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Alexander M.m. Eggermont - One of the best experts on this subject based on the ideXlab platform.
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Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2020Co-Authors: Alexander M.m. Eggermont, Christian U. Blank, Mario Mandalà, Georgina V. Long, Victoria Atkinson, Stéphane Dalle, Andrew Haydon, Adnan Khattak, Andrey Meshcheryakov, Matteo S. CarlinoAbstract:We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up. A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node Metastasis > 1 mm), IIIB, or IIIC (without In-Transit Metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors. Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1-positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600E/K v wild type). In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups.
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Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo: A Secondary Analysis of a Randomized Clinical Trial
JAMA oncology, 2020Co-Authors: Alexander M.m. Eggermont, Christian U. Blank, Mario Mandalà, Georgina V. Long, Victoria Atkinson, Stéphane Dalle, Andrew Haydon, Adnan Khattak, Michal Kicinski, Matteo S. CarlinoAbstract:Whether immune-related adverse events (irAEs) indicate drug activity in patients treated with immune checkpoint inhibitors remains unknown. To investigate the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 clinical trial comparing pembrolizumab therapy and placebo for the treatment of patients with high-risk stage III melanoma. A total of 1019 adults with stage III melanoma were randomly assigned on a 1:1 ratio to receive treatment with pembrolizumab therapy or placebo. Eligible patients were adults 18 years and older with complete resection of cutaneous melanoma metastatic to lymph nodes, classified with stage IIIA (at least 1 microMetastasis measuring >1 mm in greatest diameter), IIIB, or IIIC (without In-Transit Metastasis) cancer. Patients were randomized from August 26, 2015, to November 14, 2016. The clinical cutoff for the data set was October 2, 2017. Analyses were then performed on the database, which was locked on November 28, 2017. Participants were scheduled to receive 200 mg of pembrolizumab or placebo every 3 weeks for a total of 18 doses for approximately 1 year or until disease recurrence, unacceptable toxic effects, major protocol violation, or withdrawal of consent. The association between irAEs and RFS was estimated using a Cox model adjusted for sex, age, and AJCC-7 stage, with a time-varying covariate that had a value of 0 before irAE onset and 1 after irAE onset. Of 1011 patients who began treatment with pembrolizumab therapy or placebo, 622 (61.5%) were men and 389 (38.5%) were women; 386 patients (38.2%) were aged 50 to 64 years, 377 (37.3%) were younger than 50 years, and 248 (24.5%) were 65 years and older. Consistent with the reported main analysis in the intent-to-treat population, RFS was longer in the pembrolizumab arm compared with the placebo arm (hazard ratio [HR], 0.56; 98.4% CI, 0.43-0.74) among patients who started treatment. The incidence of irAEs was 190 (37.4%) in the pembrolizumab arm (n = 509) and 45 (9.0%) in the placebo arm (n = 502); in each treatment group, the incidence was similar for men and women. The occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm (HR, 0.61; 95% CI, 0.39-0.95; P = .03) in both men and women. However, in the placebo arm, this association was not significant. Compared with the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater after the onset of an irAE than without or before an irAE (HR, 0.37; 95% CI, 0.24-0.57 vs HR, 0.61; 95% CI, 0.49-0.77, respectively; P = .03). In this study, the occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm. ClinicalTrials.gov identifier: NCT02362594; EudraCT identifier: 2014-004944-37.
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Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial
European journal of cancer (Oxford England : 1990), 2019Co-Authors: Alexander M.m. Eggermont, Vanna Chiarion-sileni, Jean Jacques Grob, Reinhard Dummer, Jedd D. Wolchok, Henrik Schmidt, Omid Hamid, Caroline Robert, Paolo A. Ascierto, Jon M. RichardsAbstract:Since 2015, adjuvant therapy with ipilimumab is an approved treatment for stage III melanoma based on a significantly prolonged recurrence-free survival (RFS). At a median follow-up of 5.3 years, RFS, distant Metastasis-free survival (DMFS) and overall survival (OS) were each significantly prolonged in the ipilimumab group compared with the placebo group, despite a 53.3% (ipilimumab) versus 4.6% (placebo) treatment discontinuation rate due to adverse events. We present now long-term follow-up results of this European Organisation for Research and Treatment of Cancer 18071 trial. A total of 99 sites randomised 951 patients with stage III cutaneous melanoma (excluding lymph node Metastasis ≤1 mm or In-Transit Metastasis) with adequate resection of lymph nodes to receive intravenous infusions of ipilimumab 10 mg/kg or placebo, every 3 weeks for 4 doses, then every 3 months for up to 3 years. The RFS, DMFS and OS, as reported by the local investigators, were assessed by the intention-to-treat analysis. Among 431 patients randomised at 63 sites and who were still alive at the analysis reported in 2016, recent follow-up information could be obtained for 264 patients. The median OS follow-up was 6.9 years. The RFS (hazard ratio [HR] 0.75, 95% confidence interval 0.63-0.88; P < 0.001), DMFS (HR 0.76, 0.64-0.90; P = 0.002) and OS (HR 0.73, 0.60-0.89; P = 0.002) benefit observed in the ipilimumab group was durable with an 8.7% absolute difference at 7 years for OS. The benefit was consistent across subgroups. Adjuvant therapy with ipilimumab prolongs RFS, DMFS and OS significantly. The benefit is sustained long term and consistent across subgroups. Copyright © 2019 Elsevier Ltd. All rights reserved.
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Prognostic and predictive value of AJCC-8 staging in the phase III EORTC1325/KEYNOTE-054 trial of pembrolizumab vs placebo in resected high-risk stage III melanoma
European journal of cancer (Oxford England : 1990), 2019Co-Authors: Alexander M.m. Eggermont, Christian U. Blank, Mario Mandalà, Georgina V. Long, Victoria Atkinson, Stéphane Dalle, Andrew Haydon, Mikhail Lichinitser, Adnan Khattak, Matteo S. CarlinoAbstract:Abstract Background The American Joint Committee on Cancer-8 (AJCC) classification of melanoma was implemented in January 2018. It was based on data gathered when checkpoint inhibitors were not used as adjuvant therapy in stage III melanoma. The European Organization for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 double-blind phase III trial evaluated pembrolizumab vs placebo in AJCC-7 stage IIIA (excluding lymph node Metastasis ≤1 mm), IIIB or IIIC (without In-Transit Metastasis) patients after complete lymphadenectomy. Patients, methods and results Patients (n = 1019) were randomised 1:1 to pembrolizumab 200 mg or placebo every 3 weeks (total of 18 doses, ∼1 year). At 1.25-year median follow-up, pembrolizumab prolonged relapse-free survival (RFS) in the total population (1-year RFS rate: 75.4% vs 61.0%; hazard ratio [HR] 0.57; logrank P Conclusions AJCC-8 staging had a strong prognostic importance for RFS but no predictive importance: the RFS benefit of pembrolizumab was observed across AJCC-8 subgroups in resected high-risk stage III melanoma patients.
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Prognostic and predictive value of an immune-related adverse event among stage III melanoma patients included in the EORTC 1325/KEYNOTE-054 pembrolizumab versus placebo trial.
Journal of Clinical Oncology, 2019Co-Authors: Alexander M.m. Eggermont, Christian U. Blank, Mario Mandalà, Georgina V. Long, Victoria Atkinson, Stéphane Dalle, Mikhail Lichinitser, Michal Kicinski, Andrew Mark Haydon, Muhammad KhattakAbstract:2517 Background: Several studies suggested that patients (pts) with an immune-related adverse event (irAE) during immunotherapy have better outcomes than those without. It remains uncertain whether these observations can be explained by guarantee-time bias or the role of irAE as an indicator of drug activity. Here, we investigated the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 trial that compared pembrolizumab and placebo in high-risk stage III melanoma pts. Methods: Eligible pts included adults with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as stage IIIA (lymph node Metastasis > 1 mm), IIIB or IIIC (without In-Transit Metastasis) and with no active autoimmune disease that required systemic treatment in past 2 years. We used a Cox model adjusted for sex, age, and stage with a time-varying covariate taking a value zero before the irAE onset and a value one afterwards to estimate the association between the occurrence of irAEs and RFS. Results: Consistent with the main analysis in the ITT population (n = 1019, Eggermont et al, NEJM, 2018), RFS was longer in the pembrolizumab than in the placebo arm (HR = 0.56, 98.4% CI: 0.43-074) among pts who started the treatment (n = 1011). The incidence of irAE on study was 37.3% in the pembrolizumab (n = 509) and 9.0% in the placebo arm (n = 502) and, in each treatment group, it was similar in males and females. The occurrence of an irAE was significantly associated with a longer RFS in the pembrolizumab arm (HR = 0.61, 95% CI: 0.39-0.95, P = 0.03). This was true for both males and females. However, in the placebo arm, no association was observed (HR = 1.39, 95% CI: 0.83-2.32, P = 0.21). Compared to the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater (P = 0.028) after an onset of an irAE (HR = 0.37, 95% CI: 0.24-0.57) than without/before an irAE (HR = 0.61, 95% CI: 0.49-0.77). Conclusions: In the EORTC 1325/KEYNOTE-054 study conducted in high-risk stage III melanoma pts, the occurrence of an irAE was strongly associated with a longer RFS in those treated with pembrolizumab, but not with placebo. Clinical trial information: NCT02362594.
Claus Garbe - One of the best experts on this subject based on the ideXlab platform.
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Prognostic factors of melanoma patients with satellite or In-Transit Metastasis at the time of stage III diagnosis.
PloS one, 2013Co-Authors: Benjamin Weide, Christine Faller, Petra Büttner, Annette Pflugfelder, Ulrike Leiter, Thomas K. Eigentler, Jürgen Bauer, Andrea Forschner, Friedegund Meier, Claus GarbeAbstract:Prognosis of patients with loco-regional skin metastases has not been analyzed in detail and the presence or absence of concurrent lymph node Metastasis represents the only established prognostic factor thus far. Most studies were limited to patients already presenting with skin lesions at the time of initial diagnosis. We aimed to analyze the impact of a broad penal of prognostic factors in patients with skin metastases at the time of first metastatic spread, including patients with synchronous lesions already present at the time of initial diagnosis, stage I/II patients with loco-regional recurrence and patients initially presenting with skin Metastasis but unknown primary melanoma. We investigated disease-specific survival of 380 patients treated at our department between 1996 and 2010 using Kaplan Meier survival probabilities and Cox-proportional hazard analysis. Five-year survival probability was 60.1% for patients with skin metastases only and 36.3% for those with synchronous nodal metastases. The number of involved nodes and a tumor thickness of at least 3 mm had independent negative impact on prognosis. A strong relationship was identified between the risk of death and the number of involved nodes. Neither ulceration nor the timing of the first occurrence of metastases as either in stage I/II patients, at the time of excision of the primary melanoma or initially in patients with unknown primary tumor, had additional effects on survival. Lymph node involvement was confirmed as the most important prognostic factor for melanoma patients with loco-regional skin Metastasis including those with unknown primary tumor and stage I/II patients with skin recurrence. Consideration of the tumor thickness and of the number of involved lymph nodes instead of the exclusive differentiation into presence vs. absence of nodal disease may allow a more accurate prediction of prognosis for patients with satellite or In-Transit metastases.
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Improving melanoma classification by integrating genetic and morphologic features.
PLoS medicine, 2008Co-Authors: Amaya Viros, Claus Garbe, Jane Fridlyand, J. Bauer, Konstantin Lasithiotakis, Daniel Pinkel, Boris C. BastianAbstract:In melanoma, morphology-based classification systems have not been able to provide relevant information for selecting treatments for patients whose tumors have metastasized. The recent identification of causative genetic alterations has revealed mutations in signaling pathways that offer targets for therapy. Identifying morphologic surrogates that can identify patients whose tumors express such alterations (or functionally equivalent alterations) would be clinically useful for therapy stratification and for retrospective analysis of clinical trial data. We defined and assessed a panel of histomorphologic measures and correlated them with the mutation status of the oncogenes BRAF and NRAS in a cohort of 302 archival tissues of primary cutaneous melanomas from an academic comprehensive cancer center. Melanomas with BRAF mutations showed distinct morphological features such as increased upward migration and nest formation of intraepidermal melanocytes, thickening of the involved epidermis, and sharper demarcation to the surrounding skin; and they had larger, rounder, and more pigmented tumor cells (all p-values below 0.0001). By contrast, melanomas with NRAS mutations could not be distinguished based on these morphological features. Using simple combinations of features, BRAF mutation status could be predicted with up to 90.8% accuracy in the entire cohort as well as within the categories of the current World Health Organization (WHO) classification. Among the variables routinely recorded in cancer registries, we identified age < 55 y as the single most predictive factor of BRAF mutation in our cohort. Using age < 55 y as a surrogate for BRAF mutation in an independent cohort of 4,785 patients of the Southern German Tumor Registry, we found a significant survival benefit (p < 0.0001) for patients who, based on their age, were predicted to have BRAF mutant melanomas in 69% of the cases. This group also showed a different pattern of Metastasis, more frequently involving regional lymph nodes, compared to the patients predicted to have no BRAF mutation and who more frequently displayed satellite, In-Transit Metastasis, and visceral Metastasis (p < 0.0001). Refined morphological classification of primary melanomas can be used to improve existing melanoma classifications by forming subgroups that are genetically more homogeneous and likely to differ in important clinical variables such as outcome and pattern of Metastasis. We expect this information to improve classification and facilitate stratification for therapy as well as retrospective analysis of existing trial data.
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Erfahrungen mit der neuen American Joint Committee on Cancer (AJCC)‐Klassifikation des kutanen malignen Melanoms
Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG, 2005Co-Authors: Thomas K. Eigentler, Benjamin Weide, Peter Radny, Anne Kamin, Ulrich M. Caroli, Claus GarbeAbstract:Zusammenfassung Im Jahr 2001 wurde eine neue AJCC/UICC-Klassifikation und Stadieneinteilung des malignen Melanoms publiziert, die seitdem fur die Eingruppierung des malignen Melanoms gultig ist. Im Vergleich zu der vorherigen fur einen Zeitraum von etwa 15 Jahren gultigen Klassifikation wurden erhebliche Anderungen eingefuhrt. Die Klassifikation des Primartumors stutzt sich jetzt auf neue Klassenbildungen fur die Tumordicke nach Breslow (0 – 1,0 mm; 1,01 – 2,0 mm, 2,01 – 4,0 mm; > 4,0 mm). Zusatzlich wird eine histopathologisch diagnostizierte Ulzeration mit zur Einteilung herangezogen, die zur Eingruppierung in die nachsthohere T-Kategorie fuhrt. Der Invasionslevel nach Clark hat nur noch fur Tumoren mit einer Tumordicke bis 1 mm Bedeutung, hier fuhrt Level IV und V zur Einordnung in die nachsthohere T-Kategorie. Die Einteilung der regionaren Lymphknotenmetastasierung basiert auf der Unterscheidung zwischen nur mikroskopisch erkennbarer Metastasierung in der Wachterlymphknotenbiopsie oder makroskopisch-klinisch erkennbarer Metastasierung, weiterhin gehen in die Einteilung die Zahl der befallenen Lymphknoten und das Auftreten von Satelliten- und In-Transit-Metastasen mit ein. Bei Fernmetastasierung spielt die Art des Organbefalls (nur Haut und Lymphknoten vs. Lunge vs. andere Organe) sowie der LDH-Wert eine Rolle, bei dessen Erhohung eine Eingruppierung in die ungunstigste Kategorie erfolgt. Kritisch bleibt anzumerken, dass die starke Rolle, die der Ulzeration des Primartumors zukommt, anhand der Daten des deutschen Zentralregisters malignes Melanom nicht bestatigt werden konnte. Weiter ist es ungunstig, dass das Stadium IIC eine signifikant ungunstigere Prognose aufweist als das Stadium IIIA, hier ist die Klassifikation inkonsistent. Die neue Stadieneinteilung sollte dennoch, insbesondere in klinischen Studien, um eine internationale Vergleichbarkeit der Daten zu ermoglichen, verwendet werden. Summary A new AJCC/UICC staging classification of malignant melanoma was published in 2001 and has been in use since then. Compared to the TNM classification used for the previous 15 years, the new classification contains fundamental changes. The classification of the primary tumor is now based on newly defined classes for Breslow's tumor thickness (0 – 1.0 mm; 1.01 – 2.0 mm, 2.01 – 4.0 mm; > 4.0 mm). Histopathologically diagnosed ulceration is the second prognostic factor in primary melanoma and its presence leads to upstaging into the next higher T category. Clark level of invasion is now only relevant for tumors up to 1 mm thick; levels IV and V are also reasons for upstaging. Classification of regional lymph node Metastasis distinguishes between microscopic Metastasis only as detected with sentinel lymph node biopsy and clinically detectable macroscopic Metastasis. Additionally, the number of metastatic nodes and the presence of satellite and In-Transit Metastasis are prognostic factors for classification of regional lymph node Metastasis. In distant Metastasis, the kind of organ involvement has a role for classification (only skin and lymph nodes vs. lung vs. other organs) and an elevated LDH value leads to upstaging. A critical analysis of data of the German Central Malignant Melanoma Registry did not confirm the strong role of histopathological ulceration of the primary tumor in all T- and N-stages. Furthermore, there is an inconsistency of the classification as stage IIC displays a significantly worse prognosis as compared to stage IIIA. In spite of these drawbacks the new staging classification should used particularly in clinical trials in order to make data internationally comparable.
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The natural course of cutaneous melanoma
Journal of surgical oncology, 2004Co-Authors: Ulrike Leiter, Friedegund Meier, Birgit Schittek, Claus GarbeAbstract:The natural course of cutaneous melanoma (CM) is determined by its metastatic spread and depends on tumor thickness, ulceration, gender, localization, and the histologic subtype of the primary tumor. CM Metastasis develops via three main metastatic pathways and occurs as satellite or In-Transit Metastasis, as regional lymph node Metastasis or as distant Metastasis at the time of primary recurrence. About 50% of all CM patients with tumor progression firstly develop regional lymph node metastases. In the other 50% the first metastases are satellite or In-Transit metastases (about 20%), or immediately distant metastases (about 30%). Development of distant Metastasis appears to be an early event in metastatic spread and may in the majority of cases originate from the primary tumor, only few cases may develop secondarily to locoregional Metastasis. Reporting of organ involvement in distant Metastasis greatly differs between the results of imaging techniques and autopsy results in respect to the metastatic patterns detected, pointing out that there is a need of improved imaging systems. Proliferation, neovascularization, lymphangiogenesis, invasion, circulation, and embolism are important steps in the pathogenesis of CM Metastasis, with tumor vascularity as an important independent significant prognostic factor. The expression of chemokine receptors in cancer cells associated with the expression of the respective chemokine receptor ligands in the target sites of the Metastasis is an interesting observation which may stimulate the development of new therapeutic strategies.
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Clinical risk factors and prognostic significance of local recurrence in cutaneous melanoma.
The British journal of dermatology, 2004Co-Authors: Matthias Moehrle, Claus Garbe, A. Kraemer, Wilfried Schippert, Gernot Rassner, Helmut BreuningerAbstract:True local recurrence (LR) means clinically detectable regrowth of parts of the tumour which were not completely excised. In the literature the term 'LR' has been used in a vague and inconsistent manner that may include satellite and In-Transit Metastasis. The aim of this study was to establish clinical, histological and surgical risk factors for the manifestation of LR and to evaluate the prognostic significance of LR. Data from 3960 Stage I and II melanoma patients who visited the melanoma clinic of the Department of Dermatology at the University of Tuebingen from 1980 to 1999 were documented in a prospective manner. A retrospective comparative analysis of patients with and without LR was performed. Of all patients 1.4% had a LR as a first recurrence and 1.7% had a LR in the course of the follow-up period. LR were most frequent after previous clinical or histological misdiagnosis and inadequate therapy. In the univariate analysis significant risk factors for LR-free survival were age, tumour surface area, locality, tumour thickness, level of invasion, histological type, associated naevus, surgery (one step vs. multiple steps) and compliance with recommended excision margins. In the multivarate analysis the factors locality (P < 0.0001), tumour thickness (P = 0.0086) and compliance with recommendations on excision margins (P = 0.014) were significant independent risk factors for the manifestation of LR. The overall survival of patients with LR as first progression did not significantly differ from the overall survival of the other patients with melanoma (P = 0.60). True LR is a rare event for which tumour locality, tumour thickness and surgery are independent risk factors. The occurrence of LR might not impair the prognosis of melanoma patients. However, in the published literature numerous definitions of 'LR', including lymphogenic Metastasis, complicate comparison.
John F. Thompson - One of the best experts on this subject based on the ideXlab platform.
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Staging 18F-FDG PET/CT influences the treatment plan in melanoma patients with satellite or In-Transit metastases.
Melanoma research, 2020Co-Authors: Lodewijka H. J. Holtkamp, John F. Thompson, Robyn P. M. Saw, Jonathan R. Stretch, Annette Hougaard Chakera, Sebastian Fung, Kenneth K. Lee, María Jesús González González, Louise EmmettAbstract:Whole-body positron emission tomography/computed tomography (PET/CT) and brain magnetic resonance imaging (MRI) are commonly used to stage patients with palpable lymph node metastases from melanoma, but their role in patients with satellite and/or In-Transit Metastasis (S&ITM) is unclear. The aim of this study was to establish the diagnostic value of PET/CT and brain MRI in these patients, and to assess their influence on subsequent management decisions. In this prospective study, 25 melanoma patients with a first presentation of S&ITM who had no clinical evidence of palpable nodal or distant Metastasis underwent whole-body F-FDG PET/CT and brain MRI after a tentative pre-scan treatment plan had been made. Sensitivity and specificity of imaging were determined by pathological confirmation, clinical outcome and repeat PET/CT and MRI at 6 months. PET/CT led to a modification of the initial treatment plan in four patients (16%). All four were upstaged (AJCC stage eighth edition). PET/CT was false-positive in one patient, who had a Schwannoma in his trapezius muscle. A thyroid carcinoma was an incidental finding in another patient. The sensitivity of PET/CT was 58% and specificity 83%. In 6 months following the baseline PET/CT, further sites of In-Transit or systemic disease were identified in 10 patients (40%). Brain MRI did not alter the treatment plan or change the disease stage in any patient. Whole-body PET/CT improved staging in melanoma patients with S&ITM and changed the originally-contemplated treatment plan in 16%. MRI of the brain appeared not to be useful.
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Sentinel Node Biopsy for Melanoma Patients with a Local Recurrence or In-Transit Metastasis
Annals of surgical oncology, 2019Co-Authors: Amanda A. G. Nijhuis, Ivan D. De A. O. Santos Filho, Lodewijka H. J. Holtkamp, Roger F. Uren, John F. Thompson, Omgo E. NiewegAbstract:Sentinel node (SN) biopsy (SNB) is not routinely performed for melanoma patients with local recurrence (LR) or In-Transit Metastasis (ITM). This study aimed to describe the technique, findings, and prognostic value of this procedure, and the outcome for such patients at our institution. Prospectively collected data were obtained from the Melanoma Institute Australia database. Patients who had SNB for LR or ITM between 1992 and 2015 were included in the study. Patient and primary tumor characteristics, lymphoscintigrams, SNB results, and follow-up data were analyzed. Overall, 7999 patients underwent SNB, 128 (1.6%) of whom met the selection criteria. The SNB procedure was performed for 85 of 1516 patients with LR (6%), 17 of 1671 patients with ITM from a known primary tumor (1%), and 26 of 170 patients who presented with ITM from an unknown primary site (15%). The SN identification rate was 100%. Metastatic melanoma was identified in an SN from 16 of the 128 patients (13%). Follow-up data were available for 114 patients. The false-negative rate was 27%. The SN-positive patients had significantly worse overall survival than the SN-negative patients, with respective 5-year survival rates of 54% and 81% (P = 0.01). The SNB procedure was performed infrequently for LR or ITM. The SNs were positive for 13% of the patients with LR or ITM. Positive SNs were associated with worse overall survival. Despite the false-negative rate of 27%, the procedure yielded information that was relevant for staging and prognosis. The SNB procedure should be considered for patients with LR or ITM.
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Angiotropism is an independent predictor of local recurrence and In-Transit Metastasis in primary cutaneous melanoma.
The American journal of surgical pathology, 2008Co-Authors: Simone L. Van Es, John F. Thompson, Marjorie H. Colman, Stanley W. Mccarthy, Richard A. ScolyerAbstract:The migration of melanoma cells along the external surface of blood vessels (angiotropism) has recently been proposed as a mechanism for melanoma Metastasis (termed extravascular migratory Metastasis). To determine whether the presence of angiotropism, as seen in the routine hematoxylin and eosin sections of primary cutaneous melanomas (PCMs), predicts the development of local or In-Transit melanoma recurrence, 32 patients with a PCM who developed local or In-Transit recurrence were matched for Breslow thickness with 59 "control" patients with a PCM who did not. The slides from both groups of patients were analyzed in a "blinded" manner for evidence of angiotropism. Other histologic and clinical variables were also assessed. Angiotropism was found more often in patients who developed local or In-Transit recurrence (cases) compared with those patients who did not (controls) (P=0.02). Variables that showed a statistically significant association with angiotropism on univariate analysis were: increasing Breslow thickness (P
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Interim analysis of toxicity and response in phase 1 trial of systemic targeted alpha therapy for metastatic melanoma.
Cancer biology & therapy, 2007Co-Authors: Chand Raja, John F. Thompson, Peter Graham, Syed M. Abbas Rizvi, Emma Song, Helen Goldsmith, Anja K. Bosserhoff, Alfred Morgenstern, Christos Apostolidis, John H. KearsleyAbstract:Purpose. The aim is to assess toxicity and response of systemic alpha therapy for metastatic melanoma.Experimental design. This is an open-labelled Phase 1 dose escalation study to establish the effective dose of the alpha-immunoconjugate 213Bi-cDTPA-9.2.27 mAb (AIC). Tools used to investigate the effects were physical examination; imaging of tumours; pathology; GFR; CT and changes in tumour marker. Responses were assessed using RECIST criteria. Results and Discussion. 22 patients with stage IV melanoma/ In-Transit Metastasis were treated with activities of 55-947 MBq. Using RECIST criteria 50% showed stable disease and 14% showed partial response. One patient (6%) showed near complete response and was retreated because of an excellent response to the initial treatment. Another patient showed response in his tumour on mandible and reduction in lung lesions. Overall 30% showed progressive disease. The tumour marker melanoma inhibitory activity protein (MIA) showed reductions over 8 weeks in most of the pat...
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A Sentinel Node Biopsy Does Not Increase the Incidence of In-Transit Metastasis in Patients With Primary Cutaneous Melanoma
Annals of surgical oncology, 2005Co-Authors: Daan Van Poll, John F. Thompson, Marjorie H. Colman, J. Gregory Mckinnon, Robyn P. M. Saw, Jonathan R. Stretch, Richard A. Scolyer, Roger F. UrenAbstract:It has been suggested that performing a sentinel node biopsy (SNB) in patients with cutaneous melanoma increases the incidence of In-Transit Metastasis (ITM). ITM rates for 2018 patients with primary melanomas > or =1.0 mm thick treated at a single institution between 1991 and 2000 according to 3 protocols were compared: wide local excision (WLE) only (n = 1035), WLE plus SNB (n = 754), and WLE plus elective lymph node dissection (n = 229). The incidence of ITM for the three protocols was 4.9%, 3.6%, and 5.7%, respectively (not significant), and as a first site of recurrent disease the incidence was 2.5%, 2.4%, and 4.4%, respectively (not significant). The subset of patients who were node positive after SNB and after elective lymph node dissection also had similar ITM rates (10.8% and 7.1%, respectively; P = .11). On multivariate analysis, primary tumor thickness and patient age predicted ITM as a first recurrence, but type of treatment did not. Patients who underwent WLE only and who had a subsequent therapeutic lymph node dissection (n = 149) had an ITM rate of 24.2%, compared with 10.8% in patients with a tumor-positive sentinel node treated with immediate dissection (n = 102; P = .03). Performing an SNB in patients with melanoma treated by WLE does not increase the incidence of ITM.
Jon M. Richards - One of the best experts on this subject based on the ideXlab platform.
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Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial
European journal of cancer (Oxford England : 1990), 2019Co-Authors: Alexander M.m. Eggermont, Vanna Chiarion-sileni, Jean Jacques Grob, Reinhard Dummer, Jedd D. Wolchok, Henrik Schmidt, Omid Hamid, Caroline Robert, Paolo A. Ascierto, Jon M. RichardsAbstract:Since 2015, adjuvant therapy with ipilimumab is an approved treatment for stage III melanoma based on a significantly prolonged recurrence-free survival (RFS). At a median follow-up of 5.3 years, RFS, distant Metastasis-free survival (DMFS) and overall survival (OS) were each significantly prolonged in the ipilimumab group compared with the placebo group, despite a 53.3% (ipilimumab) versus 4.6% (placebo) treatment discontinuation rate due to adverse events. We present now long-term follow-up results of this European Organisation for Research and Treatment of Cancer 18071 trial. A total of 99 sites randomised 951 patients with stage III cutaneous melanoma (excluding lymph node Metastasis ≤1 mm or In-Transit Metastasis) with adequate resection of lymph nodes to receive intravenous infusions of ipilimumab 10 mg/kg or placebo, every 3 weeks for 4 doses, then every 3 months for up to 3 years. The RFS, DMFS and OS, as reported by the local investigators, were assessed by the intention-to-treat analysis. Among 431 patients randomised at 63 sites and who were still alive at the analysis reported in 2016, recent follow-up information could be obtained for 264 patients. The median OS follow-up was 6.9 years. The RFS (hazard ratio [HR] 0.75, 95% confidence interval 0.63-0.88; P < 0.001), DMFS (HR 0.76, 0.64-0.90; P = 0.002) and OS (HR 0.73, 0.60-0.89; P = 0.002) benefit observed in the ipilimumab group was durable with an 8.7% absolute difference at 7 years for OS. The benefit was consistent across subgroups. Adjuvant therapy with ipilimumab prolongs RFS, DMFS and OS significantly. The benefit is sustained long term and consistent across subgroups. Copyright © 2019 Elsevier Ltd. All rights reserved.
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Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial
The Lancet. Oncology, 2015Co-Authors: Alexander M.m. Eggermont, Vanna Chiarion-sileni, Jean Jacques Grob, Reinhard Dummer, Jedd D. Wolchok, Henrik Schmidt, Omid Hamid, Caroline Robert, Paolo A. Ascierto, Jon M. RichardsAbstract:Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node Metastasis ≤1 mm or In-Transit Metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28-3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3-39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4-21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64-0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5-51·3) in the ipilimumab group versus 34·8% (30·1-39·5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome. Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant Metastasis-free survival and overall survival endpoints to define its definitive value. Bristol-Myers Squibb. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Ipilimumab versus placebo after complete resection of stage III melanoma: Initial efficacy and safety results from the EORTC 18071 phase III trial.
Journal of Clinical Oncology, 2014Co-Authors: Alexander M.m. Eggermont, Vanna Chiarion-sileni, Jean Jacques Grob, Reinhard Dummer, Jedd D. Wolchok, Henrik Schmidt, Omid Hamid, Caroline Robert, Paolo A. Ascierto, Jon M. RichardsAbstract:LBA9008 Background: Ipilimumab (Ipi), a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses, is an approved treatment for advanced melanoma. Here, we report the results of a phase III trial designed to evaluate Ipi as an adjuvant therapy for resected stage III melanoma at high risk of recurrence. Methods: In this randomized, double-blind trial, eligible patients (pts) included those ≥18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node Metastasis ≤1 mm or In-Transit Metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to receive Ipi 10 mg/kg (n=475) or placebo (Pbo, n=476) every 3 wks for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. The primary endpoint was recurrence-free survival (RFS), analyzed on the intent-to-treat population. 512 RFS events (recurrence or death) were needed to provide 90% power to detect an Ip...
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1087OEFFICACY, SAFETY, AND QUALITY OF LIFE (QOL) DATA FROM THE EORTC 18071 PHASE III TRIAL OF IPILIMUMAB (IPI) VERSUS PLACEBO AFTER COMPLETE RESECTION OF STAGE III MELANOMA
Annals of Oncology, 2014Co-Authors: A. M. M. Eggermont, Vanna Chiarion-sileni, Jean Jacques Grob, Reinhard Dummer, Jedd D. Wolchok, Henrik Schmidt, Omid Hamid, Caroline Robert, Paolo A. Ascierto, Jon M. RichardsAbstract:ABSTRACT Aim: Ipi, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses, is an approved treatment for advanced melanoma. We report primary efficacy data and ongoing analyses from a phase III trial to evaluate Ipi as an adjuvant therapy for resected stage III melanoma at high risk of recurrence. Methods: In this randomized, double-blind trial, eligible patients (pts) included those ≥18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node Metastasis ≤1 mm or In-Transit Metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to Ipi 10 mg/kg (n = 475) or placebo (Pbo, n = 476) q3w for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included safety and health-related QoL. Results: Overall, 20%/44%/36% of pts had stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement. At a median follow-up of 2.7 yrs, Ipi significantly improved RFS vs Pbo (234/475 vs 294/476 events): median RFS 26.1 mos for Ipi vs 17.1 mos for Pbo (HR 0.75, 0.64–0.90; log-rank P = 0.0013). 3-yr RFS rates were 46.5% and 34.8%, respectively. RFS benefit was consistent across subgroups (e.g., stage IIIB or IIIC, ulcerated primary). Most common grade 3/4 immune-related adverse events (irAEs) in the Ipi and Pbo arms were gastrointestinal (15.9% vs 0.8%), hepatic (10.6% vs 0.2%), and endocrine (8.5% vs 0%). Most irAEs were managed and resolved using established algorithms. Of 471 pts who started Ipi, 245 (52%) discontinued treatment due to AEs (182 [38.6%] within 12 weeks); 5 (1.1%) died due to drug-related AEs. RFS analyses adjusted for prognostic factors and key HRQoL data will be presented. Conclusions: In this phase III trial, Ipi as adjuvant therapy provided a clinically and statistically significant improvement in RFS vs Pbo for pts with stage III melanoma at high risk of recurrence. AE profile was generally consistent with that observed in advanced melanoma, although with a higher incidence of endocrinopathies. Disclosure: A.M.M. Eggermont: Financial interest: Advisory boards for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, MedImmune, and MSD; V. Chiarion-Sileni: Advisory board participation: Bristol-Myers Squibb, GlaxoSmithKline, and Roche; J.-. Grob: Consultant or advisory role: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck; honoraria: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck; R. Dummer: Consultant or advisory role, honoraria, and research funding: AstraZeneca, Novartis, Cephalon, MSD, Bristol-Myers Squibb, GlaxoSmithKline, Roche, Amgen, Bayer; J.D. Wolchok: Grants and personal fees: Bristol-Myers Squibb, during conduct of the study; grants and personal fees from Medimmune, Glaxo SmithKline; personal fees: Merck Sharpe and Dohme, EMDSerono, Johnson and Johnson; H. Schmidt: Advisory board: Roche; speakers' bureau: Bristol-Myers Squibb; O. Hamid: Consultant or advisory role: Bristol-Myers Squibb; speakers' bureau: Bristol-Myers Squibb; research funding from Bristol-Myers Squibb to The Angeles Clinic; C. Robert: Consultant or advisory role: Bristol-Myers Squibb, GlaxoSmithKline, Roche, MSD; honoraria: Bristol-Myers Squibb, GlaxoSmithKline, Roche; P.A. Ascierto: Consultant or advisory role: Bristol-Myers Squibb, Roche-Genentech, MSD, GlaxoSmithKline, Novartis, Ventana; honoraria: Bristol-Myers Squibb, Roche-Genentech, GlaxoSmithKline; research funding: Bristol-Myers Squibb, Ventana; J.M. Richards: Stock ownership: Bristol-Myers Squibb; C. Lebbe: Advisory boards: Bristol-Myers Squibb, Roche, Novartis, GlaxoSmithKline, Amgen.; M. Smylie: Consultant or advisory role: Bristol-Myers Squibb; honoraria: Bristol-Myers Squibb; J.S. Weber: Advisory boards: Bristol-Myers Squibb (less than 10,000 USD annually for advisory boards); grants from Bristol-Myers Squibb to Moffitt for the conduct of the trial in question; M. Maio: Consultant or advisory role: Bristol-Myers Squibb; honoraria: Bristol-Myers Squibb; research funding: Bristol-Myers Squibb; C. Konto: Employee of Bristol-Myers Squibb; V. De Pril: Employee of Bristol-Myers Squibb; stock ownership: Bristol-Myers Squibb; A. Testori: Consultant or advisory role: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Amgen, Celgene; honoraria: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
Paolo A. Ascierto - One of the best experts on this subject based on the ideXlab platform.
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Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial
European journal of cancer (Oxford England : 1990), 2019Co-Authors: Alexander M.m. Eggermont, Vanna Chiarion-sileni, Jean Jacques Grob, Reinhard Dummer, Jedd D. Wolchok, Henrik Schmidt, Omid Hamid, Caroline Robert, Paolo A. Ascierto, Jon M. RichardsAbstract:Since 2015, adjuvant therapy with ipilimumab is an approved treatment for stage III melanoma based on a significantly prolonged recurrence-free survival (RFS). At a median follow-up of 5.3 years, RFS, distant Metastasis-free survival (DMFS) and overall survival (OS) were each significantly prolonged in the ipilimumab group compared with the placebo group, despite a 53.3% (ipilimumab) versus 4.6% (placebo) treatment discontinuation rate due to adverse events. We present now long-term follow-up results of this European Organisation for Research and Treatment of Cancer 18071 trial. A total of 99 sites randomised 951 patients with stage III cutaneous melanoma (excluding lymph node Metastasis ≤1 mm or In-Transit Metastasis) with adequate resection of lymph nodes to receive intravenous infusions of ipilimumab 10 mg/kg or placebo, every 3 weeks for 4 doses, then every 3 months for up to 3 years. The RFS, DMFS and OS, as reported by the local investigators, were assessed by the intention-to-treat analysis. Among 431 patients randomised at 63 sites and who were still alive at the analysis reported in 2016, recent follow-up information could be obtained for 264 patients. The median OS follow-up was 6.9 years. The RFS (hazard ratio [HR] 0.75, 95% confidence interval 0.63-0.88; P < 0.001), DMFS (HR 0.76, 0.64-0.90; P = 0.002) and OS (HR 0.73, 0.60-0.89; P = 0.002) benefit observed in the ipilimumab group was durable with an 8.7% absolute difference at 7 years for OS. The benefit was consistent across subgroups. Adjuvant therapy with ipilimumab prolongs RFS, DMFS and OS significantly. The benefit is sustained long term and consistent across subgroups. Copyright © 2019 Elsevier Ltd. All rights reserved.
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Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial
The Lancet. Oncology, 2017Co-Authors: Corneel Coens, Vanna Chiarion-sileni, Jean Jacques Grob, Reinhard Dummer, Jedd D. Wolchok, Henrik Schmidt, Omid Hamid, Caroline Robert, Stefan Suciu, Paolo A. AsciertoAbstract:The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial. Here, we report the results of the secondary endpoint, health-related quality of life (HRQoL), of this trial. EORTC 18071 was a multinational, double-blind, randomised, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node Metastasis ≤1 mm or In-Transit Metastasis) in 19 countries worldwide. Participants were randomly assigned (1:1) centrally by an interactive voice response system, to receive either ipilimumab 10 mg/kg or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. HRQoL was assessed with the EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and every 12 weeks thereafter up to 2 years, irrespective of disease progression. Results were summarised by timepoint and in a longitudinal manner in the intention-to-treat population. Two summary scores were calculated for each HRQoL scale: the average score reported during induction (ipilimumab or placebo at a dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43, and 64-ie, four doses in 3 weeks), and the average score reported after induction. A predefined threshold of a 10 point difference between arms was considered clinically relevant. The primary HRQoL endpoint was the global health scale, with the predefined hypothesis of no clinically relevant differences after induction between groups. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to treatment: 475 in the ipilimumab group and 476 in the placebo group. Compliance with completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693 (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global health scores during (77·32 [SD 17·36] vs 72·96 [17·82]; p=0·00011) and after induction (76·48 [17·52] vs 72·32 [18·60]; p=0·00067) were statistically significantly different between groups but were not clinically relevant. Mean global health scores differed most between the groups at week 7 (77 [SD 19] in the placebo group vs 72 [22] in the ipilimumab group) and week 10 (77 [20] vs 70 [23]). Mean HRQoL scores differed by more than 10 points at week 10 between treatment groups for diarrhoea (7·67 [SD 17·05] for placebo vs 18·17 [28·35] for ipilimumab) and insomnia (15·17 [22·53] vs 25·60 [29·19]). Despite increased toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3-4 investigator-reported adverse events. Bristol-Myers Squibb. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial
The Lancet. Oncology, 2015Co-Authors: Alexander M.m. Eggermont, Vanna Chiarion-sileni, Jean Jacques Grob, Reinhard Dummer, Jedd D. Wolchok, Henrik Schmidt, Omid Hamid, Caroline Robert, Paolo A. Ascierto, Jon M. RichardsAbstract:Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node Metastasis ≤1 mm or In-Transit Metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28-3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3-39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4-21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64-0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5-51·3) in the ipilimumab group versus 34·8% (30·1-39·5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome. Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant Metastasis-free survival and overall survival endpoints to define its definitive value. Bristol-Myers Squibb. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Ipilimumab versus placebo after complete resection of stage III melanoma: Initial efficacy and safety results from the EORTC 18071 phase III trial.
Journal of Clinical Oncology, 2014Co-Authors: Alexander M.m. Eggermont, Vanna Chiarion-sileni, Jean Jacques Grob, Reinhard Dummer, Jedd D. Wolchok, Henrik Schmidt, Omid Hamid, Caroline Robert, Paolo A. Ascierto, Jon M. RichardsAbstract:LBA9008 Background: Ipilimumab (Ipi), a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses, is an approved treatment for advanced melanoma. Here, we report the results of a phase III trial designed to evaluate Ipi as an adjuvant therapy for resected stage III melanoma at high risk of recurrence. Methods: In this randomized, double-blind trial, eligible patients (pts) included those ≥18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node Metastasis ≤1 mm or In-Transit Metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to receive Ipi 10 mg/kg (n=475) or placebo (Pbo, n=476) every 3 wks for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. The primary endpoint was recurrence-free survival (RFS), analyzed on the intent-to-treat population. 512 RFS events (recurrence or death) were needed to provide 90% power to detect an Ip...
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1087OEFFICACY, SAFETY, AND QUALITY OF LIFE (QOL) DATA FROM THE EORTC 18071 PHASE III TRIAL OF IPILIMUMAB (IPI) VERSUS PLACEBO AFTER COMPLETE RESECTION OF STAGE III MELANOMA
Annals of Oncology, 2014Co-Authors: A. M. M. Eggermont, Vanna Chiarion-sileni, Jean Jacques Grob, Reinhard Dummer, Jedd D. Wolchok, Henrik Schmidt, Omid Hamid, Caroline Robert, Paolo A. Ascierto, Jon M. RichardsAbstract:ABSTRACT Aim: Ipi, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses, is an approved treatment for advanced melanoma. We report primary efficacy data and ongoing analyses from a phase III trial to evaluate Ipi as an adjuvant therapy for resected stage III melanoma at high risk of recurrence. Methods: In this randomized, double-blind trial, eligible patients (pts) included those ≥18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node Metastasis ≤1 mm or In-Transit Metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to Ipi 10 mg/kg (n = 475) or placebo (Pbo, n = 476) q3w for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included safety and health-related QoL. Results: Overall, 20%/44%/36% of pts had stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement. At a median follow-up of 2.7 yrs, Ipi significantly improved RFS vs Pbo (234/475 vs 294/476 events): median RFS 26.1 mos for Ipi vs 17.1 mos for Pbo (HR 0.75, 0.64–0.90; log-rank P = 0.0013). 3-yr RFS rates were 46.5% and 34.8%, respectively. RFS benefit was consistent across subgroups (e.g., stage IIIB or IIIC, ulcerated primary). Most common grade 3/4 immune-related adverse events (irAEs) in the Ipi and Pbo arms were gastrointestinal (15.9% vs 0.8%), hepatic (10.6% vs 0.2%), and endocrine (8.5% vs 0%). Most irAEs were managed and resolved using established algorithms. Of 471 pts who started Ipi, 245 (52%) discontinued treatment due to AEs (182 [38.6%] within 12 weeks); 5 (1.1%) died due to drug-related AEs. RFS analyses adjusted for prognostic factors and key HRQoL data will be presented. Conclusions: In this phase III trial, Ipi as adjuvant therapy provided a clinically and statistically significant improvement in RFS vs Pbo for pts with stage III melanoma at high risk of recurrence. AE profile was generally consistent with that observed in advanced melanoma, although with a higher incidence of endocrinopathies. Disclosure: A.M.M. Eggermont: Financial interest: Advisory boards for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, MedImmune, and MSD; V. Chiarion-Sileni: Advisory board participation: Bristol-Myers Squibb, GlaxoSmithKline, and Roche; J.-. Grob: Consultant or advisory role: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck; honoraria: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck; R. Dummer: Consultant or advisory role, honoraria, and research funding: AstraZeneca, Novartis, Cephalon, MSD, Bristol-Myers Squibb, GlaxoSmithKline, Roche, Amgen, Bayer; J.D. Wolchok: Grants and personal fees: Bristol-Myers Squibb, during conduct of the study; grants and personal fees from Medimmune, Glaxo SmithKline; personal fees: Merck Sharpe and Dohme, EMDSerono, Johnson and Johnson; H. Schmidt: Advisory board: Roche; speakers' bureau: Bristol-Myers Squibb; O. Hamid: Consultant or advisory role: Bristol-Myers Squibb; speakers' bureau: Bristol-Myers Squibb; research funding from Bristol-Myers Squibb to The Angeles Clinic; C. Robert: Consultant or advisory role: Bristol-Myers Squibb, GlaxoSmithKline, Roche, MSD; honoraria: Bristol-Myers Squibb, GlaxoSmithKline, Roche; P.A. Ascierto: Consultant or advisory role: Bristol-Myers Squibb, Roche-Genentech, MSD, GlaxoSmithKline, Novartis, Ventana; honoraria: Bristol-Myers Squibb, Roche-Genentech, GlaxoSmithKline; research funding: Bristol-Myers Squibb, Ventana; J.M. Richards: Stock ownership: Bristol-Myers Squibb; C. Lebbe: Advisory boards: Bristol-Myers Squibb, Roche, Novartis, GlaxoSmithKline, Amgen.; M. Smylie: Consultant or advisory role: Bristol-Myers Squibb; honoraria: Bristol-Myers Squibb; J.S. Weber: Advisory boards: Bristol-Myers Squibb (less than 10,000 USD annually for advisory boards); grants from Bristol-Myers Squibb to Moffitt for the conduct of the trial in question; M. Maio: Consultant or advisory role: Bristol-Myers Squibb; honoraria: Bristol-Myers Squibb; research funding: Bristol-Myers Squibb; C. Konto: Employee of Bristol-Myers Squibb; V. De Pril: Employee of Bristol-Myers Squibb; stock ownership: Bristol-Myers Squibb; A. Testori: Consultant or advisory role: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Amgen, Celgene; honoraria: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
