Novel Tyrosine Kinase Targets in Urothelial Carcinoma

Urothelial carcinoma represents one of the most prevalent types of cancer worldwide, and its incidence is expected to grow. Although the treatment of the advanced disease was based on chemotherapy for decades, the developments of different therapies, such as immune checkpoint inhibitors, antibody drug conjugates and tyrosine kinase inhibitors, are revolutionizing the therapeutic landscape of this tumor. This development coincides with the increasing knowledge of the pathogenesis and genetic alterations in urothelial carcinoma, from the non-muscle invasive setting to the metastatic one. The purpose of this article is to provide a comprehensive review of the different tyrosine kinase targets and their roles in the therapeutic scene of urothelial carcinoma.

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Cost-Effectiveness of Immune Checkpoint Inhibitors in Urothelial Carcinoma—A Review

Cancers ◽

10.3390/cancers14010073 ◽

2021 ◽

Vol 14 (1) ◽

pp. 73

Author(s):

Arman S. Walia ◽

Randy F. Sweis ◽

Piyush K. Agarwal ◽

Andrew K. Kader ◽

Parth K. Modi

Keyword(s):

Cost Effectiveness ◽

Urothelial Carcinoma ◽

Neoadjuvant Therapy ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Advanced Disease ◽

Checkpoint Inhibitors ◽

Cost Effective ◽

Muscle Invasive ◽

Effectiveness Studies

Over the last decade, an increasing number of immune checkpoint inhibitors (ICIs) have been assessed for therapeutic efficacy in urothelial carcinoma (UC). The high cost has prompted multiple cost-effectiveness analyses for the various disease stages, with no established consensus. We reviewed the literature to assess the available cost-effectiveness studies and summarize their findings. Studies were filtered for a calculated incremental cost-effectiveness ratio (ICER) to standardize comparison. Over 2600 articles were narrowed to eight primary investigations: one for BCG-refractory non-muscle invasive (NMI), one for neoadjuvant therapy in muscle-invasive (MI), and six for advanced disease. Cost-effectiveness was not achieved for NMI disease. Atezolizumab met the willingness-to-pay (WTP) threshold as neoadjuvant therapy for MI disease compared to chemotherapy, but with multiple limitations on the interpretation. Of the six studies on advanced disease, the results were mixed. This was at least partially attributable to varied methodologies including extrapolated time horizons, inconsistent cost inputs, and different WTP thresholds. Overall, the aggregate results were not compelling enough to establish ICIs as cost-effective compared to conventional chemotherapy. Value may improve with continued investigation into long-term outcomes, refined patient selection, and pricing discounts.

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Urothelial carcinoma in the era of immune checkpoint inhibitors

Immunotherapy ◽

10.2217/imt-2021-0042 ◽

2021 ◽

Author(s):

Nadine Khalife ◽

Claude Chahine ◽

Manal Kordahi ◽

Tony Felefly ◽

Hampig Raphael Kourie ◽

...

Keyword(s):

Bladder Cancer ◽

Urothelial Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Invasive Disease ◽

Line Treatment ◽

First Line ◽

Metastatic Urothelial Carcinoma ◽

Muscle Invasive

Bladder cancer is the seventh most frequent cancer worldwide. The majority of patients present with nonmuscle invasive disease, while 20% of the patients are diagnosed with muscle-invasive bladder cancer. The treatment of nonmuscle invasive disease is endoscopic resection followed by intravesical adjuvant treatment for high risk patients. The standard treatment of localized muscle-invasive disease is neoadjuvant chemotherapy followed by radical cystectomy. Platinum-based chemotherapy is the first-line treatment in locally advanced or metastatic urothelial carcinoma. Immune checkpoint inhibitors have been approved for the treatment of metastatic urothelial carcinoma as second-line treatment or first-line in platinum-ineligible patients. Recently, pembrolizumab have been approved in BCG-refractory nonmuscle invasive bladder cancer. This review summarizes the current evidence concerning immunotherapy in the treatment of urothelial carcinoma.

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Targeting ERBB2 mutations in urothelial carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.354 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 354-354

Author(s):

Francois Audenet ◽

Sumit Isharwal ◽

Maria E. Arcila ◽

Samuel Funt ◽

Jonathan E. Rosenberg ◽

...

Keyword(s):

Bladder Cancer ◽

Urothelial Carcinoma ◽

Allele Frequency ◽

Kinase Inhibitors ◽

Hot Spot ◽

Genetic Alterations ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Stage Disease ◽

Muscle Invasive

354 Background: ERBB2 encodes human epidermal growth factor receptor 2 (HER2), a member of the EGFR family of receptor tyrosine kinases that signal through the pro-oncogenic MAP- and PI3K-kinase pathways. ERBB2 is altered by amplification and/or overexpression in various cancers, including urothelial carcinoma (UC). These alterations could confer sensitivity to ERBB2 kinase inhibitors in selected patients with UC. Methods: Patients diagnosed with UC were enrolled onto an institutional review board approved prospective sequencing protocol. Tumor and matched germline DNA were analyzed using the MSK-IMPACT assay that detects alterations in 410 oncogenes and tumor suppressor genes, including ERBB2. Results: Overall, 449 samples from 429 patients were sequenced from 2013 to August 2016. Genetic alterations in ERBB2 were found in 78 samples (17%). At the time of sample collection, 24 patients (31%) had non-muscle invasive bladder cancer (NMIBC), 30 patients (38%) had muscle-invasive bladder cancer (MIBC), 18 (23%) had metastatic disease and 7 (8%) had upper tract urothelial carcinoma (UTUC). Sixteen samples (21%) came from metastatic specimens. Of the observed 78 ERBB2 alterations, 20 samples had amplifications (26%) and 58 samples had mutations (74%). Seven samples (9%) had both. We identified 71 missense, 2 inframe and 1 fusion alteration, corresponding to a somatic mutation rate of 13.1%. Thirty-seven mutations (50%) were functionally characterized hot spots that are potentially actionable. Of note, the hot spot mutation S310F/Y was found in 29 samples (37%). Its mutation allele frequency varied significantly. There was a trend towards a higher mutant allele frequency of S310F/Y in higher stage disease without reaching statistical significance (Table). In our cohort, 3 patients were enrolled in clinical trials with ERBB2 kinase inhibitors based upon the presence of an ERBB2alteration. Conclusions: ERBB2is a frequent mutation at different stages of UC. In higher stage disease, clonal selection of the S310F/Y hot-spot mutation may occur and requires further study. [Table: see text]

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Transarterial Chemoembolization Improves Survival in Advanced Hepatocellular Carcinoma Patients Treated with Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors

10.21203/rs.3.rs-679376/v1 ◽

2021 ◽

Author(s):

Yue Hu ◽

Tao Pan ◽

Xi Cai ◽

Quansheng He ◽

Yubao Zheng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tyrosine Kinase ◽

Immune Checkpoint ◽

Transarterial Chemoembolization ◽

Immune Checkpoint Inhibitors ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Hcc ◽

Tace Group

Abstract BackgroundThe survival benefit and safety of transarterial chemoembolization (TACE) for advanced Hepatocellular Carcinoma (HCC) patients treated with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) is unclear. We aimed to investigate the efficacy and safety of TACE combined with TKIs and ICIs the treatment of advanced HCC. MethodsIn this study, the conditions of 147 patients with advanced HCC who underwent TKIs plus ICIs treatment between July 2017 and April 2020 were evaluated. We divided these patients into the TACE group and non-TACE group based on whether they were treated with TACE during TKIs plus ICIs treatment, and compared their survival outcomes, especially overall survival (OS), and whether they were exposed to unexpected toxicities. ResultsIn this study, a total of 98 patients who underwent TACE during TKIs plus ICIs treatment were included in the TACE group, while the other 49 patients were included in the non-TACE group. According to the Modified Response Evaluation Criteria in Solid Tumors (mRECIST), the objective response rate (ORR) of the TACE group was higher than that of the non-TACE group (ORR 74.5% vs. 40.8%, p ＜0.001). The OS of the TACE group was significantly longer than the non-TACE group (OS 19.3 months vs. 10.8 months, p = 0.010). The incidence of grade 3-4 toxicities in the TACE group was similar to that in the non-TACE group (33.7% vs. 28.6%, p = 0.532). ConclusionsThe TACE treatment combined with TKIs plus ICIs resulted in longer OS compared to the treatment of systemic TKIs plus ICIs without TACE during the process of advanced HCC.

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Tyrosine kinase inhibitors plus immune checkpoint inhibitors as neoadjuvant therapy for hepatocellular carcinoma: an emerging option?

Expert Opinion on Investigational Drugs ◽

10.1080/13543784.2021.1948533 ◽

2021 ◽

Author(s):

Alessandro Rizzo

Keyword(s):

Hepatocellular Carcinoma ◽

Tyrosine Kinase ◽

Neoadjuvant Therapy ◽

Tyrosine Kinase Inhibitors ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors

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Pulmonary complications of tyrosine kinase inhibitors and immune checkpoint inhibitors in patients with non-small cell lung cancer

Cancer Treatment and Research Communications ◽

10.1016/j.ctarc.2021.100439 ◽

2021 ◽

pp. 100439

Author(s):

Kushagra Gupta ◽

Toribiong Uchel ◽

Gregory Karamian ◽

Anthony Loschner

Keyword(s):

Lung Cancer ◽

Tyrosine Kinase ◽

Small Cell Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Pulmonary Complications ◽

Small Cell ◽

Small Cell Lung

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Safety and Efficacy of Transarterial Chemoembolization Combined With Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.657512 ◽

2022 ◽

Vol 11 ◽

Author(s):

Fei Yang ◽

Jun Yang ◽

Wei Xiang ◽

Bin-Yan Zhong ◽

Wan-Ci Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Immune Checkpoint ◽

Transarterial Chemoembolization ◽

Immune Checkpoint Inhibitors ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Safety And Efficacy

PurposeTo explore the safety and efficacy of transarterial chemoembolization (TACE) in combination with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the treatment of unresectable hepatocellular carcinoma (uHCC).Materials and MethodsFrom August 2019 to July 2020, patients who received TACE combined with ICIs and TKIs were retrospectively analyzed. Treatment-related adverse events (AEs) were recorded. The Kaplan–Meier method was used to estimate time to progression (TTP) and progression-free survival (PFS).ResultsIn total, 31 patients with uHCC were included. Eleven patients were classified as BCLC-C. Nineteen patients had multiple lesions, and the cumulative targeted lesions were 69 mm (range, 21-170 mm) according to mRECIST. Twenty-nine (93%) patients experienced at least one AE during the treatment. Four (12.9%) patients developed AEs of higher grade (grade≥3). The objective response rate (ORR) and disease control rate (DCR) were 64.5% and 77.4%, respectively. The median time to response was 7 weeks (range, 4-30 w), and the duration of response was 17.5 weeks (range, 2-46 w). From the first ICIs, TTP and PFS were 6.5 months (95% CI, 3.5-11) and 8.5 months (95% CI, 3.5-NE), respectively.ConclusionsTACE combined with ICIs and TKIs shows an acceptable safety profile and considerable efficacy in patients with HCC.

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