent reports have indicated its anti-cancer effects in various cancers, and it is known to have synergistic effects with other drugs. We investigated the possibility of coadministering everolimus and metformin as an effective treatment for RCC. RCC cells treated with a combination of the two drugs showed significantly inhibited cell viability, cell migration, and invasion, and increased apoptosis compared to those treated with each drug alone. An anti-cancer synergistic effect was also confirmed in the xenograft model. Transcriptome analysis for identifying the underlying mechanism of the combined treatment showed the downregulation of mitochondrial fusion genes and upregulation of mitochondrial fission genes by the combination treatment. Changes in mitochondrial dynamics following the combination treatment were observed using LysoTracker, LysoSensor, and JC-1 staining. In conclusion, the combination of everolimus and metformin inhibited RCC growth by disrupting mitochondrial dynamics. Therefore, we suggest that a treatment combining metformin and everolimus disrupts mitochondrial dynamics in RCC, and may be a novel strategy for RCC treatment.

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Nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial

Cited by 87 publications

References 23 publications

Analysis of Spatial Heterogeneity of Responses in Metastatic Sites in Renal Cell Carcinoma Patients Treated with Nivolumab

Analysis of Spatial Heterogeneity of Responses in Metastatic Sites in Renal Cell Carcinoma Patients Treated with Nivolumab

Molecular Profiles of Advanced Urological Cancers in the PERMED-01 Precision Medicine Clinical Trial

Synergic Effect of Metformin and Everolimus on Mitochondrial Dynamics of Renal Cell Carcinoma

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