Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study

Lee, Chung-Han; Shah, Amishi Yogesh; Rasco, Drew W.; Rao, Arpit; Taylor, Matthew H.; Simone, Christopher Di; Hsieh, James J.; Pinto, Álvaro; Shaffer, David R.; Sarrió, Regina Gironés; Cohn, Allen Lee; Vogelzang, Nicholas J.; Bilen, Mehmet Asım; Ribe, Sara Gunnestad; Goksel, Musaberk; Tennøe, Øyvind; Richards, Donald A.; Sweis, Randy F.; Courtright, Jay; Heinrich, Daniel; Jain, Sharad; Wu, Jane; Schmidt, Emmett V.; Perini, Rodolfo F.; Kubiak, Peter; Okpara, Chinyere; Smith, Alan D.; Motzer, Robert J.

doi:10.1016/s1470-2045(21)00241-2

Cited by 136 publications

(83 citation statements)

References 21 publications

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“…The latest results of a phase III clinical trials combining relatlimab and nivolumab have demonstrated an improved antitumor activity in patients who showed tumor progression on PD-1 treatment, with a prominently prolonged median PFS versus nivolumab monotherapy (10.1 months vs 4.6 months) companied with higher incidence of treatment-related adverse events in the treatment of advanced melanoma. 636 , 637 Clinical trials aiming to evaluate the safety and efficacy of relatlimab plus nivolumab are recruiting melanoma patients whose disease progressed on PD-1 monotherapy or naive to prior immunotherapy, as well as relatlimab in uveal melanoma. 638…”

Section: Present Advances In Therapies Targeting Tumor Immunology and Ongoing Clinical Trialsmentioning

confidence: 99%

Signal pathways of melanoma and targeted therapy

Guo

Wang

2021

Sig Transduct Target Ther

190

119

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Melanoma is the most lethal skin cancer that originates from the malignant transformation of melanocytes. Although melanoma has long been regarded as a cancerous malignancy with few therapeutic options, increased biological understanding and unprecedented innovations in therapies targeting mutated driver genes and immune checkpoints have substantially improved the prognosis of patients. However, the low response rate and inevitable occurrence of resistance to currently available targeted therapies have posed the obstacle in the path of melanoma management to obtain further amelioration. Therefore, it is necessary to understand the mechanisms underlying melanoma pathogenesis more comprehensively, which might lead to more substantial progress in therapeutic approaches and expand clinical options for melanoma therapy. In this review, we firstly make a brief introduction to melanoma epidemiology, clinical subtypes, risk factors, and current therapies. Then, the signal pathways orchestrating melanoma pathogenesis, including genetic mutations, key transcriptional regulators, epigenetic dysregulations, metabolic reprogramming, crucial metastasis-related signals, tumor-promoting inflammatory pathways, and pro-angiogenic factors, have been systemically reviewed and discussed. Subsequently, we outline current progresses in therapies targeting mutated driver genes and immune checkpoints, as well as the mechanisms underlying the treatment resistance. Finally, the prospects and challenges in the development of melanoma therapy, especially immunotherapy and related ongoing clinical trials, are summarized and discussed.

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Section: Present Advances In Therapies Targeting Tumor Immunology and Ongoing Clinical Trialsmentioning

confidence: 99%

Signal pathways of melanoma and targeted therapy

Guo

Wang

2021

Sig Transduct Target Ther

190

119

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“…In patients with metastatic RCC initially treated with anti-PD-1 therapy plus VEGF TKI, salvage nivolumab plus ipilimumab has demonstrated activity and is approved regardless of IMDC risk group [40][41][42]. A recent phase 1b/2 clinical trial in advanced solid tumors including RCC demonstrated encouraging anti-tumor activity for lenvatinib plus pembrolizumab for post-ICI treatment [43]. The role of continuing the anti-PD-1/PD-L1 backbone in post-ICI treatment is being evaluated in the CONTACT-03 trial of atezolizumab plus cabozantinib versus cabozantinib alone in patients with metastatic RCC after progression on anti-PD-1/PD-L1 treatment (NCT04338269).…”

Section: Second Linementioning

confidence: 99%

Immune Checkpoint Inhibitors for Genitourinary Cancers: Treatment Indications, Investigational Approaches and Biomarkers

Labadie

Balar

Luke

2021

Cancers

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Cancers of the genitourinary (GU) tract are common malignancies in both men and women and are a major source of morbidity and mortality. Immune checkpoint inhibitors (ICI) targeting CTLA-4, PD-1 or PD-L1 have provided clinical benefit, particularly in renal cell and urothelial carcinoma, and have been incorporated into standard of care treatment in both localized and metastatic settings. However, a large fraction of patients do not derive benefit. Identification of patient and tumor-derived factors which associate with response have led to insights into mechanisms of response and resistance to ICI. Herein, we review current approvals and clinical development of ICI in GU malignancies and discuss exploratory biomarkers which aid in personalized treatment selection.

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“…5 Although immune checkpoint blockade therapy and combination regimens have increased the survival of RCC patients, the prognosis of patients with advanced RCC, including reRCC, remains poor. [7][8][9] A thorough investigation of reRCC could enhance our understanding on the mechanisms of tumor development and progression, and more importantly, facilitate the discovery of more effective therapeutic regimens for RCC.…”

Section: Introductionmentioning

confidence: 99%

Single-cell transcriptomics reveals a low CD8⁺T cell infiltrating state mediated by fibroblasts in recurrent renal cell carcinoma

Peng

Xiong

Zhou

et al. 2022

J Immunother Cancer

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PurposeRecurrent renal cell carcinoma(reRCC) is associated with poor prognosis and the underlying mechanism is not yet clear. A comprehensive understanding of tumor microenvironment (TME) of reRCC may aid in designing effective anticancer therapies, including immunotherapies. Single-cell transcriptomics holds great promise for investigating the TME, however, this technique has not been used in reRCC. Here, we aimed to explore the difference in the TME and gene expression pattern between primary RCC (pRCC) and reRCC at single-cell level.Experimental designWe performed single-cell RNA sequencing analyses of 32,073 cells from 2 pRCC, 2 reRCC, and 3 adjacent normal kidney samples. 41 pairs of pRCC and reRCC samples were collected as a validation cohort to assess differences observed in single-cell sequencing. The prognostic significance of related cells and markers were studied in 47 RCC patients underwent immunotherapy. The function of related cells and markers were validated via in vitro and in vivo experiments.ResultsreRCC had reduced CD8+ T cells but increased cancer-associated fibroblasts (CAFs) infiltration compared with pRCC. Reduced CD8+ T cells and increased CAFs infiltration were significantly associated with a worse response from immunotherapy. Remarkably, CAFs showed substantial expression of LGALS1 (Gal1). In vitro, CAFs could induce CD8+ T cells apoptosis via Gal1. In vivo, knockdown of Gal1 in CAFs suppressed tumor growth, increased CD8+ T cells infiltration, reduced the proportion of apoptotic CD8+ T cells and enhanced the efficacy of immunotherapy.ConclusionsWe delineated the heterogeneity of reRCC and highlighted an innovative mechanism that CAFs acted as a suppressor of CD8+ T cells via Gal1. Targeting Gal1 combined with anti-PD1 showed promising efficacy in treating RCC.

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Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study

Cited by 136 publications

References 21 publications

Signal pathways of melanoma and targeted therapy

Signal pathways of melanoma and targeted therapy

Immune Checkpoint Inhibitors for Genitourinary Cancers: Treatment Indications, Investigational Approaches and Biomarkers

Single-cell transcriptomics reveals a low CD8⁺T cell infiltrating state mediated by fibroblasts in recurrent renal cell carcinoma

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Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study

Cited by 136 publications

References 21 publications

Signal pathways of melanoma and targeted therapy

Signal pathways of melanoma and targeted therapy

Immune Checkpoint Inhibitors for Genitourinary Cancers: Treatment Indications, Investigational Approaches and Biomarkers

Single-cell transcriptomics reveals a low CD8+T cell infiltrating state mediated by fibroblasts in recurrent renal cell carcinoma

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Product

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Single-cell transcriptomics reveals a low CD8⁺T cell infiltrating state mediated by fibroblasts in recurrent renal cell carcinoma