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]

A randomized phase II trial with gemcitabine with or without pertuzumab (rhuMAb 2C4) in platinum-resistant ovarian cancer (OC): Preliminary safety data

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13001-13001 ◽  
Author(s):  
D. Glenn ◽  
F. Ueland ◽  
A. Bicher ◽  
D. Dizon ◽  
M. Gold ◽  
...  
Keyword(s):  
Adverse Events ◽  
Controlled Trial ◽  
Single Agent ◽  
Safety Data ◽  
Study Drug ◽  
Hematological Toxicity ◽  
Serious Adverse Events ◽  
Platinum Resistant ◽  
Platinum Based Chemotherapy ◽  
Grade 3

13001 Background: Pertuzumab (P), a humanized HER2 antibody, represents a new class of targeted agents called HER dimerization inhibitors (HDIs). P inhibits dimerization of HER2 with EGFR, HER3 and HER4, and subsequently inhibits signaling through MAP and PI3 kinases. Single agent P has demonstrated clinical benefit in advanced OC (ASCO 2005 abstract #5051). Methods: 40 pts with platinum-resistant OC (progressed within 6 months of receiving a platinum-based chemotherapy) were enrolled in this 1:1 randomized, double blind, placebo controlled trial of gemcitabine with or without P. Gemcitabine was administered IV on day 1 and 8 at 800 mg/m2 of a 21 day cycle. Blinded placebo or 420 mg P was administered IV on day 1. Gemcitabine was dose reduced for neutropenia or thrombocytopenia. P was not dose reduced. Results: 40 pts have been enrolled and treated with at least 1 cycle of gemcitabine in combination with blinded study drug. The median age was 58.5 (range 18–82); 26 had PS ECOG 0, 13 ECOG 1, 1 ECOG 2. The most common grade 3/4 events were neutropenia in 7 pts (17.5%), thrombocytopenia in 6 pts (15%), small bowel obstruction in 4 pts (10%), constipation in 3 pts (7.5%) and elevated ALT in 3 pts (7.4%). There was one grade 3 diarrhea, but no grade 3 or 4 rash. There were 4 serious adverse events (SAEs) attributed to study drug. These were a pleural effusion, thrombocytopenia, febrile neutropenia, and a deep vein thrombosis. Nine pts required one or two dose reductions of gemcitabine for hematological toxicity. Of 29 pts with post-baseline echo or MUGA values obtained, no pt had LVEF drop to <50%. The adverse events evaluated after 40 pts did not meet the prespecified criteria to call for an independent safety monitoring board evaluation of unblinded data. Conclusions: Preliminary safety data indicate that pertuzumab or placebo combined with gemcitabine is well tolerated with no unexpected additive toxicity. The nature and frequency of the adverse events are similar to what has been observed with either single agent gemcitabine or P. Updated data will be presented at ASCO. [Table: see text]

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.

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.

Comparative efficacy, safety, and tolerability of immune checkpoint inhibitors (ICIs) in cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15151-e15151
Author(s):  
Laith Al-Showbaki ◽  
Michelle Nadler ◽  
Alexandra Desnoyers ◽  
Fahad Almugbel ◽  
David W. Cescon ◽  
...  
Keyword(s):  
Adverse Events ◽  
Urothelial Cancer ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Single Agent ◽  
Similar Efficacy ◽  
Microsoft Excel ◽  
Serious Adverse Events ◽  
Comparative Safety ◽  
Grade 3

e15151 Background: Multiple ICIs have been approved, and in some diseases there is a choice of more than one ICI. The comparative safety, efficacy, and tolerability are not known. Here we report on a network meta-analysis comparing different ICIs targeting PD1 or PDL1. Methods: Randomized trials (RCTs) supporting the registration of a single agent anti-PD1 or anti-PDL1 inhibitors between 2015-2019 were identified. We extracted the hazard ratio (HR) for overall survival (OS) and calculated the odds ratio (OR) for commonly reported safety and tolerability outcomes. We then performed a network meta-analysis including only disease sites in which more than one ICI has been approved. Multiple pair-wise comparisons were then performed. When more than 2 comparisons were available for a pair of ICIs these were pooled into a single estimate. Analyses were performed in Microsoft Excel and RevMan 5.3. Results: Of 16 RCTs included, 10 in non-small-cell lung cancer, 2 in melanoma, 2 in head and neck squamous cell carcinoma and 2 in urothelial cancer. There was a total of 10673 patients in the analysis. Compared to pembrolizumab, efficacy was similar for nivolumab (HR 1.06, 95% CI 0.97-1.16) and for atezolizumab (HR 1.05, 95% CI 0.93-1.20). However, avelumab appeared inferior (HR 1.29, 95% CI 1.07-1.57). Pembrolizumab showed similar odds of serious adverse events (SAEs) as nivolumab (OR 1.12, 95% CI 0.56-2.27) and atezolizumab (OR 1.05, 95% CI 0.55-2.04). However, compared to nivolumab, atezolizumab was associated with more SAEs (OR 2.14, 95% CI 1.47-3.12). Avelumab had the lowest odds of grade 3-4 adverse events compared to pembrolizumab (OR 0.42, 95% CI 0.24-0.74), nivolumab (OR 0.38, 95% CI 0.24-0.62) and atezolizumab (OR 0.21, 95% CI 0.14-0.33). Atezolizumab was associated with more grade 3-4 adverse events than nivolumab (OR 1.84, 95% CI 1.37-2.47). The odds of treatment discontinuation without progression were similar between nivolumab and atezolizumab (OR 1.20, 95% CI 0.73-2.00), but higher with pembrolizumab compared to nivolumab (OR 1.35, 95% CI 0.83-2.17) and atezolizumab (OR 2.56, 95% CI 1.29-5.00). Pembrolizumab was associated with higher OR of immune related adverse events (IRAEs) compared to nivolumab (OR 2.12, 95% CI 1.49-3.03) and atezolizumab (OR 1.63, 95% CI 1.09-2.43), while the OR of IRAEs was almost similar between nivolumab and atezolizumab. Conclusions: Pembrolizumab, nivolumab, and atezolizumab have similar efficacy. Avelumab appears efficacious. Safety and tolerability seem better with avelumab, but worse with atezolizumab and pembrolizumab.

A Phase Ib Dose-Finding Study of Oral Panobinostat In Combination with Cytarabine (ara-C) and Mitoxantrone as Salvage Therapy for Refractory or Relapsed Acute Myeloid Leukemia (AML)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3310-3310
Author(s):  
Jürgen Krauter ◽  
Richard F. Schlenk ◽  
Markus Schaich ◽  
Didier Bouscary ◽  
Hervé Dombret ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Fixed Dose ◽  
Phase Ib ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Abstract 3310 Background: Panobinostat (PAN) is an oral pan-deacetylase inhibitor (pan-DACi) that increases acetylation of a series of proteins such as HSP90, p53, α-tubulin and HIF-1α which are involved in cell cycle regulation, gene transcription, angiogenesis, and tumor cell survival. Preclinical studies demonstrated that PAN potentiates the activity of cytarabine (ara-C) and fludarabine and has synergistic activity in combination with doxorubicin in AML cell lines and patient (pt) blast cells. Clinical activity of single-agent PAN has been demonstrated in a phase I trial, including complete responses in pts with AML. Acute myeloid leukemia (AML) is associated with a poor prognosis, particularly in pts with relapsed or refractory disease. The addition of PAN to a chemotherapeutic regimen that is active in pts with AML who have relapsed or are refractory to prior induction therapy has the potential to improve therapeutic outcomes in this setting. Methods: This phase Ib, multicenter, open-label study is comprised of 3 parts: 1) dose-escalation to determine the maximum tolerated dose (MTD) of PAN in combination with ara-C and mitoxantrone, 2) dose-expansion to assess safety and preliminary activity at the MTD, and 3) optional dose extension to assess safety of single-agent PAN (60 mg thrice weekly) in pts who responded but are not eligible for other therapies. The primary objective is to determine the MTD of PAN in combination with a fixed dose of ara-C and mitoxantrone. The primary endpoint is incidence of dose-limiting toxicities (DLTs) within the first treatment cycle. Secondary and exploratory objectives include assessment of the safety profile of PAN and evaluation of anti-leukemic activity. Adult pts with AML (WHO criteria) who are relapsed or refractory to 1 prior treatment regimen with an ECOG PS ≤2 were eligible for enrollment on the study. PAN was orally administered (20 mg starting dose) thrice weekly on Days (D) 1, 3, 5, 8, 10, and 12, in combination with iv ara-C (1 g/m2) D1–6, and iv mitoxantrone (5 mg/m2) D1–5 of a 28-D cycle (C). Pts can receive a maximum of 3 cycles of combination therapy. Pts who are eligible for the optional dose extension part received single-agent PAN (60 mg thrice weekly). Results: As of July 29, 2010, 23 pts have been enrolled, 5 in cohort 1 (20 mg PAN), 8 in cohort 2 (30 mg PAN), and 10 in cohort 3 (40 mg PAN). Safety and efficacy analyses are based on 18 pts. The median age of the pts was 53.5 years (range 19–72). Prior to treatment, all had received ara-C. One DLT has been observed (sepsis and tachyarrhythmia) in the 40 mg cohort. Adverse events were observed with 16 pts (89%): hematologic adverse events (AEs) were observed in 12 pts (67%): including thrombocytopenia, febrile neutropenia, anemia, leukopenia and neutropenia. Non-hematologic AEs included: general disorders and administration site conditions (16 [89%]), gastrointestinal and metabolism/nutrition disorders (15 [83%] each), infections (12 [67%]), respiratory/thoracic disorders (11 [61%]), vascular and skin/subcutaneous tissue disorders (10 [56%] each) and cardiac disorders (8 [44%]). Most frequent Grade 3/4 adverse events (AEs) observed in all cohorts to date were hematologic, including febrile neutropenia and thrombocytopenia (8 [44%] each), leukopenia (5 [28%]), anemia and neutropenia (4 [22%] each). Grade 3/4 AEs suspected to be study treatment related were mostly related to thrombocytopenia (6 [33%]) and neutropenia (4 [22%]). Serious AEs were observed in all cohorts, with most related to infectious complications (8 [44%]), febrile neutropenia (6 [33%]) pneumonia and fungal pneumonia (2 [11%]). QTcF prolongation of ≥480 ms (but < 500 ms) was observed in 2 pts (11%), but no pt demonstrated QTcF prolongation of > 500 ms. Encouraging clinical efficacy was observed, especially with higher doses of PAN, with 8 responders (partial response [PR] or better) (44%): 3 complete remissions (CR), 2 complete remissions with incomplete blood count recovery (CRi) and 3 partial responses (PR). Conclusions: The MTD of PAN in combination with ara-C and mitoxantrone has not been reached, and the study is ongoing. The current data show that the addition of PAN to ara-C and mitoxantrone is safe with no unexpected toxicities and showing promising activity in refractory or relapsed AML pts. Updated data, including safety and preliminary efficacy data will be presented at the meeting. Disclosures: Krauter: Novartis: Research Funding. Off Label Use: Panobinostat is an investigational agent currently being evaluated for the treatment of hematologic and solid malignancies. Schlenk:Novartis: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Amgen: Research Funding; Cephalon: Research Funding. Winiger:Novartis Pharma AG: Employment. Squier:Novartis: Employment. Bengoudifa:Novartis Pharma AG: Employment. Ottmann:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3629
Author(s):  
Hsiao-Ling Chen ◽  
Yu-Kang Tu ◽  
Hsiu-Mei Chang ◽  
Tai-Huang Lee ◽  
Kuan-Li Wu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Small Cell ◽  
Randomized Controlled ◽  
Extensive Stage ◽  
Grade 3

Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary endpoints in terms of overall survival (OS), progression free survival (PFS), and objective response rate (ORR), as well as our secondary endpoint in terms of adverse events. The fractional polynomial model was used to evaluate the adjusted hazard ratios for the survival indicators (OS and PFS). Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being best (Prbest) reference. EP plus nivolumab, atezolizumab or durvalumab had significant benefits compared with EP alone in terms of OS (Hazard Ratio HR = 0.67, 95% Confidence Interval CI = 0.46–0.98 for nivolumab, HR = 0.70, 95% CI = 0.54–0.91 for atezolizumab, HR = 0.73, 95% CI = 0.59–0.90 for durvalumab) but no significant differences were observed for pembrolizumab or ipilimumab. The probability of nivolumab being ranked first among all treatment arms was highest (SCURA = 78.7%, Prbest = 46.7%). All EP plus ICI combinations had a longer PFS compared with EP alone (HR = 0.65, 95% CI = 0.46–0.92 for nivolumab, HR = 0.77, 95% CI = 0.61–0.96 for atezolizumab, HR = 0.78, 95% CI = 0.65–0.94 for durvalumab, HR = 0.75, 95% CI = 0.61–0.92 for pembrolizumab), and nivolumab was ranked first in terms of PFS (SCURA = 85.0%, Prbest = 66.8%). In addition, nivolumab had the highest probability of grade 3–4 adverse events (SUCRA = 84.8%) in our study. We found that nivolumab had the best PFS and OS in all combinations of ICIs and EP, but nivolumab also had the highest probability of grade 3–4 adverse events in our network meta-analysis. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions.

Immune-related adverse events associated with immune checkpoint inhibitors in patients with cancer

2020 ◽  
pp. 030089162095346
Author(s):  
Nilay Sengul Samanci ◽  
Duygu Ilke Cikman ◽  
Kerem Oruc ◽  
Sahin Bedir ◽  
Emir Çelik ◽  
...  
Keyword(s):  
Adverse Events ◽  
Health Care Providers ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Care Providers ◽  
Patients With Cancer ◽  
Combination Treatments ◽  
Grade 3

Introduction: With the widespread use of immune checkpoint inhibitors (ICIs), we are facing challenges in the management of immune-related adverse events (irAEs). We aimed to characterize the spectrum of toxicity, management, and outcomes for irAEs. Methods: Patients who were treated with at least one ICI in clinical trials, expanded access programs, or routine clinical practice were included. Clinical and laboratory parameters were collected retrospectively to determine the incidence of irAEs, methods of management, and treatment outcomes. Results: A total of 255 patients were screened retrospectively. Of these, 71 (27.8%) patients developed irAEs. More than 2 different types of irAEs were detected in 16 (6.2%) out of 255 patients. A total of 3177 doses were given to 255 patients. In 93 (2.9%) of the 3177 doses, 1 episode of irAEs was experienced. A total of 22 out of 93 (23.7%) episodes were reported as grade 1, 49 (52.7%) as grade 2, 19 (20.4%) as grade 3, and 3 (3.2%) as grade 4. The most frequently seen irAEs were pneumonitis, hepatitis, and hypothyroidism. With regard to treatment, 39 out of 93 episodes (42%) of any grade irAEs occurred after anti–programmed cell death-1 therapy, 47 (50.5%) occurred following administration of anti–programmed death-ligand 1, and 7 (7.5%) occurred after combination treatments. Conclusion: With the increased use of immunotherapeutic agents, increased awareness and early recognition are required for effective management of irAEs. Our experience as a single institution might be of use for health care providers in oncology.

scholarly journals Comparative risk of serious and fatal treatment-related adverse events caused by 19 immune checkpoint inhibitors used in cancer treatment: a network meta-analysis

2020 ◽  
Vol 12 ◽  
pp. 175883592094092 ◽  
Author(s):  
Tingting Liu ◽  
Bo Jin ◽  
Jun Chen ◽  
Hui Wang ◽  
Shuiyu Lin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cancer Treatment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Combinatorial Therapy ◽  
Grade 5 ◽  
Comparative Risk ◽  
Grade 3

Background: This network meta-analysis assessed the comparative risk of grade 3–5 and grade 5 treatment-related adverse events (TRAEs) for immune checkpoint inhibitors (ICIs), either alone or in combination with other modalities, for cancer treatment. Methods: PubMed, Embase, Cochrane Library, Web of Science, and recent predominant oncology congresses were searched for relevant phase II and phase III randomized controlled trials (RCTs). As outcomes, grade 3–5, and grade 5 TRAE outcomes were reported as odds ratios and 95% confidence intervals. Results: In 67 RCTs involving 36,422 patients and 19 ICIs, the incidence of grade 3–5 and grade 5 TRAEs was 17.9% and 0.8% with ICI monotherapy and 46.3% and 1.4%, respectively, with combinatorial therapy. Pneumonitis was the most common cause of grade 5 TRAEs following either monotherapy (16.3%) or combinatorial therapy (11.4%). Regarding grade 3–5 TRAEs, atezolizumab + chemotherapy (CT) and antiangiogenic therapy (AT) (atezolizumab + CAT), pembrolizumab + CT, ipilimumab + CT, and atezolizumab + CT were more toxic than any ICI monotherapy, pembrolizumab or nivolumab + radiotherapy (RT), and ICIs dual therapy (durvalumab + tremelimumab and nivolumab + ipilimumab). Tremelimumab, ipilimumab, durvalumab, and pembrolizumab were, however, associated with higher grade 5 TRAEs than combinatorial treatments. Atezolizumab + CAT was the most toxic and nivolumab + RT was the least toxic of combinatorial treatments; among monotherapies, tremelimumab and avelumab were the most and least toxic, respectively. The toxicity ranking changed with type of grade 3–5 TRAEs. Conclusions: Compared with combinatorial therapy, ICI monotherapy caused lower grade 3–5 TRAEs, but some monotherapies resulted in a higher incidence of fatal TRAEs. Atezolizumab + CAT and nivolumab + RT were the most and least toxic of combinatorial treatments, respectively, and tremelimumab and avelumab were the most and least toxic of the monotherapies, respectively.

scholarly journals Treatment Outcomes of Immune-Related Cutaneous Adverse Events

2019 ◽  
Vol 37 (30) ◽  
pp. 2746-2758 ◽  
Author(s):  
Gregory S. Phillips ◽  
Jennifer Wu ◽  
Matthew D. Hellmann ◽  
Michael A. Postow ◽  
Naiyer A. Rizvi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Odds Ratio ◽  
Immunoglobulin E ◽  
Checkpoint Inhibitors ◽  
Tertiary Care ◽  
Laboratory Data ◽  
Maculopapular Rash ◽  
Clinicopathologic Characteristics ◽  
Systemic Treatments ◽  
Grade 3

PURPOSE The aim of the current study was to report the efficacy of topical and systemic treatments for immune-related cutaneous adverse events (ircAEs) attributed to checkpoint inhibitors in an uncontrolled cohort of patients referred to oncodermatology clinics. METHODS A retrospective analysis of patients with ircAEs evaluated by dermatologists from January 1, 2014, to December 31, 2017, at three tertiary care hospitals and cancer centers were identified through electronic medical records. Clinicopathologic characteristics, dermatologic therapy outcome, and laboratory data were analyzed. RESULTS A total of 285 patients (median age, 65 years [range, 17 to 89 years]) with 427 ircAEs were included: pruritus (n = 138; 32%), maculopapular rash (n = 120; 28%), psoriasiform rash (n = 22; 5%), and others (n = 147; 34%). Immune checkpoint inhibitor class was associated with ircAE phenotype ( P = .007), where maculopapular rash was predominant in patients who received combination therapy. Severity of ircAEs was significantly reduced (mean Common Terminology Criteria for Adverse Events grade: 1.74 v 0.71; P < .001) with dermatologic interventions, including topical corticosteroids, oral antipruritics, and systemic immunomodulators. A total of 88 ircAEs (20%) were managed with systemic immunomodulators. Of these, 22 (25%) of 88 persisted or worsened. In seven patients with corticosteroid-refractory ircAEs, improvement resulted from targeted biologic immunomodulatory therapies that included rituximab and dupilumab. Serum interleukin-6 (IL-6) was elevated in 34 (52%) of 65 patients; grade 3 or greater ircAEs were associated with increased absolute eosinophils (odds ratio, 4.1; 95% CI, 1.3 to 13.4) and IL-10 (odds ratio, 23.8; 95% CI, 2.1 to 262.5); mean immunoglobulin E serum levels were greater in higher-grade ircAEs: 1,093 kU/L (grade 3), 245 kU/L (grade 2), and 112 kU/L (grade 1; P = .043). CONCLUSION Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL-6, IL-10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.

Sign in / Sign up

Export Citation Format

Share Document