Dataset Information

Systematic review and network meta-analysis of overall survival comparing 3 mg/kg ipilimumab with alternative therapies in the management of pretreated patients with unresectable stage III or IV melanoma.

ABSTRACT:

Objective

To compare the overall survival (OS) of patients treated with 3 mg/kg ipilimumab versus alternative systemic therapies in pretreated unresectable stage III or IV melanoma patients.

Methods

A systematic literature search was performed to identify relevant randomized clinical trials. From these trials, Kaplan-Meier survival curves for each intervention were digitized and combined by means of a Bayesian network meta-analysis (NMA) to compare different drug classes.

Results

Of 38 trials identified, 15 formed one interlinked network by drug class to allow for an NMA. Ipilimumab, at a dose of 3 mg/kg, was associated with a greater mean OS time (18.8 months; 95% credible interval [CrI], 15.5-23.0 months) than single-agent chemotherapy (12.3 months; 95% CrI, 6.3-28.0 months), chemotherapy combinations (12.2 months; 95% CrI, 7.1-23.3 months), biochemotherapies (11.9 months; 95% CrI, 7.0-22.0 months), single-agent immunotherapy (11.1 months; 95% CrI, 8.5-16.2 months), and immunotherapy combinations (14.1 months; 95% CrI, 9.0-23.8 months).

Conclusion

Results of this NMA were in line with previous findings and suggest that OS with ipilimumab is expected to be greater than with alternative systemic therapies, alone or in combination, for the management of pretreated patients with unresectable stage III or IV melanoma.

SUBMITTER: Dequen P

PROVIDER: S-EPMC3500357 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Systematic review and network meta-analysis of overall survival comparing 3 mg/kg ipilimumab with alternative therapies in the management of pretreated patients with unresectable stage III or IV melanoma.

Dequen Pascale P Lorigan Paul P Jansen Jeroen P JP van Baardewijk Marc M Ouwens Mario J N M MJ Kotapati Srividya S

The oncologist 20120928 11

<h4>Objective</h4>To compare the overall survival (OS) of patients treated with 3 mg/kg ipilimumab versus alternative systemic therapies in pretreated unresectable stage III or IV melanoma patients.<h4>Methods</h4>A systematic literature search was performed to identify relevant randomized clinical trials. From these trials, Kaplan-Meier survival curves for each intervention were digitized and combined by means of a Bayesian network meta-analysis (NMA) to compare different drug classes.<h4>Resul ...[more]

PMID: 23024154

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Project description:PURPOSE:CheckMate 032 is an open-label, multicohort study that includes patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) treated with nivolumab 3 mg/kg monotherapy every 2 weeks (NIVO3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO3+IPI1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO1+IPI3). We report on the expanded NIVO1+IPI3 cohort and extended follow-up for the NIVO3 and NIVO3+IPI1 cohorts. METHODS:Patients with platinum-pretreated mUC were enrolled in this phase I/II multicenter study to receive NIVO3, NIVO3+IPI1, or NIVO1+IPI3 until disease progression or unacceptable toxicity. Primary end point was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, including duration of response. RESULTS:Seventy-eight patients were treated with NIVO3 (minimum follow-up, 37.7 months), 104 with NIVO3+IPI1 (minimum follow-up, 38.8 months), and 92 with NIVO1+IPI3 (minimum follow-up, 7.9 months). Objective response rate was 25.6%, 26.9%, and 38.0% in the NIVO3, NIVO3+IPI1, and NIVO1+IPI3 arms, respectively. Median duration of response was more than 22 months in all arms. Grade 3 or 4 treatment-related adverse events occurred in 21 (26.9%), 32 (30.8%), and 36 (39.1%) patients treated with NIVO3, NIVO3+IPI1, and NIVO1+IPI3, respectively. Grade 5 treatment-related pneumonitis occurred in one patient each in the NIVO3 and NIVO3+IPI1 arms. CONCLUSION:With longer follow-up, NIVO3 demonstrated sustained antitumor activity alone and in combination with ipilimumab. NIVO1+IPI3 provided the greatest antitumor activity of all regimens, with a manageable safety profile. This result not only supports additional study of NIVO1+IPI3 in mUC, but demonstrates the potential benefit of immunotherapy combinations in this disease.

Project description:BACKGROUND:Neoadjuvant immunotherapy utilizing novel combinations has the potential to transform the standard of care for locally/regionally advanced melanoma. We hypothesized that neoadjuvant ipilimumab in combination with high dose IFN?2b (HDI) is safe and associated with durable pathologic complete responses (pCR). METHODS:Patients with locally/regionally advanced melanoma were randomized to ipilimumab 3 or 10 mg/kg ×?4 doses bracketing definitive surgery, then every 12 weeks ×?4. HDI was given concurrently. We evaluated the safety and efficacy of the combination with ipilimumab 3 or 10 mg/kg. The impact on T-cell fraction and clonality were investigated in tumor and blood. RESULTS:Thirty patients (age 37-76), 15 each at 3 and 10 mg/kg, 18 male and 12 female were treated. Considering immune related adverse events (irAEs) of interest, more grade 3/4 irAEs were seen with ipilimumab 10 mg/kg versus 3 mg/kg (p?=?0.042). Among 28 evaluable patients, 11 relapsed, of whom 5 died. Median follow-up for 17 patients who have not relapsed was 32 months. The radiologic preoperative response rate was 36% (95% CI, 21-54); 4 patients at ipilimumab 3 mg/kg and 6 at 10 mg/kg and 2 (at 10 mg/kg) later relapsed. The pCR was 32% (95% CI, 18-51); 5 patients at ipilimumab 3 mg/kg and 4 at 10 mg/kg and one (at 3 mg/kg) had a late relapse. In patients with pCR, T-cell fraction was significantly higher when measured in primary melanoma tumors (p?=?0.033). Higher tumor T-cell clonality in primary tumor and more so following neoadjuvant therapy was significantly associated with improved relapse free survival. CONCLUSIONS:Neoadjuvant ipilimumab-HDI was relatively safe and exhibited promising tumor response rates with an associated measurable impact on T-cell fraction and clonality. Most pCRs were durable supporting the value of pCR as a primary endpoint in neoadjuvant immunotherapy trials. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01608594 . Registered 31 May 2012.

Project description:In an international, randomized Phase III trial ipilimumab demonstrated a significant overall survival benefit in previously treated advanced melanoma patients. This report summarizes health-related quality of life (HRQL) outcomes for ipilimumab with/without gp100 vaccine compared to gp100 alone during the clinical trial's 12 week treatment induction period.The Phase III clinical trial (MDX010-20) was a double-blind, fixed dose study in 676 previously treated advanced unresectable stage III or IV melanoma patients. Patients were randomized 3:1:1 to receive either ipilimumab (3 mg/kg q3w x 4 doses)?+?gp100 (peptide vaccine; 1 mg q3w x 4 doses; ipilimumab plus gp100, n = 403); gp100 vaccine + placebo (gp100 alone, n = 136); or ipilimumab + placebo (ipilimumab alone, n = 137). The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed HRQL. Baseline to Week 12 changes in EORTC QLQ-C30 function, global health status, and symptom scores were analyzed for ipilimumab with/without gp100 vaccine compared to gp100 alone. Mean change in scores were categorized "no change" (0-5), "a little" (5-10 points), "moderate" (10-20 points), and "very much" (>20).In the ipilimumab plus gp100 and ipilimumab alone groups, mean changes from baseline to Week 12 generally indicated "no change" or "a little" impairment across EORTC QLQ-C30 global health status, function, and symptom subscales. Significant differences in constipation, favoring ipilimumab, were observed (p < 0.05). For ipilimumab alone arm, subscales with no or a little impairment were physical, emotional, cognitive, social function, global health, nausea, pain, dyspnea, constipation, and diarrhea subscales. For the gp100 alone group, the observed changes were moderate to large for global health, role function, fatigue, and for pain.Ipilimumab with/without gp100 vaccine does not have a significant negative HRQL impact during the treatment induction phase relative to gp100 alone in stage III or IV melanoma patients.Clinicaltrials.gov identification number NCT00094653.

Dataset Information

Systematic review and network meta-analysis of overall survival comparing 3 mg/kg ipilimumab with alternative therapies in the management of pretreated patients with unresectable stage III or IV melanoma.

Objective

Methods

Results

Conclusion

Publications

Systematic review and network meta-analysis of overall survival comparing 3 mg/kg ipilimumab with alternative therapies in the management of pretreated patients with unresectable stage III or IV melanoma.

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