Effectiveness and Tolerability of Ipilimumab

Eigentler, Thomas; Schlaak, Max; Hassel, Jessica C.; Loquai, Carmen; Stoffels, Ingo; Gutzmer, Ralf; Pätzold, Sylvie; Mohr, Peter; Keller, Ulrich; Starz, Hans; Ulrich, Jens; Tsianakas, Athanasios; Kähler, Katharina C.; Hauschild, Axel; Janssen, Eva; Schuler‐Thurner, Beatrice; Weide, Benjamin; Garbe, Claus

doi:10.1097/cji.0000000000000046

Cited by 23 publications

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“…In our study, four doses of ipilimumab, the absence of brain metastases, and an ALC ≥1000/µl at week 4 were identified as factors independently associated with a better OS in the 83 patients with cutaneous melanoma. These findings enforce the current level of evidence gained by several studies that the completion of the four-dose-induction phase [ 14 , 26 ], the absence of brain metastases [ 14 – 16 ], and high ALC counts and/or changes in ALC pharmacodynamics [ 16 – 18 , 26 – 29 ] are predictive for a significant prolongation of survival of ipilimumab-treated patients. Investigations continue to further clarify the role of ALC as an on-treatment pharmacodynamic marker of ipilimumab activity.…”

Section: Discussionsupporting

confidence: 86%

“…The reported OS rate at 12 months of 38 % for patients with cutaneous melanoma is fitting with data from several other studies (range 33–38 %) (Additional file 4 : Table S4) enrolling daily clinical routine patients with a high portion of this melanoma subgroup [ 14 – 17 ]; a report on an EAP run in the Netherlands and the UK with cutaneous melanoma patients only also resulted into an 1-year OS rate of 38 % [ 18 ]. In a pivotal, randomized phase II dose-ranging study, in which patients with ocular and mucosal melanoma were excluded as well as patients with brain metastases, the OS rate at 12 months for the ipilimumab 3 mg/kg arm of a similar size was 39 % [ 19 ].…”

Section: Discussionsupporting

confidence: 79%

“…This prospective DeCOG phase II trial evaluated the efficacy and safety of ipilimumab in a cohort of 103 patients with 83 pretreated metastatic cutaneous, seven mucosal and 13 occult melanoma. The distribution rate of these clinical subgroups in our trial—considered as representative for a daily routine hospital setting—has been very similar to the rates reported for a named-patient program in Germany with approximately 200 patients [ 14 ] [Data not disclosed]. In both multi-center studies, patients with pretreated cutaneous melanoma represented approximately 80 % of all patients; patients with mucosal melanoma (DeCOG: 7 %; expanded access program (EAP) Germany: 5 %) and with occult melanoma (DeCOG: 13 %; EAP Germany: 11 %) were enrolled less frequently.…”

Section: Discussionsupporting

confidence: 73%

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Open-label, multicenter, single-arm phase II DeCOG-study of ipilimumab in pretreated patients with different subtypes of metastatic melanoma

et al. 2015

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BackgroundIpilimumab is an approved immunotherapy that has shown an overall survival benefit in patients with cutaneous metastatic melanoma in two phase III trials. As results of registrational trials might not answer all questions regarding safety and efficacy of ipilimumab in patients with advanced melanoma seen in daily clinical practice, the Dermatologic Cooperative Oncology Group conducted a phase II study to assess the efficacy and safety of ipilimumab in patients with different subtypes of metastatic melanoma.Patients and methodsWe undertook a multicenter phase II study in melanoma patients irrespective of location of the primary melanoma. Here we present data on patients with pretreated metastatic cutaneous, mucosal and occult melanoma 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.Results103 pretreated patients received at least one dose of ipilimumab, including 83 cutaneous, seven mucosal and 13 occult melanomas. 1-year OS rates for cutaneous, mucosal and occult melanoma were 38 %, 14 % and 27 %, respectively. Median OS was 6.8 months (95 % CI 5.3–9.9) for cutaneous, 9.6 months (95 % CI 1.6–11.1) for mucosal, and 9.9 months (lower 95 % CI 2.3, upper 95 % CI non-existent) for occult melanoma. Overall response rates for cutaneous, mucosal and occult melanoma were 16 %, 17 % and 11 %, respectively. Eleven patients had partial response (16 %) and ten patients experienced stable disease (14 %), none achieved a complete response. Treatment-related AEs were observed in 71 patients (69 %), including 20 grade 3–4 events (19 %). No new and unexpected safety findings were noted.ConclusionsIpilimumab is a treatment option for pretreated patients with advanced cutaneous melanoma seen in daily routine. Toxicity was manageable when treated as per protocol-specific guidelines.Trial registration: Clinical Trials.gov NCT01355120Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0716-5) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 73%

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Open-label, multicenter, single-arm phase II DeCOG-study of ipilimumab in pretreated patients with different subtypes of metastatic melanoma

et al. 2015

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“…Across disease sites, patients who experience IRAEs while on therapy with anti-PD-1 and anti-PD-L1 antibodies have been documented to experience improved outcomes as measured by overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) [13–20]. In patients treated with anti-CTLA-4 antibodies, this association has been less uniform [21–25]. Key questions regarding the complete nature of the relationship between IRAEs and ICI efficacy remain unsettled.…”

Section: Introductionmentioning

confidence: 99%

Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors

Das

Johnson

2019

j. immunotherapy cancer

799

555

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Although immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with many advanced malignancies, only 15–60% of patients respond, leaving a broad swath of patients who do not derive benefit. Identifying biomarkers to optimally identify patients who will benefit from ICIs is a major research focus for the oncology community. Thus far, predictive biomarker research has focused on tumor signatures such as microsatellite instability, programmed death-ligand 1 (PD-L1) expression and tumor mutational burden; clinical biomarkers have been far less studied. One potential clinical biomarker for ICI response in patients is immune-related adverse event (IRAE) onset.IRAEs are thought to represent bystander effects from activated T-cells and it is plausible that patients responding to ICIs would have greater likelihood of autoimmune toxicities (e.g. due to a more competent/treatment-responsive immune system, or cross-reactivity between tumor and host tissue). Earlier studies in melanoma patients however, suggested no association between IRAE onset and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody efficacy. In contrast, a growing body of literature suggests IRAE onset is predictive of anti-programmed cell death protein 1 (PD-1) and anti-PD-L1 antibody response across a variety of solid tumors. Most of these studies report that patients who experienced IRAEs demonstrate marked improvements in progression-free survival, overall survival and overall response rate compared to those lacking toxicity.Key questions regarding the association between IRAE onset and ICI efficacy remain. The most pertinent of these involve whether the association is only relevant for patients treated with anti-PD-1 and anti-PD-L1 antibodies and whether IRAE site, severity, timing of onset and management influence ICI efficacy. Herein, we discuss the seminal studies which have begun to address these questions and have shaped the narrative about the predictive value of IRAE onset for patients on ICIs, in this review.

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“…Multivariate analysis showed that absence of toxicity was a prognostic factor for poor overall survival (OS) and progression-free survival. In an analysis of 198 patients in Germany treated with ipilimumab, the occurrence of immune-related adverse events correlated significantly with response to treatment and prolonged OS [13].…”

Section: Discussionmentioning

confidence: 99%

Prognostic and predictive factors associated with ipilimumab-related adverse events: a retrospective analysis of 11 NCI-sponsored phase I clinical trials

Chauhan

Kabir

et al. 2020

Oncotarget

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Background: We review factors impacting ipilimumab-associated adverse events through the experience from National Cancer Institute (NCI)-sponsored phase I immunotherapy clinical trials.Materials and Methods: Attributable ipilimumab-related adverse events from NCI-sponsored phase I immunotherapy clinical trials were queried retrospectively by anonymized patient experience reports for observed adverse events like decreased hematological cell counts, blood electrolytes or proteins, or reduced patient performance status. The prevalence of ipilimumab-related toxicity was associated by patient to the duration of ipilimumab exposure, radiographic responses, progressionfree survival, and overall survival.Results: 373 patients from 11 phase 1 ipilimumab clinical trials were analyzed. Patients experiencing at least one grade 3 or 4 adverse event associated with observed radiographic response were included. The average number of grade 3/4 adverse events in responders was 1.167 versus 0.645 in non-responders (p = 0.001). Patient performance status did not significantly impact observed toxicity grade. Pretherapy lymphocyte count or chemistries were not associated with ipilimumab-associated toxicity. The number of agents combined with ipilimumab on trial was associated with average number of grade 3/4 toxicities-ipilimumab monotherapy (0.631) versus ipilimumab + 1 agent (0.877) versus ipilimumab + 2 agents (1.408) (p = 0.014). Number of low grade (grade 1/2) toxicities was associated with duration of treatment, Pearson correlation coefficient r = 0.456 (p < 0.0001); whereas the number of high grade (grade 3/4) toxicities was not, r = 0.032 (p = 0.546).Conclusions: Ipilimumab-attributed grade 3/4 toxicity was associated with therapeutic response. The number of co-administered agents added to ipilimumab significantly raised the likelihood of toxicity. Extended duration of treatment increased the incidence of low but not high-grade toxicity.

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Effectiveness and Tolerability of Ipilimumab

Abstract: In this named-patient program including heavily pretreated patients, the efficacy and tolerability of ipilimumab 3 mg/kg corresponds with findings from the confirmatory clinical trial.

Cited by 23 publications

References 0 publications

Open-label, multicenter, single-arm phase II DeCOG-study of ipilimumab in pretreated patients with different subtypes of metastatic melanoma

Open-label, multicenter, single-arm phase II DeCOG-study of ipilimumab in pretreated patients with different subtypes of metastatic melanoma

Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors

Prognostic and predictive factors associated with ipilimumab-related adverse events: a retrospective analysis of 11 NCI-sponsored phase I clinical trials

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