Characteristics and outcomes of patients (pts) who developed immune-related adverse events (irAEs) with an initial presentation in the emergency department (ED).

2020 ◽  
Vol 38 (29_suppl) ◽  
pp. 201-201
Author(s):  
Ryan Holstead ◽  
Baskoro Kartolo ◽  
Tara D. Baetz
Keyword(s):  
Chart Review ◽  
Checkpoint Inhibitors ◽  
Point Of Care ◽  
Single Agent ◽  
Outpatient Setting ◽  
Timely Initiation ◽  
Ed Visits ◽  
Grade 3 ◽  
High Degree ◽  
Median Admission

201 Background: Management of irAEs due to immune checkpoint inhibitors (ICIs) requires a high degree of suspicion, and management of severe irAEs require timely initiation of corticosteroids (CS). This can be challenging in the ED, where providers may not be aware of an individual pt’s cancer treatment or its toxicities. Methods: We performed a retrospective single-center chart review for pts treated with ICIs in 2018 and 2019 who subsequently presented to ED. New irAEs with first presentation in ED were analyzed and pt outcomes were recorded. Descriptive statistics compared this population to irAEs identified in outpatient setting, as well as rates of ED utilization in pts on doublet ICI (dICI). Results: Of 351 evaluable pts treated with an ICI, 129 (37%) had at least one presentation to ED. Seventeen pts had a first presentation of a new irAE. These pts had received a median 2 cycles of ICI prior to presentation (interquartile range [IQR] 1-3) Twelve of these pts presented with generalized fatigue or pain, twelve required admission, 4 were admitted to intensive care within 30 days, and two died. Toxicities included hypophysitis (5), arthritis (2), colitis (2), myocarditis (2), neuritis (2), pneumonitis (2), adrenalitis (1), hepatitis (1). Median admission was 8.5 days (IQR 2-32), and median time to corticosteroids was 30.5 hours (range 4-269). Grade 3 or higher toxicity was more frequent in the ED pts compared to the total ICI pt population (70.5% vs. 32.2%). Pts on dICI (n = 41) had a higher rate of ED utilization (n = 23, 56.1%) and ED visits were more likely to be for first presentation of a new irAE (n = 7, 30.4% of dICI ED visits) compared to single-agent ICI regimens. Conclusions: Pts with irAEs that first present at the ED often have generalized symptoms, prolonged hospitalizations, and can have long delays to initiation of CS. Development of a protocolized approach for pts on ICI at the point of care in the ED may improve identification of irAEs, ‘door-to-steroid’ time, and patient outcomes.

Retrospective Analysis of Fractionated High-Dose Melphalan (F-MEL) and Bortezomib-Thalidomide-Dexamethasone (VTD) with Autotransplant (AT) Support for Advanced and Refractory Multiple Myeloma (AR-MM).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3102-3102 ◽  
Author(s):  
Mauricio Pineda-Roman ◽  
Michelle H. Fox ◽  
Klaus A. Hollmig ◽  
Elias J. Anaissie ◽  
Frits van Rhee ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Single Agent ◽  
Patient Characteristics ◽  
Median Number ◽  
Outpatient Setting ◽  
High Dose ◽  
Life Threatening ◽  
Grade 3 ◽  
High Dose Melphalan ◽  
Asco 2006

Abstract Background: MEL is an effective and safe AT regimen for MM, usually administered as a single dose at 200mg/m2; mucositis is dose-limiting. There is recent pre-clinical and clinical evidence of synergistic interaction of MEL with both immuno-modulatory agents (thalidomide, MPT [Palumbo, Lancet, 2006], lenalidomide, RMP [Palumbo, ASCO, 2006]) and with the first-in-class proteasome inhibitor, bortezomib (VelcadeR) (VMP, Mateos, ASCO, 2006). We previously reported on the marked activity of VTD in AR-MM, even in a setting of resistance to single agent thalidomide and bortezomib (Blood, January, 2004). In a clinical setting of AR-MM, we administered IV MEL after bortezomib (V) on days 1, 4, 7 +/− d 10, along with daily thalidomide (T) and dexamethasone (D), in order to achieve maximum pharmacological synergy of all 4 drugs. Patients and Methods: A retrospective analysis was performed of 22 patients with AR-MM, who were treated with the F-MEL-VTD regimen with the following MEL fractions: 3-F at 50–80mg/m2 for total doses of 150–240 mg/m2, 18 patients; 4-F at 50–60mg/m2 for total doses of 200–240 mg/m2, 4 patients; 5-F at 15–50 mg/m2 for total doses of 150–250 mg/m2, 2 patients. V was given at doses of 1.0–1.3 mg/m2 immediately preceding each MEL fraction; T was dosed at 100–200 mg/d from day 1 until the last day of MEL; D was given at 20–40 mg on the day of and after V and MEL. Two patients received 2 cycles of F-MEL-VTD, so that 24 courses could be evaluated. Results: Patient characteristics included a median age of 61yr (range, 46–75yr), median creatinine of 0.85mg/dL (range, 0.6–1.9mg/dL); abnormal cytogenetics (CA) were present in 15/22 (68%) - typifying the high-risk nature of their disease; the median number of prior regimens was 6 (range, 1–14); prior AT: 0 in 3 patients, 1 in 11, 2 in 8 and 3 in 1 patients. F-MEL-VTD was initiated in the outpatient setting in 15, only 3 of whom required subsequent hospital admission. Toxicities included grade 3–4 diarrhea mainly due to C. difficile in 8 (33%) and oral mucositis > grade 2 in only 1; grade 3 fever in 3 (12%) with Aspergillus pneumonia in 2 patients; no transplant-related mortality. Hematopoietic recovery was excellent with median times to ANC>500/microL of 10 days (range, 8–19d) and platelets > 50.000/microL of 17 days (range, 10–24d); 2 patients receiving 1.88 and 1.95 x 106 CD34+ cells/kg failed to recover platelet counts to >50.000/microL. Response rates were measured at 6 weeks, using Blade criteria: CR, 11 (46%) with an additional 3 achieving near-CR (>=n-CR, 59%); PR, 4 (17%); the remainder 24% had transient or no response. Conclusion: F-MEL-VTD was remarkably well tolerated, permitting total MEL dose escalation to > 200mg/m2 in 13 of 22 patients, without incurring grade >2 stomatitis in the majority of patients. Due to the protracted administration involved in this regimen, the median duration of neutropenia was 10 d (range, 8 to 19d) with life-threatening infections observed in only 2 patients. These encouraging data form the basis for a randomized trial of VTD followed by standard 1-F MEL versus 3-F MEL with VTD preceding each MEL dose.

Safety and efficacy of retreatment with immune checkpoint inhibitors (ICIs) in patients with metastatic RCC (mRCC) who have previously received an ICI.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 698-698
Author(s):  
Praful Ravi ◽  
Ziad Bakouny ◽  
Ronan Flippot ◽  
David A. Braun ◽  
Sarah Abou Alaiwi ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Median Number ◽  
Investigational Agent ◽  
Prior Therapy ◽  
First Line Therapy ◽  
Best Response ◽  
Grade 3 ◽  
Metastatic Rcc

698 Background: Several ICIs are approved for use in first and subsequent lines of therapy in mRCC, either alone or in combination with another ICI or targeted therapy. There is limited data on whether patients who receive an ICI derive benefit from a subsequent line of ICI-based therapy. Methods: We reviewed mRCC patients at our institution who were treated with an ICI between 2009 and 2018 having previously received ICI-based therapy. The primary outcomes of interest were radiologic response and time to treatment failure (TTF) on ICI retreatment. Immune-related adverse events (irAEs) were graded using CTCAE v5.0. Results: A total of 31 patients were retreated with an ICI, either alone (n=15) or in combination with another ICI (n=8), tyrosine kinase inhibitor (n=2) or investigational agent (n=6); reasons for discontinuation of prior ICI were disease progression (n=23), toxicity (n=7) and study completion (n=1). Median age at the start of first-line therapy was 62 years and the majority of patients (n=30, 90%) had International Metastatic RCC Database Consortium intermediate- or poor-risk disease; median follow-up was 3.4 years (95% CI 2.5-4.6). The median number of lines of therapy received prior to ICI retreatment was 3 (range 1-7). Of 27 evaluable patients, 3 (11%) had a partial response (PR) to ICI retreatment (2 with ICI-ICI combination therapy and 1 with single-agent ICI), 13 (48%) had stable disease, and 11 (41%) had progressive disease (PD) as their best response; of the 3 with a PR, 2 had a PR and 1 had SD to prior ICI therapy. In comparison, 13 of 31 patients (42%) had a PR or better to first ICI-based therapy, with 4 (13%) having PD. Median TTF on ICI retreatment was 3.2 months (95% CI 1.8-5.2), compared to 8.2 months (3.3-10.0) on prior ICI. 19 patients experienced an irAE with ICI retreatment, with 8 (26%) suffering a grade 3 or higher irAE. Conclusions: Retreatment with ICIs after prior therapy with an ICI was relatively safe but demonstrated limited efficacy. Additional data, ideally from prospective studies, assessing outcomes of retreating patients with ICIs are needed to determine whether using different ICIs in sequence has a role in treatment of mRCC.

Novel evidence synthesis system to support living systematic reviews and living guidelines for cancer immunotherapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2054-2054
Author(s):  
Irbaz Bin Riaz ◽  
Samarth C Rawal ◽  
Rabbia Siddiqi ◽  
Noureen Asghar ◽  
Mahnoor Islam ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Systematic Reviews ◽  
Checkpoint Inhibitors ◽  
Point Of Care ◽  
Evidence Synthesis ◽  
Meta Analysis ◽  
Single Agent ◽  
Forest Plot ◽  
Toxicity Data ◽  
Efficient Manner

2054 Background: Systematic reviews that summarize the toxicity of Immune checkpoint inhibitors (ICIs) become outdated very soon after publication. Therefore, we reported results of a toxicity meta-analysis at 2019 ASCO meeting and informed the intent to create a living systematic review (LSR). LSRs combine human and machine effort and support rapid evidence synthesis and living clinical practice guidelines. Now, we report our experience maintaining a LSR on toxicity of ICIs. Methods: Steps include quarterly literature searches to identify new clinical trials reporting ICI-associated adverse events (AEs), AI-enabled screening of new citations which meet the inclusion criteria, automated cumulative meta-analysis and an online reporting platform. Standard data formats and protocols were designed for inputting text, tables and graphics. Software was written to interpret these data and output the information in the appropriate format, such as a forest plot and summary tables. Finally, a dynamic interface that enables user inputs and displays the associated output was designed. Results: The LSR is continuously updated incorporating toxicity data from new clinical trials as it becomes available. We have screened 8000 relevant citations and summarized the odds of Grade 3 or higher AEs and AEs of special interest in patient receiving ICIs. The results are updated on quarterly basis and are available online. The results are updated on quarterly basis and will be available on a website at the time of publication. Prototype with dummy data is available at this link . This interface can also be manipulated via user input to organize and sort data tables and forest plots by type of cancer, name or mechanism (PD-1 or PD-L1) of ICI agent, single agent or combination, type of control arm, line of treatment and several other clinically relevant filters. For example, a user can instantaneously generate a meta-analysis summarizing the risk of colitis or pneumonitis in metastatic lung cancer trials with pembrolizmuab. Conclusions: This LSR engine can prospectively synthesize toxicity data from ICI trials in an efficient manner providing accurate and timely information for advanced clinical decision support at point-of-care. Efforts are ongoing to improve efficiency of screening, improve AI-enabled processes for automated screening and data abstraction, and test across multiple clinical questions.

Racial differences in development of immune-related adverse events.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15148-e15148 ◽  
Author(s):  
Shruti Bhandari ◽  
Rohit Kumar ◽  
Laura Nice ◽  
Anmol Cheema ◽  
Goetz H. Kloecker
Keyword(s):  
African Americans ◽  
Adverse Events ◽  
Autoimmune Diseases ◽  
Racial Differences ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Retrospective Chart Review ◽  
Cancer Type ◽  
Immune System Activation ◽  
Grade 3

e15148 Background: Immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) are caused by non-specific immune system activation and develop in 30-70% of patients. The goal of this study is to examine the association of race with the development of irAEs secondary to ICIs as autoimmune diseases generally exhibit racial differences. Methods: A retrospective chart review was done using University of Louisville pharmacy database. Patients with solid cancers who received ICIs between Jan 2016 to June 2019 were included. IrAEs were identified through the review of electronic medical records. Descriptive analysis evaluated the incidence and severity of irAEs. Multivariable logistic regression was used to calculate standardized incidence of irAEs among Whites and African Americans. Results: A total of 476 patients were included in this study. The mean age was 61 years, 57% were males and 89.7% were whites. A majority of patients had melanoma (50%). The remainder of the dataset included lung (33.4%), gastrointestinal (7.4%), head & neck (4.8%), breast (2.5%) and genitourinary (1.9%) cancers. ICIs included single agent anti-PD-1 (74.8%), single agent anti-PD-L1 (9.4%), combination anti-CTLA-4 with anti-PD-1 (7.1%). Some patients were also treated with > 1 ICI as subsequent therapy (8.6%). Overall, the rate of irAEs was 44.3% with 33.8% grade 1-2 and 12.4% grade 3-4 irAEs. There was no difference in development of any grade irAEs in Whites as compared to African Americans after adjusting for age, sex, cancer type and ICIs (44.3% vs 44.2%; OR: 0.99, 95% CI: 0.50 – 1.97; p = 0.99). There was also no difference in development of grade 3-4 irAEs in whites as compared to African Americans (12.8% vs 14.5%; OR: 1.16, 95% CI: 0.43 – 3.12; p = 0.75). Conclusions: In this study, we found no racial difference in the development of irAEs between Whites and African Americans. This is in contrast to general autoimmune diseases which exhibit racial differences with higher prevalence among African Americans compared to Whites. We will continue to accrue patients to this study as larger sample size is needed to confirm these findings.

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]

Improved survival among patients with malignant pleural mesotheliomas who develop immune-related adverse events on immunotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8556-8556
Author(s):  
Michael Offin ◽  
Jacklynn V. Egger ◽  
Caroline G. McCarthy ◽  
Vasilisa Rudneva ◽  
Jason Beattie ◽  
...  
Keyword(s):  
Adverse Events ◽  
Median Time ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Progression Free Survival ◽  
Clinicopathologic Characteristics ◽  
Kaplan Meier ◽  
Clinicopathologic Feature ◽  
Thoracic Radiation ◽  
Grade 3

8556 Background: While immune checkpoint inhibitors (ICI) are a standard option for patients with malignant pleural mesotheliomas (MPM), there is limited data on the rate of immune related adverse events (irAEs) and effects on clinical outcomes. Methods: 61 patients with MPM who received ICI between January 2016 and October 2020 were assessed and followed through November 2020. irAEs (CTCAE v5.0) were noted along with the time from ICI start to irAE onset. Patients were grouped into irAE ever versus never. Clinicopathologic characteristics, prior treatments, and investigator assessed clinical benefit rate (CBR; partial response [PR] + stable disease [SD]) were compared by Fisher’s Exact and Mann-Whitney Tests. Overall survival (OS) and investigator assessed progression free survival (PFS) from ICI start were compared using Kaplan Meier. In consented patients (n = 56), next generation sequencing (MSK-IMPACT) was performed with HLA genotyping analysis by POLYSOLVER software and alleles for the three major MHC class I (HLA-A, -B, -C) genes were obtained from whole exome recapture. Results: Most patients were male (72%), smokers (55%), > 70 years old (median 72, range 34-90), and had epithelioid histology (67%). No patients had baseline autoimmune disease. The median line of prior systemic therapies to ICI start was 2 (range 1-5). 17 patients (28%) developed an irAE on therapy including 7 (11%) with grade 3 to 5 events (pneumonitis, myositis, pancreatitis, nephritis, encephalitis and adrenal insufficiency). The median time from ICI start to irAE was 2.5 months (range 2 days – 5.8 months). There was no association with dual ICI (n = 6) vs single agent (n = 11) and sooner onset (2.1 vs 4.0 months; p = 0.10) nor higher grade (median grade 2 vs 3; p = 0.31) of irAEs. 1 patient developed grade 5 pneumonitis with onset 2 days after initial dose of dual-ICI. Comparing patients with irAEs to those without, there was no difference in distribution of epithelioid histology (n = 10 vs 31; p = 0.54), median age (71 vs 72 years old; p = 0.43), nor prior thoracic radiation (n = 5 vs 11; p = 0.75).There was no difference in HLA type nor the fraction of HLA alleles of individual genes amongst the groups. Patients who had an irAE were on ICI longer than those that did not (median time on ICI 5.4 vs 0.9 months, respectively; p = 0.02). OS was higher in patients with irAEs compared to those without (21.1 vs 4.7 months; p = 0.003) as was PFS (6.8 vs 1.7 months; p = 0.01). There was a significant increase in the CBR between those that had an irAE (65%; 5 PR, 6 SD) and those that did not (27%; 2 PR, 10 SD; p = 0.006). Conclusions: 28% of patients with MPM who received ICIs developed an irAE and onset tended to be early in the course of treatment. There was no clear predictive clinicopathologic feature that correlated with the occurrence of irAE. There was a significant increase in OS, PFS, and CBR in patients that had an irAE compared to those that did not.

scholarly journals Investigating the Impact of Immune-Related Adverse Events, Glucocorticoid Use and Immunotherapy Interruption on Long-Term Survival Outcomes

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2365
Author(s):  
Charline Lafayolle de la Bruyère ◽  
Pierre-Jean Souquet ◽  
Stéphane Dalle ◽  
Pauline Corbaux ◽  
Amélie Boespflug ◽  
...  
Keyword(s):  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Progression Free Survival ◽  
Long Term Outcomes ◽  
Term Survival ◽  
Glucocorticoid Administration ◽  
Grade 3 ◽  
The Impact

It remains unclear whether immune-related adverse events (irAEs) and glucocorticoid use could impact long-term outcomes in patients treated for solid tumors with immune checkpoint inhibitors (ICI). All patients treated with a single-agent ICI for any advanced cancer were included in this retrospective unicentric study. The objectives were to assess the impact of grade ≥3 irAEs, glucocorticoid use and the interruption of immunotherapy on progression-free survival (PFS) and overall survival (OS). In this 828-patient cohort, the first occurrence of grade ≥3 irAEs had no significant impact on PFS or OS. Glucocorticoid administration for the irAEs was associated with a significantly shorter PFS (adjusted HR 3.0; p = 0.00040) and a trend toward shorter OS. ICI interruption was associated with a significantly shorter PFS (adjusted HR 3.5; p < 0.00043) and shorter OS (HR 4.5; p = 0.0027). Glucocorticoid administration and ICI interruption were correlated. In our population of patients treated with single agent ICI, grade ≥3 irAEs did not impact long-term outcomes. However, the need for glucocorticoids and the interruption of immunotherapy resulted in poorer long-term outcomes. The impact of grade ≥3 irAEs reported in other studies might then be explained by the management of the irAEs.

Cabozantinib in advanced HCC patients previously treated with immune checkpoint inhibitors: A territory-wide cohort study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16179-e16179
Author(s):  
Jeffrey Sum Lung Wong ◽  
Yawen Dong ◽  
Vikki Tang ◽  
Thomas Wai-Tong Leung ◽  
Cynthia SY Yeung ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Acquired Resistance ◽  
Previous Treatment ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Primary Resistance ◽  
Grade 3

e16179 Background: Cabozantinib is licensed for use as second- or third-line treatment for sorafenib-exposed advanced hepatocellular carcinoma (aHCC) based on the phase III CELESTIAL trial. However, its use in the post-immune checkpoint inhibitors (ICI) setting has yet to be described. We evaluated the pattern of use, efficacy, survival and tolerability of cabozantinib in aHCC patients with previous treatment by ICIs. Methods: We did a multi-centre, territory-wide study analysing aHCC patients who received cabozantinib after prior ICIs. Objective response rate (ORR), disease control rate (DCR), time-to-progression (TTP), overall survival (OS) and treatment related adverse events (TRAEs) were assessed. Results: Thirty-one patients were included. The median age was 58.0 (range 41-85) and 77.4% had Child-Pugh A cirrhosis. 51.6% of patients received single agent cabozantinib and 48.4% received cabozantinib in combination with ICIs. ≥80% of patients received cabozantinib beyond the second-line and 93.5% of patients had prior TKIs. All patients received prior anti-PD-1 and 61.3% had prior anti-CTLA-4. The median follow-up was 15.2 months. For single agent cabozantinib patients, the ORR was 6.3%, DCR was 31.3% and median TTP was 3.5 months (95% C.I. 1.2-5.8). For cabozantinib-ICI combination patients, the ORR was 6.7%, DCR was 26.7% and median TTP was 2.3 months (95% C.I. 1.4-3.1). The overall median OS was 8.9 months (95% C.I. 5.7-11.9). Single agent cabozantinib patients had a significantly shorter OS compared to cabozantinib-ICI combination patients (8.3 months (95% C.I. 1.3-15.2) vs. 15.1 months (95% C.I. 11.1-19.2), p = 0.047). There was no significant difference in OS among patients with primary resistance to prior ICI regimes compared to those with acquired resistance (primary resistance 8.28 months (95% C.I. 5.04-11.5) vs. acquired resistance 8.90 months (95% C.I. 3.49-14.3), p = 0.472). Overall, 67.7% and 6.5% of patients experienced TRAEs of all grade and grade ≥3 respectively. The most common TRAE was hand-foot syndrome. 62.5% of single agent cabozantinib patients had any grade TRAE and no such patients had grade ≥3 TRAE. Conclusions: Cabozantinib had good anti-tumour activity and survival outcomes with acceptable toxicity in aHCC patients with previous treatment by ICIs.

Tivozanib combined with nivolumab: Phase Ib/II study in metastatic renal cell carcinoma (mRCC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 618-618 ◽  
Author(s):  
Bernard Escudier ◽  
Philippe Barthelemy ◽  
Alain Ravaud ◽  
Sylvie Negrier ◽  
Michael N. Needle ◽  
...  
Keyword(s):  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Elevated Serum ◽  
Safety Data ◽  
Growth Factor Receptor ◽  
High Specificity ◽  
Serum Lipase ◽  
Phase Ib ◽  
Grade 3

618 Background: Tivozanib is a VEGFR-TKI with high specificity and lower incidence of class effect adverse events. As combinations of vascular endothelial growth factor receptor tyrosine kinase inhibitiors (VEGFR-TKIs) and checkpoint inhibitors have proven to be toxic, alternatives with an improved AE profile are required. We present safety data from a phase Ib/II combination of tivozanib and nivolumab Methods: In this phase Ib/II study, tivozanib was administered orally at two dose levels, 1.0 mg and 1.5 mg, once daily for 21 days every 28 day cycle in combination with nivolumab 240 mg every 14 days intravenously. Results: Eighteen patients have been enrolled. Phase Ib is complete. Safety data is available for 13, 3 at 1.0 mg tivo; 10 at 1.5 mg tivo. The median age was 62; 11 patients were ECOG 0 and 5 ECOG 1; and there were 13 males. 16 had clear cell histology No patient in phase Ib experienced an DLT in cycle 1. Patients in phase II are receiving tivozanib at 1.5 mg. All patients experienced at least one AE. The most common adverse events were hypertension, asthenia, mucositis, diarrhea, hand foot syndrome, arthralgia, and pruritis. Five patients (38%) had grade 3-4 AEs. One patient had both elevated serum lipase and amylase and one patient had an SAE of symptomatic malignant hypertension complicated by a seizure. The other grade 3-4 AEs were pneumonitis, stomatitis, and elevated ALT. Conclusions: As expected from a VEGFR-TKI with high specificity and a preferable toxicity pattern as a single agent, the combination of tivozanib with nivolumab is safe and manageable at full dose of both drugs. Efficacy is pending. This data is based on limited exposure and should be interpreted with caution. Additional patients are being enrolled and treated. This begs the question if tivozanib could be added to a triple combination with ipilimumab and nivolumab. Clinical trial information: NCT03136627. [Table: see text]

NKTR-214 + nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): Updated results from PIVOT-02.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 388-388 ◽  
Author(s):  
Arlene O. Siefker-Radtke ◽  
Mayer N. Fishman ◽  
Arjun Vasant Balar ◽  
Giovanni Grignani ◽  
Adi Diab ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Unmet Need ◽  
Standard Of Care ◽  
Target Lesion ◽  
Clinical Activity ◽  
First Line ◽  
Evaluable Population ◽  
Grade 3 ◽  
Tumor Biopsies

388 Background: Single-agent checkpoint inhibitors have changed the mUC treatment landscape; however, unmet need remains in first-line (1L) cisplatin ineligible mUC, particularly for PD-L1 negative (–) patients (pts). NKTR-214 is a CD122-biased agonist designed to provide sustained signaling through the IL-2 βγ receptor. PIVOT-02 is an ongoing study of NKTR-214 + nivolumab (nivo) in pts with advanced cancers, including mUC. Methods: Pts with mUC who were 1L cisplatin ineligible or refused standard of care (SOC) received NKTR-214 IV 0.006 mg/kg + nivo IV 360 mg q3w. Responses were assessed every 8 wks. Matched blood and tumor biopsies were evaluated for biomarkers including PD-L1 expression (assessed by Dako 28-8 PharmaDx IHC; PD-L1+ defined as ≥ 1% tumor cell staining). Results: As of 11 Oct. 2018, 34 pts received ≥ 1 dose of treatment (cisplatin ineligible [n=22]; refused SOC [n=12]). Median age was 70. Of 34 pts, 23 were efficacy evaluable (defined per protocol as having ≥ 1 post-treatment scan), 7 were pending a first scan, 1 pt was excluded for non-eligibility (no target lesion), and 3 discontinued prior to first scan. Thresholds for efficacy were exceeded in all 1L mUC cohorts under a pre-specified Fleming ORR analysis. In the efficacy evaluable population, overall ORR was 48% (11/23; 95% CI 27–69%) with a 17% CR rate (4/23) and 70% (16/23) DCR. The ORR was 50% in PD-L1– pts (5/10; 95% CI 19–81%) and 56% in PD-L1+ pts (5/9; 95% CI 21–86%). PD-L1 status was unknown in 4 efficacy-evaluable pts. The most common treatment-related AEs (TRAE, >30%) were fatigue (59%), pyrexia (38%), chills (32%), and flu-like symptoms (32%). Grade ≥ 3 TRAEs occurred in 18% of pts and 8.8% discontinued due to TRAEs. No G4/G5 TRAEs occurred. 22 pts had available baseline PD-L1 results (PD-L1+ [n=11]; PD-L1– [n=11]). 10 of the 11 PD-L1– baseline samples had matched wk 3 biopsies. Of these, 6/10 (60%) converted to PD-L1+ at wk 3. Updated results will be presented. Conclusions: NKTR-214 + nivo showed encouraging clinical activity, including CRs, and an acceptable preliminary safety profile in pts with mUC. Efficacy appears independent of PD-L1 status with a similar ORR in PD-L1– and + tumors. These data support further evaluation of the combination. Clinical trial information: NCT02983045.

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