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10 pages, 922 KiB

Open AccessArticle

Tumor Growth Rate Decline despite Progressive Disease May Predict Improved Nivolumab Treatment Outcome in mRCC: When RECIST Is Not Enough

by Veronica Mollica, Stefano Brocchi, Filippo Gustavo Dall’Olio, Laura Marcolin, Alexandro Paccapelo, Matteo Santoni, Alessandro Rizzo, Rodolfo Montironi, Rita Golfieri, Francesco Massari and Andrea Ardizzoni

Cancers 2021, 13(14), 3492; https://doi.org/10.3390/cancers13143492 - 12 Jul 2021

Cited by 4 | Viewed by 2541

Abstract

Treatment response is usually assessed by the response evaluation criteria in solid tumors (RECIST). These criteria may not be adequate to evaluate the response to immunotherapy, considering the peculiar patterns of response reported with this therapy. With the advent of immunotherapy these criteria [...] Read more.

Treatment response is usually assessed by the response evaluation criteria in solid tumors (RECIST). These criteria may not be adequate to evaluate the response to immunotherapy, considering the peculiar patterns of response reported with this therapy. With the advent of immunotherapy these criteria have been modified to include the evaluation of the peculiar responses seen with this type of therapy (iRECIST criteria), including pseudoprogressions and hyperprogressions. Tumor growth rate (TGR) is a dynamic evaluation that takes into account the kinetics of response to treatment and may help catch the real efficacy of an immunotherapy approach. We performed a retrospective monocentric study to explore the impact of TGR change after nivolumab administration as the second or later line of treatment in patients with metastatic renal cell carcinoma (RCC). We evaluated 27 patients, divided into three categories: Disease control (DC) if there was no PD; lower velocity PD (LvPD) if disease progressed but the TGR at second assessment (TGR2) was lower than the TGR at first assessment (TGR1); higher velocity PD (HvPD) if TGR2 was higher than TGR1. The median OS for the DC group was 11.0 months (95% CI 5.0–17.0) (reference) vs. (not reached) NR (95% CI NR-NR) for LvPD (HR 0.27; 95% CI 0.06–1.30; p 0.102) vs. NR (95% CI NR–NR) for HvPD (HR 0.23; 95% CI 0.06–0.88; p 0.032). There was no difference between LvPD and DC (HR 1.21; 95% CI 0.20–7.28; p 0.838). In patients with metastatic RCC, the second or later line of nivolumab treatment may lead to a deceleration in TGR resulting in an improved survival outcome similar to that observed in patients experiencing tumor regression. In this subgroup, especially in the presence of a clinical benefit, continuing the treatment beyond progression can be recommended. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors for Genitourinary Cancers)

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Review

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16 pages, 861 KiB

Open AccessReview

Metastatic Clear-Cell Renal Cell Carcinoma in the Era of Immune Checkpoint Inhibitors: Therapies and Ongoing Trials

by Tony Zibo Zhuang, Katherine Case, Timothy Anders Olsen, Jacqueline T. Brown, Bradley C. Carthon, Omer Kucuk, Jamie Goldman, Wayne Harris, Mehmet Asim Bilen and Bassel Nazha

Cancers 2022, 14(12), 2867; https://doi.org/10.3390/cancers14122867 - 10 Jun 2022

Cited by 16 | Viewed by 4140

Abstract

Immune checkpoint inhibitors (ICI) are now the bedrock for the treatment of metastatic renal cell carcinoma (RCC). Clear cell RCC (ccRCC) represents the most common subtype of this malignancy. Herein, we explore the therapeutic landscape of ccRCC by discussing the standard of care [...] Read more.

Immune checkpoint inhibitors (ICI) are now the bedrock for the treatment of metastatic renal cell carcinoma (RCC). Clear cell RCC (ccRCC) represents the most common subtype of this malignancy. Herein, we explore the therapeutic landscape of ccRCC by discussing the standard of care whose backbone consists of immune checkpoint inhibitors (ICI) and vascular endothelial growth factor inhibitors (VEGF). For ccRCC, pembrolizumab-axitinib, pembrolizumab-lenvatinib, and avelumab-axitinib or nivolumab-cabozantinib are now FDA-approved frontline options for all risk groups while nivolumab-ipilimumab is reserved for intermediate- and poor-risk groups. Monotherapy with pembrolizumab or nivolumab is a potential option for patients who are unable to take VEGFR-tyrosine kinase inhibitors. While outcomes have improved with the adoption of ICI therapies, many patients develop therapy-resistant disease, creating an unmet need for further investigation. The efficacy of novel therapies as well as novel combinations in the post-ICI era is unclear. This review summarizes the most significant clinical trials involving dual ICI/ICI and ICI/VEGFR therapies, in addition to other selected combination therapies that are likely to inform management in the near future. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors for Genitourinary Cancers)

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22 pages, 1611 KiB

Open AccessReview

Mechanism and Management of Checkpoint Inhibitor-Related Toxicities in Genitourinary Cancers

by Haoran Li, Kamal K. Sahu and Benjamin L. Maughan

Cancers 2022, 14(10), 2460; https://doi.org/10.3390/cancers14102460 - 17 May 2022

Cited by 2 | Viewed by 3724

Abstract

The use of immune checkpoint inhibitors (ICIs) is rapidly increasing as more combinations and clinical indications are approved in the field of genitourinary malignancies. Most immunotherapeutic agents being approved are for the treatment of renal cell carcinoma and bladder cancer, which mainly involve [...] Read more.

The use of immune checkpoint inhibitors (ICIs) is rapidly increasing as more combinations and clinical indications are approved in the field of genitourinary malignancies. Most immunotherapeutic agents being approved are for the treatment of renal cell carcinoma and bladder cancer, which mainly involve PD-1/PD-L1 and CTLA-4 pathways. There is an ongoing need for recognizing and treating immunotherapy-related autoimmune adverse effects (irAEs). This review aims to critically appraise the recent literature on the mechanism, common patterns, and treatment recommendations of irAEs in genitourinary malignancies. We review the epidemiology of these adverse effects as well as general treatment strategies. The underlying mechanisms will also be discussed. Diagnostic considerations including differential diagnosis are also included in this review. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors for Genitourinary Cancers)

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33 pages, 1389 KiB

Open AccessReview

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

by Brian W. Labadie, Arjun V. Balar and Jason J. Luke

Cancers 2021, 13(21), 5415; https://doi.org/10.3390/cancers13215415 - 28 Oct 2021

Cited by 20 | Viewed by 3593

Abstract

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, [...] Read more.

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. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors for Genitourinary Cancers)

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26 pages, 410 KiB

Open AccessReview

Immunotherapies in Genitourinary Oncology: Where Are We Now? Where Are We Going?

by Albert Jang, David M. Adler, Grant P. Rauterkus, Mehmet A. Bilen and Pedro C. Barata

Cancers 2021, 13(20), 5065; https://doi.org/10.3390/cancers13205065 - 10 Oct 2021

Cited by 14 | Viewed by 3642

Abstract

For decades, limited options existed to treat metastatic genitourinary cancers, including treatment options that could be classified as immunotherapy. Historically, immunotherapy centered on systemic cytokines for the treatment of metastatic kidney cancer, which had several adverse effects, as well as the Bacillus Calmette–Guérin [...] Read more.

For decades, limited options existed to treat metastatic genitourinary cancers, including treatment options that could be classified as immunotherapy. Historically, immunotherapy centered on systemic cytokines for the treatment of metastatic kidney cancer, which had several adverse effects, as well as the Bacillus Calmette–Guérin vaccine for non-metastatic bladder cancer. Within the past decade, advances in immunotherapy have led to several approvals from the United States Food and Drug Administration, particularly in the field of immune checkpoint inhibition. Immune checkpoint inhibitors (ICIs) are now being used extensively to treat multiple solid tumors, including kidney and bladder cancers, and they are also being tested in many other cancers. Despite encouraging data from phase 2/3 clinical trials, less is known about biomarkers that may predict better response to ICIs. The effect of ICIs in genitourinary cancers is heterogeneous, with some tumor types having little clinical data available, or ICIs having limited activity in other tumors. In this review, we briefly discuss approved immunotherapy agents prior to the time of ICIs. Then, given the emergence of this class of agents, we summarize the several important ICIs and the clinical trials that led to their approval. Finally, we mention ongoing and future clinical trials. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors for Genitourinary Cancers)

19 pages, 888 KiB

Open AccessReview

Immune Checkpoint Inhibitors in Urothelial Bladder Cancer: State of the Art and Future Perspectives

by Giandomenico Roviello, Martina Catalano, Raffaella Santi, Valeria Emma Palmieri, Gianmarco Vannini, Ilaria Camilla Galli, Eleonora Buttitta, Donata Villari, Virginia Rossi and Gabriella Nesi

Cancers 2021, 13(17), 4411; https://doi.org/10.3390/cancers13174411 - 31 Aug 2021

Cited by 41 | Viewed by 6509

Abstract

Bladder cancer (BC) is the most common malignancy of the genitourinary tract, with high morbidity and mortality rates. Until recently, the treatment of locally advanced or metastatic urothelial BC was based on the use of chemotherapy alone. Since 2016, five immune checkpoint inhibitors [...] Read more.

Bladder cancer (BC) is the most common malignancy of the genitourinary tract, with high morbidity and mortality rates. Until recently, the treatment of locally advanced or metastatic urothelial BC was based on the use of chemotherapy alone. Since 2016, five immune checkpoint inhibitors (ICIs) have been approved by the Food and Drug Administration (FDA) in different settings, i.e., first-line, maintenance and second-line treatment, while several trials are still ongoing in the perioperative context. Lately, pembrolizumab, a programmed death-1 (PD-1) inhibitor, has been approved for Bacillus Calmette–Guérin (BCG)-unresponsive high-risk non-muscle invasive bladder cancer (NMIBC), using immunotherapy at an early stage of the disease. This review investigates the current state and future perspectives of immunotherapy in BC, focusing on the rationale and results of combining immunotherapy with other therapeutic strategies. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors for Genitourinary Cancers)

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12 pages, 496 KiB

Open AccessReview

Efficacy of Immune Checkpoint Inhibitors in Upper Tract Urothelial Carcinomas: Current Knowledge and Future Directions

by Jonathan Thouvenin, Nieves Martínez Chanzá, Omar Alhalabi, Hervé Lang, Nizar M. Tannir, Philippe Barthélémy and Gabriel G. Malouf

Cancers 2021, 13(17), 4341; https://doi.org/10.3390/cancers13174341 - 27 Aug 2021

Cited by 11 | Viewed by 3179

Abstract

Upper tract urothelial carcinoma (UTUC) represents a rare and aggressive malignancy arising from the renal pelvis or ureter. It can develop sporadically or have a hereditary origin, such as Lynch syndrome, caused by DNA mismatch repair deficiency, leading to microsatellite instability phenotype. According [...] Read more.

Upper tract urothelial carcinoma (UTUC) represents a rare and aggressive malignancy arising from the renal pelvis or ureter. It can develop sporadically or have a hereditary origin, such as Lynch syndrome, caused by DNA mismatch repair deficiency, leading to microsatellite instability phenotype. According to molecular characterization studies, UTUC presents different mutational profiles as compared to urinary bladder urothelial carcinomas. In particular, it has been reported that UTUC harbored a higher level of FGFR3 alterations associated with a T-cell depleted immune microenvironment. The therapeutic landscape in urothelial carcinoma is rapidly evolving, with immune checkpoint inhibitors forming part of the standard of care. A greater understanding of the molecular alterations and immune microenvironment leads to the development of new treatment combinations and targeted therapy. This review summarizes the available evidence concerning the use of immune checkpoint inhibitors and the biological rationale underlying their use in high-grade UTUC. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors for Genitourinary Cancers)

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14 pages, 279 KiB

Open AccessReview

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

by Kevin Zarrabi, Emily Walzer and Matthew Zibelman

Cancers 2021, 13(15), 3652; https://doi.org/10.3390/cancers13153652 - 21 Jul 2021

Cited by 19 | Viewed by 3235

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors for Genitourinary Cancers)

23 pages, 1261 KiB

Open AccessReview

Immune Checkpoint Inhibitors in Prostate Cancer

by Shobi Venkatachalam, Taylor R. McFarland, Neeraj Agarwal and Umang Swami

Cancers 2021, 13(9), 2187; https://doi.org/10.3390/cancers13092187 - 2 May 2021

Cited by 66 | Viewed by 6738

Abstract

Metastatic prostate cancer is a lethal disease with limited treatment options. Immune checkpoint inhibitors have dramatically changed the treatment landscape of multiple cancer types but have met with limited success in prostate cancer. In this review, we discuss the preclinical studies providing the [...] Read more.

Metastatic prostate cancer is a lethal disease with limited treatment options. Immune checkpoint inhibitors have dramatically changed the treatment landscape of multiple cancer types but have met with limited success in prostate cancer. In this review, we discuss the preclinical studies providing the rationale for the use of immunotherapy in prostate cancer and underlying biological barriers inhibiting their activity. We discuss the predictors of response to immunotherapy in prostate cancer. We summarize studies evaluating immune checkpoint inhibitors either as a single agent or in combination with other checkpoint inhibitors or with other agents such as inhibitors of androgen axis, poly ADP-ribose polymerase (PARP), radium-223, radiotherapy, cryotherapy, tumor vaccines, chemotherapy, tyrosine kinase inhibitors, and granulocyte-macrophage colony-stimulating factor. We thereafter review future directions including the combination of immune checkpoint blockade with inhibitors of adenosine axis, bispecific T cell engagers, PSMA directed therapies, adoptive T-cell therapy, and multiple other miscellaneous agents. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors for Genitourinary Cancers)

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