Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results

Sharma, Padmanee; Siefker-Radtke, Arlene; Braud, Filippo de; Basso, Umberto; Calvo, Emiliano; Bono, Petri; Morse, Michael A.; Ascierto, Paolo A.; López-Martín, José A.; Brossart, Peter; Rohrberg, Kristoffer Staal; Mellado, Begoña; Fischer, Bruce S.; Meadows–Shropshire, S.; Saci, Abdel; Callahan, Margaret K.; Rosenberg, Jonathan E.

doi:10.1200/jco.19.00538

Cited by 200 publications

(210 citation statements)

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“…After removing duplicates, 1,352 studies were assessed for abstract and full-text review. Finally, 10 studies involving eight RCTs were included in this meta-analysis (Larkin et al, 2015;Postow et al, 2015;Antonia et al, 2016;Hodi et al, 2016;Wolchok et al, 2017;D'angelo et al, 2018;Hellmann et al, 2018b;Long et al, 2018;Omuro et al, 2018;Sharma et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…In the combination group, all the patients received intervention with nivolumab and ipilimumab. Three studies compared the efficacy of two different doses of drug combinations: nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) (Antonia et al, 2016;Omuro et al, 2018;Sharma et al, 2019). In the monotherapy group, patients received intervention with either ipilimumab (Larkin et al, 2015;Postow et al, 2015;Hodi et al, 2016;Wolchok et al, 2017) or nivolumab alone (Larkin et al, 2015;Antonia et al, 2016;Wolchok et al, 2017;D'angelo et al, 2018;Hellmann et al, 2018b;Long et al, 2018;Omuro et al, 2018;Sharma et al, 2019).…”

Section: The Characteristics and Quality Assessment Of Included Rctsmentioning

confidence: 99%

“…Three studies compared the efficacy of two different doses of drug combinations: nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) (Antonia et al, 2016;Omuro et al, 2018;Sharma et al, 2019). In the monotherapy group, patients received intervention with either ipilimumab (Larkin et al, 2015;Postow et al, 2015;Hodi et al, 2016;Wolchok et al, 2017) or nivolumab alone (Larkin et al, 2015;Antonia et al, 2016;Wolchok et al, 2017;D'angelo et al, 2018;Hellmann et al, 2018b;Long et al, 2018;Omuro et al, 2018;Sharma et al, 2019). The included RCTs involved five kinds of tumors: lung cancer in two studies (Antonia et al, 2016;Hellmann et al, 2018b), melanoma in three studies (Larkin et al, 2015;Postow et al, 2015;Hodi et al, 2016;Wolchok et al, 2017;Long et al, 2018), metastatic sarcoma in one study (D'angelo et al, 2018), urothelial carcinoma (Sharma et al, 2019), and recurrent glioblastoma in one study (Omuro et al, 2018).…”

Section: The Characteristics and Quality Assessment Of Included Rctsmentioning

confidence: 99%

“…Five studies involving 1524 patients were included for metaanalysis (Antonia et al, 2016;Wolchok et al, 2017;Long et al, 2018;Omuro et al, 2018;Sharma et al, 2019). The incidences of any-grade hyperthyroidism were 9.3% (64/689) vs 3.0% (25/835) in the combination vs monotherapy group; and 3-5 grade were 0.4% (3/689) vs 0% (0/835) in the combination vs monotherapy group.…”

Section: Meta-analysis Of Any-grade and 3-5 Grade Hyperthyroidismmentioning

confidence: 99%

“…The incidences of IRAEs based on drugs (nivolumab alone, ipilimumab alone, and nivolumab plus ipilimumab) were summarized in Table 4. In the combination group, three studies included two different doses of drug combinations: nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) (Antonia et al, 2016;Omuro et al, 2018;Sharma et al, 2019). The subgroups analysis showed that there was no difference in the incidence of total any-grade organ-specific IRAEs between N3I1 and N1I3 groups (RR, 0.99; 95% CI, 0.89-1.09; p = 0.84), but the incidence of the total 3-5 grade IRAEs was significantly higher in the N1I3 group (RR, 1.70; 95% CI, 1.25-2.30; p < 0.05).…”

Section: Different Drug Dosesmentioning

confidence: 99%

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Organ-Specific Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitor Monotherapy Versus Combination Therapy in Cancer: A Meta-Analysis of Randomized Controlled Trials

Teng

Wang

et al. 2020

Front. Pharmacol.

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Background: Although combination therapy with immune checkpoint inhibitors (ICIs) provides a promising efficacy in multiple cancers, their use is facing challenges for a high incidence of adverse effects. This meta-analysis was conducted to compare the risks of organ-specific immune-related adverse events (IRAEs) associated with ICI monotherapy versus combination therapy among cancer patients.Methods: Electronic databases were systematically searched to include eligible randomized controlled trials (RCTs). Any-grade and 3-5 grade IRAEs (colitis, pneumonitis, hepatitis, hypothyroidism, hyperthyroidism, and hypophysitis) were extracted for meta-analysis. Two reviewers independently assessed the methodological quality. The RevMan 5.3.5 software was used for meta-analysis.Results: A total of 10 studies involving 8 RCTs with 2716 patients were included in this study. The most common any-grade adverse event was colitis (14.5%), followed by hypothyroidism (13.8%), hepatitis (10.4%), hypophysitis (10.0%), hyperthyroidism (9.3%), and pneumonitis (4.6%). Meta-analysis showed that ICI combination therapy significantly increased the risks of any-grade IRAEs in colitis [relative risk (RR), 3.56; 95% confidence interval (CI), 1.56-8.12; p < 0.05], pneumonitis (RR, 2.31; 95% CI, 1.54-3.45; p < 0.05), hepatitis (RR, 2.54; 95% CI, 1.65-3.91; p < 0.05), hypothyroidism (RR, 2.17; 95% CI, 1.71-2.76; p < 0.05), hyperthyroidism (RR, 3.13; 95% CI, 2.08-4.70; p < 0.05), and hypophysitis (RR, 3.54; 95% CI, 2.07-6.07; p < 0.05) compared with ICI monotherapy, as well as 3-5 grade IRAEs in colitis (RR, 2.50; 95% CI, 1.62-3.86; p < 0.05), pneumonitis (RR, 1.99; 95% CI, 1.00-3.93; p = 0.05), and hepatitis (RR, 2.70; 95% CI, 1.29-5.63; p < 0.05). Conclusions:This meta-analysis demonstrated that, compared with ICI monotherapy, patients receiving ICI combination therapy significantly increased organ-specific IRAEs in colitis, hypothyroidism, hepatitis, hypophysitis, hyperthyroidism, and pneumonitis. The incidence and severity of organ-specific IRAEs were drug and dose independent.

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Section: Discussionmentioning

confidence: 99%

Section: The Characteristics and Quality Assessment Of Included Rctsmentioning

confidence: 99%

Section: The Characteristics and Quality Assessment Of Included Rctsmentioning

confidence: 99%

Section: Meta-analysis Of Any-grade and 3-5 Grade Hyperthyroidismmentioning

confidence: 99%

Section: Different Drug Dosesmentioning

confidence: 99%

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Organ-Specific Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitor Monotherapy Versus Combination Therapy in Cancer: A Meta-Analysis of Randomized Controlled Trials

Teng

Wang

et al. 2020

Front. Pharmacol.

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Changes in Health Care Costs, Survival, and Time Toxicity in the Era of Immunotherapy and Targeted Systemic Therapy for Melanoma

Bateni,

Nguyen,

Eskander

et al. 2023

JAMA Dermatol

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ImportanceMelanoma treatment has evolved during the past decade with the adoption of adjuvant and palliative immunotherapy and targeted therapies, with an unclear impact on health care costs and outcomes in routine practice.ObjectiveTo examine changes in health care costs, overall survival (OS), and time toxicity associated with primary treatment of melanoma.Design, Setting, and ParticipantsThis cohort study assessed a longitudinal, propensity score (PS)–matched, retrospective cohort of residents of Ontario, Canada, aged 20 years or older with stages II to IV cutaneous melanoma identified from the Ontario Cancer Registry from January 1, 2018, to March 31, 2019. A historical comparison cohort was identified from a population-based sample of invasive melanoma cases diagnosed from the Ontario Cancer Registry from January 1, 2007, to December 31, 2012. Data analysis was performed from October 17, 2022, to March 13, 2023.ExposuresEra of melanoma diagnosis (2007-2012 vs 2018-2019).Main Outcomes and MeasuresThe primary outcomes were mean per-capita health care and systemic therapy costs (Canadian dollars) during the first year after melanoma diagnosis, time toxicity (days with physical health care contact) within 1 year of initial treatment, and OS. Standardized differences were used to compare costs and time toxicity. Kaplan-Meier methods and Cox proportional hazards regression were used to compare OS among PS-matched cohorts.ResultsA PS-matched cohort of 731 patients (mean [SD] age, 67.9 [14.8] years; 437 [59.8%] male) with melanoma from 2018 to 2019 and 731 patients (mean [SD] age, 67.9 [14.4] years; 440 [60.2%] male) from 2007 to 2012 were evaluated. The 2018 to 2019 patients had greater mean (SD) health care (including systemic therapy) costs compared with the 2007 to 2012 patients ($47 886 [$55 176] vs $33 347 [$31 576]), specifically for stage III ($67 108 [$57 226] vs $46 511 [$30 622]) and stage IV disease ($117 450 [$79 272] vs $47 739 [$37 652]). Mean (SD) systemic therapy costs were greater among 2018 to 2019 patients: stage II ($40 823 [$40 621] vs $10 309 [$12 176]), III ($55 699 [$41 181] vs $9764 [$12 771]), and IV disease ($79 358 [$50 442] vs $9318 [$14 986]). Overall survival was greater for the 2018 to 2019 cohort compared with the 2007 to 2012 cohort (3-year OS: 74.2% [95% CI, 70.8%-77.2%] vs 65.8% [95% CI, 62.2%-69.1%], hazard ratio, 0.72 [95% CI, 0.61-0.85]; P &lt; .001). Time toxicity was similar between eras. Patients with stage IV disease spent more than 1 day per week (&gt;52 days) with physical contact with the health care system by 2018 to 2019 (mean [SD], 58.7 [43.8] vs 44.2 [26.5] days; standardized difference, 0.40; P = .20).Conclusions and RelevanceThis cohort study found greater health care costs in the treatment of stages II to IV melanoma and substantial time toxicity for patients with stage IV disease, with improvements in OS associated with the adoption of immunotherapy and targeted therapies. These health system–wide data highlight the trade-off with adoption of new therapies, for which there is a greater economic burden to the health care system and time burden to patients but an associated improvement in survival.

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Significance of PD-L1 in Metastatic Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors

Maiorano,

Di Maio,

Cerbone

et al. 2024

JAMA Netw Open

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ImportanceImmune checkpoint inhibitors (ICIs) have broadened the metastatic urothelial carcinoma (mUC) therapeutic scenario. The association of programmed death ligand 1 (PD-L1) with response and survival in patients treated with ICIs is still controversial.ObjectivesTo evaluate the association of PD-L1 with response rate and overall survival among patients with mUC treated with ICIs.Data SourcesPubMed, Embase, American Society of Clinical Oncology and European Society for Medical Oncology Meeting Libraries, and Web of Science were searched up to December 10, 2023.Study SelectionTwo authors independently screened the studies. Included studies were randomized and nonrandomized clinical trials enrolling patients with mUC receiving ICIs with available overall survival (OS), progression-free survival (PFS), or overall response rate (ORR) data, separated between patients with PD-L1–positive and –negative tumors.Data Extraction and SynthesisThe Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Two reviewers independently extracted data. Fixed- or random-effects models were used depending on the heterogeneity among the studies.Main Outcomes and MeasuresPrimary outcomes were odds ratios (ORs) for ORR and hazard ratios (HRs) for OS, comparing patients with PD-L1–positive tumors and patients with PD-L1–negative tumors. Secondary outcomes were the PFS HR between patients with PD-L1–positive and –negative tumors and OS HR between ICI arms and non-ICI arms of only randomized clinical trials.ResultsA total of 14 studies were selected, comprising 5271 patients treated with ICIs (2625 patients had PD-L1–positive tumors). The ORR was 13.8% to 78.6% in patients with PD-L1–positive tumors and 5.1% to 63.2% in patients with PD-L1–negative tumors, with an association between PD-L1 status and ORR favoring patients with PD-L1–positive tumors (OR, 1.94; 95% CI, 1.47-2.56; P &lt; .001). Median OS ranged from 8.4 to 24.1 months in patients with PD-L1–positive tumors and from 6.0 to 19.1 months in patients with PD-L1–negative tumors. The pooled HR showed a significant reduction for patients with PD-L1–positive tumors compared with those with PD-L1–negative tumors in the risk of death (HR, 0.71; 95% CI, 0.57-0.89; P = .003) and risk of progression (HR, 0.55; 95% CI, 0.44-0.69; P &lt; .001) when ICIs were administered. PD-L1 is not likely to be a predictive biomarker of ICI response.Conclusions and RelevanceThis systematic review and meta-analysis suggests that PD-L1 expression is associated with improved ORR, OS, and PFS for patients with mUC who receive ICIs, but it is unlikely to be useful as a predictive biomarker. Developing predictive biomarkers is essential to select patients most likely to benefit from ICIs and avoid toxic effects and financial burden with these agents.

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Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results

Cited by 200 publications

References 20 publications

Organ-Specific Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitor Monotherapy Versus Combination Therapy in Cancer: A Meta-Analysis of Randomized Controlled Trials

Organ-Specific Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitor Monotherapy Versus Combination Therapy in Cancer: A Meta-Analysis of Randomized Controlled Trials

Changes in Health Care Costs, Survival, and Time Toxicity in the Era of Immunotherapy and Targeted Systemic Therapy for Melanoma

Significance of PD-L1 in Metastatic Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors

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