Relationship between plasma pazopanib concentration and incidence of adverse events in renal cell carcinoma.

345 Background: Pazopanib (P), an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit, is approved by the US FDA for the treatment of advanced renal cell cancer (mRCC). Exploratory analyses of data from a Ph II mRCC study (Hutson T, J Clin Oncol. 27, 2009:1) indicated that 70% of patients (pt) receiving 800mg once daily had a week (wk) 4 plasma P trough (Cmin) >20.6μ g/mL that is associated with improved efficacy (Suttle B, J Clin Oncol. 28, 2010:S3048). In this further analysis of the dataset, we investigated the relation between plasma P concentrations at wk 4 and clinically important adverse events (AE) reported within the first 12 wks of treatment. Methods: The % of patients with hypertension (defined as ≥ 15mmHg - baseline on 3 occasions)- a recognized PD marker for this class of agents- or other AEs (CTC grades), occurring during the first 12 wks of treatment were calculated by wk4 Cmin quartiles (Q1-Q4: median and range). Results: P concentrations at 4 wks and AE data were available for 205 out of 225 pts. The incidence of hypertension was 58% in Q1, increasing with concentration to 78% at Q4. The incidence of diarrhea, hair color change, ALT increase, HFS (marked increase), and stomatitis were concentration-dependent, with ≥ 2 fold increase from Q1 to Q4. The incidence of nausea, fatigue, vomiting, dysgeusia, and rash were variable or displayed a flat relationship with Cmin. Conclusions: The incidence of some AEs, such as diarrhea, ALT, HFS (marked relation), and stomatitis increased with plasma Cmin while others did not. We suggest that concentration-dependent AEs are more likely to respond to P dose reduction and as such, provides support for development of a dose optimization strategy. [Table: see text] [Table: see text]

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Angiogenesis Inhibitor Therapy in Renal Cell Cancer

Kidney Cancer ◽

10.1007/978-3-642-21858-3_13 ◽

2011 ◽

pp. 197-207

Author(s):

Sarmad Sadeghi ◽

Brian Rini

Keyword(s):

Renal Cell Cancer ◽

Renal Cell ◽

Cell Cancer ◽

Angiogenesis Inhibitor ◽

Inhibitor Therapy

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Incidence and risk of treatment-related mortality in patients with renal cell cancer (RCC) and non-RCC treated with mammalian target of rapamycin (mTOR) inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.347 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 347-347

Author(s):

Toni K. Choueiri ◽

Youjin Je ◽

Guru Sonpavde ◽

Matt D. Galsky ◽

Marina Kaymakcalan ◽

...

Keyword(s):

Adverse Events ◽

Renal Cell ◽

Fixed Effects ◽

Meta Analysis ◽

Cell Cancer ◽

Mammalian Target Of Rapamycin ◽

Mtor Inhibitors ◽

Target Of Rapamycin ◽

Therapeutic Modality ◽

Increased Risk

347 Background: Inhibition of the mammalian target of rapamycin (mTOR) is an established therapeutic modality for multiple malignancies including renal cell carcinoma (RCC). Agents that target mTOR have been sporadically associated with an increased risk of potentially life-threatening adverse events. We performed an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors, including RCC. Methods: MEDLINE/PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to trials of US Food and Drug Administration—approved mTOR inhibitors (everolimus and temsirolimus) that reported on patients with cancer, randomized design, and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% Confidence Intervals (CIs) by using random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results: In all 2,990 patients from 8 randomized controlled trials (RCTs) were included, 2033 from everolimus trials and 957 from temsirolimus trials. The incidence of FAEs related to mTOR inhibitors use was 3.4% (95% CI, 1.9-6.0) with a RR of 2.33 (95% CI, 1.32 to 4.10; P = .003) compared to control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types (RCC vs. non-RCC). No evidence of publication bias was observed. Conclusions: The use of mTOR inhibitors is associated with an increased risk of FAEs in RCC and non-RCC patients, compared with control patients.

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Angiogenesis Inhibitor Therapy in Renal Cell Cancer

Kidney Cancer ◽

10.1007/978-3-319-17903-2_17 ◽

2015 ◽

pp. 281-294

Author(s):

Jonathan Mathias ◽

Brian Rini

Keyword(s):

Renal Cell Cancer ◽

Renal Cell ◽

Cell Cancer ◽

Angiogenesis Inhibitor ◽

Inhibitor Therapy

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Nephrotoxicity induced by VEGF-target agents in patients with metastatic renal cell cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.432 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 432-432

Author(s):

Tomoyuki Kato ◽

Shoko Nakayama ◽

Takafumi Narisawa ◽

Atsushi Yamagishi ◽

Toshihiko Sakurai ◽

...

Keyword(s):

Targeted Therapy ◽

Adverse Events ◽

Serum Creatinine ◽

Serum Creatinine Level ◽

Creatinine Level ◽

Renal Cell Cancer ◽

Renal Cell ◽

Target Therapy ◽

Cell Cancer ◽

Metastatic Renal Cell Cancer

432 Background: A study was undertaken to investigate the association between treatment with vascular endothelial growth factor (VEGF)-targeted therapy for metastatic renal cell cancer (mRCC) and nephrotoxicity. Methods: Retrospective data were collected for mRCC patients received VEGF-targeted therapy between January 2005 and December 2010. We investigated renal adverse events and clinically significant increased serum creatinine level in patients who received VEGF target therapy. GFR was estimated with the Modification of Diet in Renal Disease (MDRD) formula. Results: Ninety one patients with mRCC who received sunitinib (n=46), sorafenib (n=38), axitnib (n=9) were included in this analysis. As for renal adverse events, acute renal failure occurred in 1 (2.2%) of 46 sunitinib recipients. Facial edema occurred 17 (37.0%) in sunitinib recipients, 2 (5.3%) of sorafenib recipients, 2 (22.2%) of axitinib recipients. In sunitinib recipients, all of these adverse events observed in ‘off’ period. During administration, gradual and significant increase of serum creatinine was observed in sunitinib recipients compared for sorafenib or axitinib recipients (p= 0.04). Significant decrease of GFR compared for baseline correlated with increase of serum creatinine level developed in ‘on’ period of 6 sunitinib administration cycle (p=0.013), but returned to baseline level after 2weeks cessation. No significant change was observed in serum creatinine level and GFR in patients received other VEGF-target agents. Conclusions: Our data suggest that nephrotoxicity developed in a high percentage of patients on sunitinib compared for sorafenib and axitinib in mRCC patients. Clinicians should observe renal function of sunitinib recipients more carefully in ‘off’ period as well as ‘on’ period.

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Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma

50 Studies Every Urologist Should Know ◽

10.1093/med/9780190655341.003.0022 ◽

2021 ◽

pp. 123-128

Author(s):

Christopher Weight

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Adverse Events ◽

Cell Carcinoma ◽

Renal Cell ◽

Antiangiogenic Therapy ◽

Cell Cancer ◽

Immune Checkpoint Blockade ◽

New Class ◽

Advanced Renal Cell Cancer

This chapter summarizes the findings of the landmark CheckMate 025 trial for the new class of drugs of immune checkpoint blockade in advanced renal cell cancer. The trial randomized patients with metastatic renal cell carcinoma who had failed antiangiogenic therapy to systemic therapy with nivolumab versus everolimus and found improved overall survival and fewer treatment-related adverse events in the nivolumab arm.

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Frequency and cost of adverse events in renal cell carcinoma (RCC) patients receiving angiogenesis inhibitor therapies

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.14609 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 14609-14609 ◽

Cited By ~ 4

Author(s):

E. Dial ◽

A. Fournier ◽

E. Moyneur ◽

M. P. Neary ◽

M. S. Duh ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Adverse Events ◽

Cell Carcinoma ◽

Renal Cell ◽

Angiogenesis Inhibitor

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A phase 1 study of alpha-1,3-galactosyltransferase-expressing allogeneic renal cell carcinoma immunotherapy in patients with metastatic renal cell cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.528 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 528-528

Author(s):

Hans J. Hammers ◽

Charles G. Drake ◽

Yousef Zakharia ◽

Eugene Paul Kennedy ◽

Nicholas N. Vahanian ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Adverse Events ◽

Cell Carcinoma ◽

Renal Cell ◽

Phase 1 ◽

Cell Cancer ◽

High Dose ◽

Tumor Type ◽

Dose Limiting Toxicity

528 Background: HyperAcute Renal (HAR) immunotherapy consists of two allogeneic renal cancer cell lines that have been genetically modified to express the carbohydrate α(1,3)Gal, to which humans have an inherent pre-existing immunity. HAR is designed to leverage this mechanism to educate the immune system towards antigens expressed by the patient’s own tumor cells. Methods: This study is a Phase 1 dose escalation trial of HAR for patients with Renal cell carcinoma (RCC). Eligible patients had recurrent or metastatic RCC with a clear cell component. Trial was a standard 3+3 design with patients receiving weekly intradermal injection of HAR (150 x106 cells/300 x106 cells intradermally) for 4 weeks followed by biweekly injections for 10 weeks. After the initial determination of dose-limiting toxicity, an expansion cohort up to 14 patients was enrolled. The primary endpoint was safety and determination of a maximum tolerated dose (MTD). Secondary endpoints are efficacy and immunological correlates. Results: A total of 18 patients (4 low dose, 14 high dose) were enrolled. The MTD was set at 300 x106 cells intradermally with no dose limiting toxicity (DLT). The most frequently reported adverse events (regardless of attribution), occurring in ≥ 20% of subjects, were abdominal pain, fatigue, pain, and injection site reactions. The most frequently reported laboratory abnormality (regardless of attribution) was anemia in 20% of subjects. There have been 5 reported serious adverse events, none deemed related to HAR. Conclusions: RCC is considered an immunogenic tumor based on its response rate to immune checkpoint blockade and IL-2, occasional spontaneous regression, and the high level of tumor T cell infiltration. HAR was well tolerated in this patient population. Therefore, RCC is an appropriate tumor type to target with combination immunotherapy including HAR. Updated results will be presented. Clinical trial information: NCT02035358.

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Association between Immune Related Adverse Events and Outcome in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors

Cancers ◽

10.3390/cancers13040860 ◽

2021 ◽

Vol 13 (4) ◽

pp. 860

Author(s):

Agnese Paderi ◽

Roberta Giorgione ◽

Elisa Giommoni ◽

Marinella Micol Mela ◽

Virginia Rossi ◽

...

Keyword(s):

Multivariate Analysis ◽

Adverse Events ◽

Immune Checkpoint ◽

Renal Cell ◽

Immune Checkpoint Inhibitors ◽

Thyroid Dysfunction ◽

Checkpoint Inhibitors ◽

Cell Cancer ◽

Progression Free Survival ◽

Favorable Clinical Outcome

Background: It has been reported that the occurrence of immune-related adverse events (irAEs) in oncological patients treated with immune-checkpoint inhibitors (ICIs) may be associated with favorable clinical outcome. We reported the clinical correlation between irAEs and the efficacy of ICIs in a real-world cohort of metastatic renal cell cancer (mRCC) patients. Methods: We retrospectively evaluated 43 patients with mRCC who were treated with nivolumab or with nivolumab plus ipilimumab. We considered seven specific classes of irAEs including pulmonary, hepatic, gastrointestinal, cutaneous, endocrine, rheumatological, and renal manifestations. We assessed progression-free survival (PFS) of specific irAEs classes compared to the no-irAEs group. Results: Twenty-nine out of 43 patients (67.4%) experienced a total of 49 irAEs registered. The most frequent irAE was thyroid dysfunction (n = 14). The median PFS after the beginning of therapy was significantly longer in patients with thyroid dysfunction and cutaneous reactions. In multivariate analysis, thyroid dysfunction was an independent factor for favorable outcome [HR: 0.29 (95% CI 0.11–0.77) p = 0.013]. Moreover, experiencing ≥2 irAEs in the same patient correlated in multivariate analysis with better outcome compared with none/one irAE [HR: 0.33 (95% CI 0.13–0.84) p = 0.020]. Conclusions: This retrospective study suggests an association between specific irAES (thyroid dysfunction and skin reaction) and efficacy of ICIs in metastatic RCC. Notably, multiple irAEs in a single patient were associated with better tumor response.

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