Ipilimumab in a real‐world population: A prospective Phase IV trial with long‐term follow‐up

Abstract

Ipilimumab was the first treatment that improved survival in advanced melanoma. Efficacy and toxicity in a real‐world setting may differ from clinical trials, due to more liberal eligibility criteria and less intensive monitoring. Moreover, high costs and lack of biomarkers have raised cost‐benefit concerns about ipilimumab in national healthcare systems and limited its use. Here, we report the prospective, interventional study, Ipi4 (NCT02068196), which aimed to investigate the toxicity and efficacy of ipilimumab in a real‐world population with advanced melanoma. This national, multicentre, phase IV trial included 151 patients. Patients received ipilimumab 3 mg/kg intravenously and were followed for at least 5 years or until death. Treatment interruption or cessation occurred in 38%, most frequently due to disease progression (19%). Treatment‐associated grade 3 to 4 toxicity was observed in 28% of patients, and immune‐related toxicity in 56%. The overall response rate was 9%. Median overall survival was 12.1 months (95% CI: 8.3‐15.9); and progression‐free survival 2.7 months (95% CI: 2.6‐2.8). After 5 years, 20% of patients were alive. In a landmark analysis from 6 months, improved survival was associated with objective response (HR 0.16, P = .001) and stable disease (HR 0.49, P = .005) compared to progressive disease. Poor performance status, elevated lactate dehydrogenase and C‐reactive protein were identified as biomarkers. This prospective trial represents the longest reported follow‐up of a real‐world melanoma population treated with ipilimumab. Results indicate safety and efficacy comparable to phase III trials and suggest that the use of ipilimumab can be based on current cost‐benefit estimates.

Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination

“…We have previously reported safety and feasibility data of this phase I/IIa clinical trial evaluating combined UV1 vaccination and ipilimumab in patients with metastatic melanoma [ 33 ]. A parallel phase 4 trial evaluating ipilimumab monotherapy at Norwegian hospitals during the same period has since been published, demonstrating clinical outcomes aligned with previously reported data on ipilimumab monotherapy [ 34 , 35 ]. Considering the combination study yielded comparatively superior progression-free survival, overall survival, and objective responses rate, we sought to further investigate whether this cohort comprised patients with favorable baseline characteristics and explore the dynamics of the vaccine-induced immune response.…”

“…The clinical read-out of our study yielded an ORR of 33%, mPFS of 6.7 months, and mOS of 66.3 months. The clinical outcomes of patients enrolled in a phase 4 clinical trial evaluating ipilimumab monotherapy at Norwegian hospitals during the same period as our study were recently published (n = 151) [ 34 ], demonstrating an ORR of 9%, mPFS of 2.7 months, and mOS of 12.1 months.…”

Health-related quality of life in patients with advanced melanoma treated with ipilimumab: prognostic implications and changes during treatment

“…Treatment-associated high-grade toxicity was observed in 28% of patients, and immune-related adverse events (irAEs) in 56%. 12 The median progression-free survival (PFS) was 2.7 months [95% confidence interval (CI) 2.6-2.8 months] and OS 12.1 months (95% CI 8.3-15.9 months), comparable to phase III trials. Poor performance status, elevated lactate dehydrogenase (LDH), and C-reactive protein (CRP) at baseline were independently associated with short survival.…”

“…A stepwise approach was applied to identify HRQL variables that were independently associated with OS in a Cox model including baseline ECOG PS, LDH, and CRP as covariates, factors previously identified as independent predictors of OS in the Ipi4 trial. 12 HRQL variables with P <0.05 in unadjusted analyses were tested one-by-one in adjusted Cox models. Variables included in the final Cox model were checked for multicollinearity by the variance inflation factor and accepted if <3.…”

The Predictive Potential of the Baseline C-Reactive Protein Levels for the Efficiency of Immune Checkpoint Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis

“…The clinical reference cutoff value for CRP is set as 0.5 mg/dl in some studies ( 40 ), but the cutoff value of high baseline CRP level remains controversial and various cutoff values have served in the literature. Our study permitted different cutoff values and the most popular applied cutoff value is still 1.0 mg/dl ( 21 , 24 , 29 , 34 , 35 , 42 , 43 , 47 , 49 – 51 ). The principal cause of the discrepancy in cutoff values is that some studies employed the median CRP level as the cutoff value, just to equalize the number of individuals in the high CRP and low CRP groups.…”