Immune-related adverse events are associated with improved outcomes in ICI-treated renal cell carcinoma patients.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 645-645 ◽  
Author(s):  
Roy Elias ◽  
Flora Yan ◽  
Nirmish Singla ◽  
Nicholas Levonyack ◽  
Joseph Formella ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Multivariate Analysis ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
Prognostic Score ◽  
University Hospital ◽  
Therapeutic Decisions ◽  
Endocrine Organs

645 Background: With the approval of immune-checkpoint inhibitors (ICI) as first and second line agents for treating metastatic renal cell carcinoma (RCC), immune-related adverse events (irAE) are a growing concern. In this study, we present the safety profile and outcomes of 90 patients with RCC treated at two centers, including a university (UT Southwestern/Clements University Hospital) and a county hospital (UT Southwestern/Parkland). Methods: All patients with RCC treated with ICI were identified from 2013 to January 31, 2018. We examined the incidence of any treatment-related adverse events and “select” irAEs and evaluated their impact on patient outcomes and therapeutic decisions. Kaplan-Meier methods and Cox proportional hazards regression models were used to compare overall survival (OS) and time to next therapy (TTNT) by the presence of irAEs. Results: Of 90 patients treated with ICI, 65 (72.2%) patients experienced adverse events, most commonly fatigue (37.8%), nausea (14%), and decreased appetite (12.2%). Select irAEs were seen in 38 (42.2%) with the most common irAEs involving the skin (15.6%), gastrointestinal tract (14%), endocrine organs (11%), and lungs (7.8%). There were 15 (16.7%) grade III/IV irAEs resulting in cessation of therapy for 12 (13.3%) patients. The median OS was 35.9 (95% CI: 24.3-not reached) and 26.5 months (95% CI: 10.2-28.8; p = 0.002) for patients with and without irAEs, respectively. The median TTNT was 17.8 (95% CI: 11.3-29.3) and 6.6 months (95% CI: 4.5-9.6; p = 0.002) for patients with and without irAEs, respectively. In multivariate analysis of irAE status and Heng prognostic score, irAEs were associated with improved OS, HR 0.376 (95% CI 0.179–0.792; p = 0.010) and TTNT, HR 0.482 (95% CI 0.280–0.829; p = 0.008). Conclusions: ICI in RCC is well tolerated with only 16.7% of patients experiencing an adverse event resulting in cessation of therapy. The development of an irAE correlated with both an improved median OS as well as median TTNT, a benefit that persisted after multivariate analysis including Heng prognostic scoring. These findings suggest that the development of irAEs may be an independent positive prognostic factor in patients with RCC treated with ICI.

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 Safety and efficacy of restarting immune checkpoint inhibitors after clinically significant immune-related adverse events in metastatic renal cell carcinoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000144 ◽  
Author(s):  
Sarah Abou Alaiwi ◽  
Wanling Xie ◽  
Amin H Nassar ◽  
Shaan Dudani ◽  
Dylan Martini ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Median Time ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Safety And Efficacy ◽  
Clinically Significant

BackgroundImmune checkpoint inhibitors (ICI) induce a range of immune-related adverse events (irAEs) with various degrees of severity. While clinical experience with ICI retreatment following clinically significant irAEs is growing, the safety and efficacy are not yet well characterized.MethodsThis multicenter retrospective study identified patients with metastatic renal cell carcinoma treated with ICI who had >1 week therapy interruption for irAEs. Patients were classified into retreatment and discontinuation cohorts based on whether or not they resumed an ICI. Toxicity and clinical outcomes were assessed descriptively.ResultsOf 499 patients treated with ICIs, 80 developed irAEs warranting treatment interruption; 36 (45%) of whom were restarted on an ICI and 44 (55%) who permanently discontinued. Median time to initial irAE was similar between the retreatment and discontinuation cohorts (2.8 vs 2.7 months, p=0.59). The type and grade of irAEs were balanced across the cohorts; however, fewer retreatment patients required corticosteroids (55.6% vs 84.1%, p=0.007) and hospitalizations (33.3% vs 65.9%, p=0.007) for irAE management compared with discontinuation patients. Median treatment holiday before reinitiation was 0.9 months (0.2–31.6). After retreatment, 50% (n=18/36) experienced subsequent irAEs (12 new, 6 recurrent) with 7 (19%) grade 3 events and 13 drug interruptions. Median time to irAE recurrence after retreatment was 2.8 months (range: 0.3–13.8). Retreatment resulted in 6 (23.1%) additional responses in 26 patients whose disease had not previously responded. From first ICI initiation, median time to next therapy was 14.2 months (95% CI 8.2 to 18.9) and 9.0 months (5.3 to 25.8), and 2-year overall survival was 76% (95%CI 55% to 88%) and 66% (48% to 79%) in the retreatment and discontinuation groups, respectively.ConclusionsDespite a considerable rate of irAE recurrence with retreatment after a prior clinically significant irAE, most irAEs were low grade and controllable. Prospective studies are warranted to confirm that retreatment enhances survival outcomes that justify the safety risks.

UNISON - nivolumab then ipilimumab + nivolumab in advanced non-clear cell renal cell carcinoma (ANZUP 1602): Part 1—Nivolumab monotherapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 325-325
Author(s):  
Craig Gedye ◽  
David William Pook ◽  
Laurence Eliot Miles Krieger ◽  
Carole A. Harris ◽  
Jeffrey C. Goh ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Disease Control ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Cell Renal Cell Carcinoma ◽  
Papillary Type

325 Background: Immune checkpoint inhibitors (ICI) are active in many cancers, but people with rare variant, non clear-cell renal cell carcinoma (nccRCC) have been excluded from most clinical trials in RCC. UNISON (NCT03177239) aimed to test 2 hypotheses; the activity of nivolumab in nccRCC (Part 1), and the benefit of adding ipilimumab to nivolumab, in people whose cancers progress on nivolumab (Part 2). Methods: 83 participants (pts) with advanced nccRCC with good (ECOG0/1) performance status, were enrolled including papillary type 1 (17%), papillary type 2 (28%), chromophobe (18%), Xp11 translocation (6%), hereditary leiomyomatosis renal cell carcinoma syndrome-associated renal cell carcinoma (6%), RCC unclassified (10%) and other (15%) histological subtypes. Participants took nivolumab (N) 240mg every two weeks in Part 1 in total. If they experienced progression and remained eligible they could take N (3mg/kg) plus ipilimumab (I; 1mg/kg) every 3 weeks for up to 4 doses (Part 2). Pts with disease control after N or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically-relevant improvement in objective tumor response rate (OTRR) from 15% to 30% in people taking N+I in Part 2 in pts whose cancers were refractory to single-agent first-line N. Here we report results of Part 1. Results: Pts experience of N appeared similar to previous reports, with most experiencing mild adverse events. 12 treatment related SAE occurred in 11 patients (13%). 14 pts (17%) experienced treatment delays, or permanent treatment discontinuation (10%). The median time on treatment was 5.1 months. The OTRR was 17% with 3 complete responses and 11 partial responses. The median duration of response was 21 months. Stable disease occurred in 49% of pts and disease progression in 34%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 4.0 months (95% CI: 3.6, 7.4). The 6 month progression-free survival (PFS) was 45% (95% CI: 34-55) and the 12 months PFS was 30% (95% CI: 21%, 40%). Conclusions: Pts with nccRCC treated with N experience similar adverse events compared to pts with other cancers. A substantial minority of people with nccRCC derive benefit, but many pts have cancers refractory to anti-PD1, similar to other reports. The activity of I and N in this PD1-refractory population is of considerable interest and will be reported at a later date. Clinical trial information: NCT03177239 .

Pembrolizumab- and/or pazopanib-induced remitting seronegative symmetrical synovitis with pitting edema in a patient with renal cell carcinoma

2019 ◽  
Vol 26 (5) ◽  
pp. 1230-1233 ◽  
Author(s):  
Onur Bas ◽  
Aral Ozbek ◽  
Denizcan Guven ◽  
Oktay Aktepe ◽  
Levent Kılıc ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Inflammatory Arthritis ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Angiogenesis Inhibitors ◽  
Immune System Activation ◽  
Pitting Edema

Introduction Immune checkpoint inhibitors and angiogenesis inhibitors are novel treatment options for renal cell carcinoma and widely used in clinical practice. They are related with adverse events that occur as a consequence of immune system activation and inhibition of angiogenesis. Herein, we report a rare case of inflammatory arthritis seen in a patient treated with an anti Programmed cell death-1 pembrolizumab and an anti-vascular endothelial growth factor pazopanib. Case report A 60-year-old Caucasian male presented to our clinic with inflammatory arthritis with pitting edema. He had been started on pembrolizumab therapy for metastatic renal cell carcinoma after enrolling in the KEYNOTE-679 study. After six cycles of treatment with pembrolizumab, metastasis had been determined in the lung. Then, the patient’s therapy was changed to pazopanib. While the patient was on pazopanib treatment, he noticed a gradual swelling of both hands. Rheumatoid factor, anti-nuclear antibody and anti-cyclic citrullinated peptide were negative. Joint ultrasonography revealed acute tenosynovitis and soft tissue swelling with pitting edema, and a diagnosis of remitting seronegative symmetrical synovitis with pitting edema was made. Management and outcome: He was started on 10 mg prednisolone daily. His symptoms dramatically responded to corticosteroid. He continued to take pazopanib. Then, the patient was discharged with 10 mg prednisolone daily. Discussion Pembrolizumab- and/or pazopanib-induced remitting seronegative symmetrical synovitis with pitting edema can be among the rare rheumatic immune-related adverse events that clinicians may encounter as the immune check point inhibitors and anti-VEGF use increases. Corticosteroid therapy can relieve symptoms and cessation of therapy may not be necessary.

Outcomes of sunitinib therapy in patients (pts) with metastatic renal cell carcinoma (mRCC) with poor risk features.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 476-476
Author(s):  
Romualdo Barroso-Sousa ◽  
Rodrigo Ramella Munhoz ◽  
Leonardo Gomes Fonseca ◽  
Angelo Bezerra de Sousa Fede ◽  
Rudinei Diogo Marques Linck ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Multivariate Analysis ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Standard Of Care ◽  
Standard Regimen ◽  
Poor Risk ◽  
Hand Foot Syndrome

476 Background: Temsirolimus is perceived as the standard of care in pts with mRCC with poor risk features. However, sunitinib (Su) is commonly used in this setting. In this study, we assessed the use of Su in an unselected mRCC population. Methods: Retrospective analysis of 51 pts with mRCC and ≥ 3 poor prognosis features, as determined in the Advanced Renal Cell Carcinoma (ARCC) trial, treated with Su between January 2006 and July 2012. Primary outcome was overall survival (OS). Clinical and laboratory parameters were evaluated, as well as Su-related adverse events (AE). Median time to treatment failure (mTTF) and OS were estimated by Kaplan–Meier methods. On exploratory grounds, univariate, and multivariate analysis using Cox regression model was performed to determine possible prognostic variables. Results: Median age was 60 years (26-89). Most had clear cell histology (98%), 19% prior systemic treatment, and 51% prior nephrectomy. 64%, 15%, and 4% had 4, 5, and 6 adverse prognosis factors respectively. 88% had diagnosis to treatment intervals < 1 year and 45% had KPS scores of < 80. A median of 2 cycles (0–12) were administered. 63% received standard regimen of Su (50 mg/d 4 wk on/2 wk off). Reasons for discontinuation were disease progression (63%) and adverse events (21%). Most grade ≥ 3 AE were fatigue (14%), neutropenia (8%), and stomatitis (8%). 17%, 25%, and 14% developed hypothyroidism, hand-foot syndrome (HFS), and hypertension, respectively. Two therapy-related deaths were observed (one febrile neutropenia and one intracranial hemorrhage). Estimated mTTF and mOS of this cohort were 2.4 and 6.6 months, respectively. Multivariate analysis revealed that in a model adjusted for type of Su regimen, KPS, presence of brain metastasis, and occurrence of HFS, only Su-associated hypothyroidism was significantly associated with survival (respectively, odds ratio [OR] = 0.23; 95% CI = 0.07-0.68). Conclusions: Pts with mRCC with poor risk features treated with Su have an OS, TTF and rates of therapy discontinuation due to AE comparable to clinical trial subsets of similar pts. Our data suggest that the development of hypothyroidism in this setting might be useful as a predictor of OS, and this finding should be further investigated.

Validation of the lung immune prognostic index (LIPI) in patients with metastatic renal cell carcinoma treated with nivolumab in the GETUG-AFU 26 NIVOREN trial.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 735-735 ◽  
Author(s):  
Pernelle Lavaud ◽  
Cécile Dalban ◽  
Sylvie Negrier ◽  
Christine Chevreau ◽  
Gwenaelle Gravis ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Prognostic Factor ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
Prognostic Score ◽  
External Validation ◽  
Objective Response ◽  
Prognostic Index ◽  
Independent Prognostic Factor

735 Background: The Lung Immune Prognostic Index (LIPI) is a prognostic score combining pretreatment dNLR (neutrophils/ (leucocytes-neutrophils) and LDH correlated to immune checkpoint inhibitors (ICI) benefit in several advanced cancers. We aimed to correlate LIPI score with Nivolumab (N) benefit in metastatic clear cell renal cell carcinoma (mccRCC) patients. Methods: We investigated the LIPI score in the GETUG-AFU 26 NIVOREN phase II trial assessing the activity and safety of N after failure of upfront VEGF-targeted therapies. A dNLR ≥ 3 and LDH ≥ upper superior limit were analyzed for the LIPI, and patients were stratified into 3 groups (good (GG), intermediate (IG) and poor (PG)) (Mezquita et al, JAMA Oncol 2018). The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and objective response rate (ORR). Results: Overall, 619 pts were included. Median age was 64 years old, 22.1% pts had received more than 2 previous lines and IMDC risk groups were 18.3%, 56.5% and 25.0% for good/intermediate and poor risk respectively. Median (m) follow up was 23.7 months (mo). The mPFS with N was 4.0 mo and mOS was not reach. LIPI classified 364 pts (58.8%) as GG, 216 pts (34.9%) as IG and 39 pts (6.3%) as PG. The PFS and OS results are summarized in the Table. In multivariate analysis, LIPI score remains an independent prognostic factor after adjustment for sex, age, ECOG PS and IMDC. ORR did not seem to be influenced by the LIPI groups. Conclusions: We report for the first time that LIPI score is associated with PFS and OS in patients treated with N for mccRCC. LIPI score appears as an independent prognostic factor even after adjustment for established risk factors. External validation in a VEGF-targeted therapy cohort is ongoing and will contribute to evaluate the predictive value of LIPI in mccRCC.[Table: see text]

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