Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors

Apolo, Andrea B.; Nadal, Rosa; Girardi, Daniel M.; Niglio, Scot A.; Ley, Lisa; Cordes, Lisa; Steinberg, Seth M.; Ortiz, Olena Sierra; Cadena, Jacqueline; Díaz, Carlos Guerrero; Mallek, Marissa; Davarpanah, Nicole N.; Costello, Rene; Trepel, Jane B.; Lee, Min Jung; Merino, María J.; Bagheri, Mohammad Hadi; Monk, Paul; Figg, William D.; Gulley, James L.; Agarwal, Piyush K.; Valera, Vladimir; Chalfin, Heather J.; Jones, Jennifer C.; Streicher, Howard; Wright, John J.; Ning, Yang‐Min; Parnes, Howard L.; Dahut, William L.; Bottaro, Donald P.; Lara, Primo N.; Saraiya, Biren; Pal, Sumanta K.; Stein, Mark N.; Mortazavi, Amir

doi:10.1200/jco.20.01652

Cited by 90 publications

(69 citation statements)

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“…Preclinical studies have demonstrated that anti-angiogenic TKIs can reduce the percentage of immunosuppressive Treg cells and MDSCs and increase T cell infiltration [ 48 , 49 ]. These findings were also confirmed in clinical studies [ 50 ] and successful combinations have been reported in multiple cancer types, such as clear cell renal cell carcinoma (ccRCC) [ 51 , 52 , 53 ], urothelial carcinoma [ 54 ], and endometrial carcinoma [ 55 ]. Both ICIs and anti-angiogenic targeted therapies are active in patients with metastatic HCC, making the combination of these two classes of treatment very attractive for these patients.…”

Section: Combination Of Immunotherapy and Targeted Therapiessupporting

confidence: 54%

“…Cabozantinib in combination with nivolumab with or without ipilimumab was evaluated in patients with metastatic urothelial carcinoma and other genitourinary tumors in a phase I trial. The treatment demonstrated manageable toxicity profiles and promising results [ 54 ]. These regimens are also being evaluated in patients with HCC.…”

Section: Combination Of Immunotherapy and Targeted Therapiesmentioning

confidence: 99%

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Immunotherapy and Targeted Therapy for Hepatocellular Carcinoma: A Literature Review and Treatment Perspectives

et al. 2020

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Advanced hepatocellular carcinoma is a prevalent and potentially aggressive disease. For more than a decade, treatment with sorafenib has been the only approved therapeutic approach. Moreover, no agent has been proven to prolong survival following the progression of disease after sorafenib treatment. However, in recent years, this scenario has changed substantially with several trials being conducted to examine the effects of immunotherapy and novel targeting agents. Several immune checkpoint inhibitors have shown promising results in early-stage clinical trials. Moreover, phase III trials with large cohorts have demonstrated remarkable improvement in survival with the use of new targeted therapies in second-line treatment. Treatment regimens involving the combination of two immune checkpoint inhibitors as well as immune checkpoint inhibitors and anti-angiogenic targeted therapies have shown potential to act synergistically in clinical trials. Recently, the combination of atezolizumab and bevacizumab evaluated in a phase III clinical trial has demonstrated survival superiority in the first-line treatment; it is the new considered standard of care. In this manuscript, we aimed to review the latest advances in the systemic treatment of advanced hepatocellular carcinoma focusing on immunotherapy and targeted therapies.

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Section: Combination Of Immunotherapy and Targeted Therapiessupporting

confidence: 54%

Section: Combination Of Immunotherapy and Targeted Therapiesmentioning

confidence: 99%

Immunotherapy and Targeted Therapy for Hepatocellular Carcinoma: A Literature Review and Treatment Perspectives

et al. 2020

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“…This was a retrospective analysis of two cohorts of patients treated at 6 centers (National Institutes of Health; City of Hope; University of California; Ohio State University; Rutgers University; University of Southern California). The clinical outcomes of the phase 1 doseescalation cohort have recently been reported (10). All patients provided signed informed consent to participate on a protocol approved by each institution's Institutional Review Board/Privacy Board prior to blood sampling, and studies were conducted in accordance with the Declaration of Helsinki, Belmont Report, and U.S. Common Rule.…”

Section: Methodsmentioning

confidence: 99%

Circulating Tumor Cell Subtypes and T-cell Populations as Prognostic Biomarkers to Combination Immunotherapy in Patients with Metastatic Genitourinary Cancer

Chalfin

Pramparo

Mortazavi

et al. 2021

Clinical Cancer Research

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Circulating tumor cells (CTCs) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of individual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of metastatic genitourinary (mGU) cancer patients treated with combination immunotherapy. Experimental Design: Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across time points. Differences in survival and disease progression were evaluated using the maximum log-rank test. Results: From 12/2016-01/2019, 183 samples from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter OS at baseline (p=0.022) but not on therapy. Five morphologic subtypes were detected, and the presence of 2 specific subtypes with unique cellular features at baseline and on therapy were associated with worse OS (0.9-2.3 mos vs. 28.2 mos,p<0.0001-0.013). Increasing CTC heterogeneity on therapy had a trend towards worse OS (p=0.045). PDL1+ CTCs on therapy were associated with worse OS (p<0.01,cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category. Conclusions: Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1+ CTCs, and low %CD4/8 T cells in mGU cancer patients. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies. Research.

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“…Ongoing trials are designed to explore novel combinations of drugs, for example anti-PD-1/PD-L1 therapy in combination with more classic drugs, thus including intravesical BCG or chemotherapy [ 48 , 49 ]. In this line, combinations of Nivolumab, Ipilimumab, and Cabozantinib have been found safe to treat different genitourinary malignancies [ 50 ]; importantly, ICI blockade in BCG-refractory non-muscle invasive bladder cancer is the topic of some ongoing trials, thus opening a new way to treat non-muscle invasive bladder cancer (NMIBC) with aggressive features [ 51 ]. In fact, trials evaluating Pembrolizumab [ 49 ] (NCT02324582, NCT02808143) or Atezolizumab [ 52 ] (NCT02792192) in combination with BCG are still recruiting patients.…”

Section: Is There Any Role Of Combination Immunotherapy In Bladdermentioning

confidence: 99%

Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer

López-Beltrán

Cimadamore

Blanca

et al. 2021

Cancers

163

100

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A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.

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Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors

Cited by 90 publications

References 44 publications

Immunotherapy and Targeted Therapy for Hepatocellular Carcinoma: A Literature Review and Treatment Perspectives

Immunotherapy and Targeted Therapy for Hepatocellular Carcinoma: A Literature Review and Treatment Perspectives

Circulating Tumor Cell Subtypes and T-cell Populations as Prognostic Biomarkers to Combination Immunotherapy in Patients with Metastatic Genitourinary Cancer

Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer

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