The price of tumor control

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Adverse events.

<p>Abbreviations: ir, immune related; ALT, alanine aminotransferases; AST, aspartate aminotransferases.</p><p>^aPatients may have had more than one adverse event.</p><p>Adverse events.</p

Phase II DeCOG-Study of Ipilimumab in Pretreated and Treatment-Naïve Patients with Metastatic Uveal Melanoma

<div><p>Purpose</p><p>Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM.</p><p>Patients and Methods</p><p>We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months.</p><p>Results</p><p>Forty five pretreated (85%) and eight treatment-naïve (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7–8.1), median progression-free survival 2.8 months (95% CI 2.5–2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3–4 events (36%). One drug-related death due to pancytopenia was observed.</p><p>Conclusions</p><p>Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://www.clinicaltrial.gov/ct2/show/NCT01355120?term=NCT01355120&rank=1" target="_blank">NCT01355120</a></p></div

Kaplan-Meier curves for overall survival (A) and progression-free survival (B) of treatment-naïve and pretreated patients with metastatic ocular melanoma who received ipilimumab 3 mg/kg.

<p>Kaplan-Meier curves for overall survival (A) and progression-free survival (B) of treatment-naïve and pretreated patients with metastatic ocular melanoma who received ipilimumab 3 mg/kg.</p

Patients characteristics.

<p>Abbreviations: ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase</p><p>Patients characteristics.</p

Kaplan-Meier curves for overall survival stratified by the lactate dehydrogenase (LDH) level before the first dose of ipilimumab (A), the number of ipilimumab doses (B), and the absolute lymphocyte count (ALC) before the third dose (week 7) of ipilimumab (C).

<p>(A) LDH level (<2-fold upper level norm (ULN) versus ≥ 2xULN). LDH < 2xULN: median OS: 9.3 months (95% CI 7.0–11.6); LDH ≥ 2xULN: median OS 2.5 months (95% CI 1.5–5.7). (B) the number of ipilimumab doses (<4 versus 4). 4 doses: median OS: 9.1 months (95% CI 6.7–13.9); < 4 doses: median OS: 2.8 monhts (95% CI 1.5–6.3). (C) ALC (<1000/μl versus ≥1000/μl). ALC ≥1000/μl: median OS: 8.6 (95% CI 7.0–14.5); ALC <1000/μl: median OS: 3.1 (95% CI 2.2–11.5).</p

Adverse events.

<p>Abbreviations: ir, immune related; ALT, alanine aminotransferases; AST, aspartate aminotransferases.</p><p>^aPatients may have had more than one adverse event.</p><p>Adverse events.</p