Rechallenge of nivolumab in metastatic renal cell carcinoma, an ambispective multicenter study (RENIVO).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 330-330
Author(s):  
Charles Vauchier ◽  
Edouard Auclin ◽  
Philippe Barthelemy ◽  
Lucia Carril ◽  
Thomas Ryckewaert ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Multicenter Study ◽  
Renal Cell ◽  
Group Performance ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Eastern Cooperative Oncology Group ◽  
Grade 3

330 Background: Immune checkpoint inhibitors (ICIs) in combination with another ICI or an antiangiogenic targeted therapy have been approved for frontline therapy in metastatic renal cell carcinoma (mRCC). However, progression disease (PD) often occurs and subsequent therapies are needed. Rechallenge of ICI may then be an option, but there is a lack of data regarding this strategy. Methods: This ambispective multicenter study included patients who received a rechallenge of Nivolumab (ICI-2) between January 2014 and September 2020, after a first-ICI therapy (ICI-1), regardless of the reason of the discontinuation. Patients could have either a non-ICI therapy or have a prolonged free-interval (≥ 12 weeks) between ICI regimens. Those with ongoing rechallenge at inclusion were followed prospectively. Primary endpoint was investigator-assessed best ORR. Results: 45 rechallenges were included from 16 centers. Median age was 60 years (range, 42-90), 64% were male. Most of them had clear cell histology (91%) and a Fuhrman or ISUP grade ≥ 3 (80%). Single-agent Nivolumab and Nivolumab-Ipilimumab association were used in 78% and 11% during ICI-1 and in 93% and 7% during ICI-2, respectively. Discontinuation for PD, toxicity or clinical decision occurred in 49%, 27% and 24% for ICI-1 and in 94%, 3% and 3% for ICI-2, respectively. The ORR were 51% (n = 23) at ICI-1 and 16% (n = 7) at ICI-2. One patient had a complete response during both ICI-1 and ICI-2 and two had a partial response at ICI-2 although they had PD as best ICI-1 response. After a median follow-up of 14.9 months (mo), median duration of response for ICI-2 was 5.1 mo (95% CI, 2.7-not reached [NR]). For ICI-1 and ICI-2: median progression-free survival (PFS) was 11.4 mo (95% CI, 9.8-23.5) and 3.5 mo (95% CI, 2.8-9.7); median overall survival was NR (95% CI, 37.8-NR) and 24 mo (95% CI, 9.9-NR). Poor prognostic factors for PFS at ICI-2 were Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2, presence of liver metastases, inflammatory syndrome and PFS under ICI-1 > 6 months. Grade ≥ 3 immune-related adverse events occurred in 24% (n = 11) during ICI-1 but only in 4% (n = 2) during ICI-2. There was no treatment-related death. Conclusions: Our study suggests that resumption of ICI with Nivolumab has a moderate efficacy in mRCC and acceptable tolerance. Predictive factors of response are needed to propose this strategy to selected mRCC patients. Larger prospective cohorts are needed to confirm these results. [Table: see text]

Activity of single-agent bevacizumab (B) in patients with metastatic renal cell carcinoma (RCC) previously treated with VEGF- and mTOR-based therapies.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 435-435
Author(s):  
Andrew J. Armstrong ◽  
James D. Turnbull ◽  
Julien Cobert ◽  
Tracy Jaffe ◽  
Michael Roger Harrison ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Mtor Inhibitor ◽  
Single Agent ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Mtor Inhibition ◽  
Grade 3

435 Background: Given a lack of clinical information on therapeutic efficacy of agents following progression after vascular endothelial growth factor (VEGF) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in metastatic renal cell carcinoma (mRCC), we investigated the activity of single agent bevacizumab (B) in this setting. Methods: We conducted a retrospective analysis of single agent B-treated patients with mRCC in the second/third line setting, and identified 21 subjects who met inclusion criteria. The primary endpoint was progression-free survival (PFS). Baseline characteristics, survival, response efficacy outcomes, and toxicities were assessed and summarized. Results: 21 patients (15 women/6 men) were treated with B at a dose of 5 mg/kg/week, dosed q2-3 weeks. Median age was 63, 80% were white, 14% black; 80% had clear cell histology. Median time from diagnosis to B therapy was 3 years (range 1-18); 100% had prior VEGF TKI therapy; 43% had prior mTOR inhibitor; 43% had prior IFN and 19% prior IL-2; median number of prior therapies was 3 (range 1-7); 100% were considered Motzer intermediate risk. Median PFS on B for all subjects was 4.4 mo (95% CI 2.8-9.6) and median OS was 19.4 mo (95% CI 9.9-NR) from start of B therapy. ORR was 2 CR/PR (9.5%), 11 SD (52%), 5 PD, 3 NE. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4/13.2 mo. Toxicities were as expected and severe adverse events included grade 3-4 fatigue (6), grade 3-4 dehydration (5), and grade 4 failure to thrive (2), grade 4 constipation (2), and grade 3 muscle weakness (2). Conclusions: Single agent B therapy has acceptable toxicity and moderate disease stabilizing activity in selected patients with mRCC who have failed prior VEGF TKI and mTOR inhibitor therapy, and suggests a benefit to continued ongoing VEGF inhibition. Further prospective study of B alone, in combination with mTOR inhibition, or with alternative targeted agents is warranted.

Novel risk scoring system for metastatic renal cell carcinoma (mRCC) patients (pts) treated with cabozantinib (C).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 734-734
Author(s):  
Meredith R Kline ◽  
Dylan J. Martini ◽  
Yuan Liu ◽  
Julie M. Shabto ◽  
Bradley Curtis Carthon ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Scoring System ◽  
Group Performance ◽  
Eastern Cooperative Oncology Group ◽  
Risk Scoring ◽  
Ecog Ps ◽  
Risk Scoring System

734 Background: Cabozantinib (C) is an effective treatment for metastatic renal cell carcinoma (mRCC) patients (pts). The international mRCC database consortium (IMDC) criteria is the gold standard for mRCC risk stratification. We created a risk scoring system for mRCC pts treated with C. Methods: We performed a retrospective review of 87 mRCC pts treated with C at Winship Cancer Institute from 2015-19. Overall survival (OS) and progression free survival (PFS) were defined as months from C initiation. The baseline characteristics and inflammation biomarkers included were monocyte, neutrophil, and platelet-to-lymphocyte ratios (MLR, NLR, and PLR respectively), RCC histology, body mass index (BMI), metastatic sites (mets), and Eastern Cooperative Oncology Group performance status (ECOG PS). Upon variable selection in multivariable analysis (MVA), elevated baseline MLR (≥0.71), presence of sarcomatoid histology, ECOG PS > 1, and absence of bone metastases were assigned 1 point. A three-level risk scoring system was created: low (score = 0-1), intermediate (score = 2), and high risk (score = 3-4). The Kaplan-Meier method, Cox proportional hazard model, and Uno’s C-statistics were used to examine performance. Results: The majority of pts were males (71%) with clear-cell RCC (75%). Most pts (67%) received 1+ prior line of therapy. High and intermediate risk pts had significantly shorter OS and PFS compared to low risk pts (Table). The C-statistics for our risk scoring system were higher than IMDC in predicting OS (0.7 vs. 0.62) and PFS (0.65 vs 0.57). Conclusions: Pts treated with C may benefit from risk scoring using RCC histology, ECOG PS, mets, and MLR. These results are hypothesis-generating and should be validated in a larger study.[Table: see text]

scholarly journals Modified Glasgow Prognostic Score associated with survival in metastatic renal cell carcinoma treated with immune checkpoint inhibitors

2021 ◽  
Vol 9 (7) ◽  
pp. e002851
Author(s):  
Jacqueline T Brown ◽  
Yuan Liu ◽  
Julie M Shabto ◽  
Dylan Martini ◽  
Deepak Ravindranathan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
Prognostic Score ◽  
Univariate Analysis ◽  
Glasgow Prognostic Score ◽  
Modified Glasgow Prognostic Score

BackgroundThe modified Glasgow Prognostic Score (mGPS) is a composite biomarker that uses albumin and C reactive protein (CRP). There are multiple immune checkpoint inhibitor (ICI)-based combinations approved for metastatic renal cell carcinoma (mRCC). We investigated the ability of mGPS to predict outcomes in patients with mRCC receiving ICI.MethodsWe retrospectively reviewed patients with mRCC treated with ICI as monotherapy or in combination at Winship Cancer Institute between 2015 and 2020. Overall survival (OS) and progression-free survival (PFS) were measured from the start date of ICI until death or clinical/radiographical progression, respectively. The baseline mGPS was defined as a summary score based on pre-ICI values with one point given for CRP>10 mg/L and/or albumin<3.5 g/dL, resulting in possible scores of 0, 1 and 2. If only albumin was low with a normal CRP, no points were awarded. Univariate analysis (UVA) and multivariate analysis (MVA) were carried out using Cox proportional hazard model. Outcomes were also assessed by Kaplan-Meier analysis.Results156 patients were included with a median follow-up 24.2 months. The median age was 64 years and 78% had clear cell histology. Baseline mGPS was 0 in 36%, 1 in 40% and 2 in 24% of patients. In UVA, a baseline mGPS of 2 was associated with shorter OS (HR 4.29, 95% CI 2.24 to 8.24, p<0.001) and PFS (HR 1.90, 95% CI 1.20 to 3.01, p=0.006) relative to a score of 0; this disparity in outcome based on baseline mGPS persisted in MVA. The respective median OS of patients with baseline mGPS of 0, 1 and 2 was 44.5 (95% CI 27.3 to not evaluable), 15.3 (95% CI 11.0 to 24.2) and 10 (95% CI 4.6 to 17.5) months (p<0.0001). The median PFS of these three cohorts was 6.7 (95% CI 3.6 to 13.1), 4.2 (95% CI 2.9 to 6.2) and 2.6 (95% CI 2.0 to 5.6), respectively (p=0.0216). The discrimination power of baseline mGPS to predict survival outcomes was comparable to the IMDC risk score based on Uno’s c-statistic (OS: 0.6312 vs 0.6102, PFS: 0.5752 vs 0.5533).ConclusionThe mGPS is prognostic in this cohort of patients with mRCC treated with ICI as monotherapy or in combination. These results warrant external and prospective validation.

191 Association of immune related adverse events with the efficacy of immune checkpoint inhibitors in metastatic renal cell carcinoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A205-A206
Author(s):  
Vasilii Bushunow ◽  
Leonard Appleman ◽  
Roby Thomas
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Kaplan Meier

BackgroundImmune checkpoint inhibitors (ICI) are first-line therapy for tumors including metastatic renal cell carcinoma (mRCC). Use of ICI is complicated by diverse immune-related adverse events (irAEs), which can add significant morbidity but are also associated with improved efficacy of therapy.1 2 Risk factors for development of irAE are still poorly understood. We hypothesized that patients with mRCC treated with ICI as first-line therapy have higher rates of developing irAE’s than patients previously treated with other therapies.MethodsWe conducted a single-institution, retrospective medical record review of patients with mRCC treated with immune-checkpoint inhibitors from March 2011 through April 15, 2020. We identified therapy duration, and presence, severity, and treatment of adverse events. We defined overall survival as time elapsed from date of diagnosis until death or until completion of study. We classified severity of adverse events according to CTCAE guidelines. Statistical methods included univariate Cox proportional hazards and logistic regression models, and Kaplan-Meier curves were plotted for subgroups.ResultsA total of 64 unique charts were reviewed. 18 patients (28%) of patients were treated with ICI as first-line therapy. 28 patients (44%) experienced immune-related adverse events with a total of 40 irAE’s identified. Most irAE were grade I-II (78%), with 7 (17%) grade III and 1 (2.4%) grade IV irAE’s. Most common sites were skin (29%), thyroid (20%) and gastrointestinal (15%). Patients with irAE had increased survival compared to those who did not have irAE (median survival not reached, vs 139 weeks, p=0.0004) (figure 1). This finding remained after excluding patients who had only experienced dermatologic irAE (median survival not reached in non-derm irAE subgroup, vs 144 weeks for dermatologic or no irAE, p=0.01) (figure 2). Patients treated with ICI as first line therapy had greater rates of developing irAE (72%) than those who had prior therapies (32%) (OR 5.4; p = 0.006). There was no association between histology type and rate of irAE.Abstract 191 Figure 1Kaplan-Meier survival plot of OS between patients with any irAE and those without any irAEAbstract 191 Figure 2Kaplan-Meier survival plot of OS between patients with non-dermatologic irAE and those without any irAE or only dermatologic irAEConclusionsThe development of irAE’s in patients with mRCC treated with ICI is associated with longer survival. This study joins the growing body of evidence showing that presence of irAE’s is associated with increased treatment efficacy. Use of ICI as first-line therapy is associated with higher risk of irAE. Given growing use of ICI as first-line therapy, further study to predict onset and severity of irAE’s is required.AcknowledgementsHong Wang, PhD, for statistical support.Ethics ApprovalThis study was approved by the University of Pittsburgh Institutional Review Board. Approval number STUDY19100386.ReferencesElias R, Yan N, Singla N, Levonyack N, Formella J, Christie A, et al. Immune-related adverse events are associated with improved outcomes in ICI-treated renal cell carcinoma patients. J Clin Oncol 2019;37(7):S645.Verzoni E, Cartenì G, Cortesi E, et al. Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program. J Immunother Cancer 2019;7(1):99.

scholarly journals Checkpoint inhibitors in patients with metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

Cancer ◽  
2018 ◽  
Vol 124 (18) ◽  
pp. 3677-3683 ◽  
Author(s):  
Steven M. Yip ◽  
Connor Wells ◽  
Raphael Moreira ◽  
Alex Wong ◽  
Sandy Srinivas ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Checkpoint Inhibitors

Cabozantinib versus other TKIs after CPI treatment in the real-world management of patients with metastatic renal cell carcinoma (mRCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 293-293
Author(s):  
Florence Marteau ◽  
Brooke Harrow ◽  
Christine McCarthy ◽  
Joel Wallace ◽  
Alisha Monnette ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Real World ◽  
Renal Cell ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
P Value ◽  
The Real ◽  
The Us

293 Background: Checkpoint inhibitors (CPIs) are a treatment option for patients with metastatic renal cell carcinoma (mRCC), but there is limited clinical data on the efficacy of targeted therapies following CPI treatment. Cabozantinib is a tyrosine kinase inhibitor (TKI) that targets multiple receptor kinases implicated in tumorigenesis. In the US, cabozantinib is approved for use in patients with advanced RCC including after CPI treatment. Methods: This retrospective observational cohort study (NCT04353765) evaluated outcomes associated with cabozantinib or other TKIs (axitinib, lenvatinib, pazopanib, sorafenib, sunitinib) in patients with mRCC following CPI treatment. Eligible patients initiated TKI therapy between May 1, 2016 and Sep 31, 2019 and had received a CPI as their last systemic treatment prior to TKI therapy. Patients were identified from the US Oncology Network iKnowMed electronic health record database through structured queries and a targeted chart review. The following real-world outcomes were assessed: 6-month response rate (RR6months; primary); overall response rate (ORR); overall survival (OS); time to treatment discontinuation (TTD); rates of dose reductions, and discontinuation due to adverse events (AEs). The p value for RR6months was used to test for non-inferiority. Results: Eligible patients ( n = 247) had a mean (SD) age of 65.9 (10.5) years and 74.1% were male; 75.7% ( n = 187) received cabozantinib and 24.3% ( n = 60) received other TKIs. All patients had intermediate or poor MSKCC score; more poor-risk patients received cabozantinib than other TKIs (28.9% vs 20%). Outcomes data are shown in the Table. Compared with other TKIs, cabozantinib was associated with a significantly higher RR6months and ORR, and TTD was twice as long with cabozantinib. Discontinuation due to AEs was more frequent with other TKIs than with cabozantinib, although this was not statistically significant; 21.7% of discontinuations occurred during the first 3 months of treatment. AEs leading to discontinuation were consistent with the known safety profile of the products. Conclusions: In this mRCC population receiving routine care in the US, cabozantinib was used more frequently than other TKIs after CPI treatment. Cabozantinib was an effective and well tolerated option post-CPI, with a high response rate in the real-world setting.abozantinib was associated with a significantly higher response rate and a lower discontinuation rate due to AEs; TTD was double that of other TKIs. [Table: see text]

scholarly journals Evolving Treatment Paradigm in Metastatic Renal Cell Carcinoma

2017 ◽  
pp. 319-329
Author(s):  
David M. Gill ◽  
Neeraj Agarwal ◽  
Ulka Vaishampayan
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Targeted Therapies ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Mtor Inhibitors ◽  
Treatment Paradigm

The treatment paradigm for advanced and metastatic renal cell carcinoma (mRCC) has evolved rapidly since the arrival of targeted therapies and novel immunotherapies. mRCC was previously treated only with cytokines. However, discoveries of mutations affecting the von Hippel–Lindau tumor suppressor gene (leading to increased expression of VEGF and hypoxia inducible factor/HIF-1) and of deregulations in the phosphatidylinositol-3 kinase/AKT/mTOR pathway (resulting in tumor angiogenesis, cell proliferation, and tumor growth) have led to the development of numerous targeted therapies. The U.S. Food and Drug Administration (FDA) has thus approved a total of nine targeted therapies since 2005, including VEGF tyrosine kinase inhibitors (sunitinib, pazopanib, axitinib, sorafenib, and lenvatinib), a monoclonal antibody targeting VEGF (bevacizumab), mTOR inhibitors (temsirolimus and everolimus), and a multityrosine kinase inhibitor (cabozantinib). Furthermore, the development of immune checkpoint inhibitors has again shifted the mRCC therapeutic landscape with the FDA’s approval of nivolumab. Herein, we discuss the unprecedented changes in the field of clear cell histology mRCC in both the first-line and salvage settings, and we also discuss future therapies and recommend a treatment paradigm on sequencing of these agents.

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