Papers by Alexander Eggermont
Oncoimmunology, 2017
Melanoma has been the most important cancer to drive immunotherapy development in the field of so... more Melanoma has been the most important cancer to drive immunotherapy development in the field of solid tumors. Where immune-stimulating approaches with cytokines in the 1980s and 1990s lead to approvals of interferon-alpha and interleukin-2, the clinical impact was rather small. Since 2010 immunotherapy has been revolutionized by the concept of breaking tolerance. It represents a major paradigm shift that marks the beginning of a new era. The impact of the first checkpoint inhibitors, i.e., anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) and anti-PD1/anti-PDL1 (programmed death-1 receptor and its ligand PD-L1), is unprecedented. In only 5 years advanced melanoma has been transformed from an incurable disease into a curable disease in over 50% of metastatic patients. We are only at the beginning of discovering its transversal impact throughout oncology. FDA-approved treatments for melanoma are at present: interferon-alpha as adjuvant therapy (1996), interleukin-2 (1998) for advanced disease, and more recently pegylated interferon-alpha as adjuvant therapy (2011). For the treatment of advanced disease approvals were obtained for the immune checkpoint inhibitors ipilimumab (2011), nivolumab (2014), pembrolizumab (2014) and the combination ipilimumab + nivolumab (2015), and the oncolytic virus vaccine laherparepvec (T-VEC) in 2015. Ipilimumab is the first checkpoint inhibitor that has also been approved as adjuvant therapy for high-risk stage III melanoma (2015). Results regarding adjuvant therapy with either nivolumab or pembrolizumab are expected in 2018. Further developments in the field of melanoma are focused on combination therapies between various immunotherapeutic agents, such as vaccines and antibodies, and combination therapies between immunotherapeutic agents with chemotherapeutic or targeted agents or even radiation therapy. Thanks to in particular anti-PD1/anti-PDL1-based immunotherapies, the activity of the combination of anti-PD1/anti-CTLA4 immunotherapy is now developed in a transversal manner across multiple tumor types (a.o. lung, head and neck, esophageal/gastric, liver, MSI-colorectal, MSI-any tumor type, renal, bladder cancers, and Hodgkin lymphoma) with unprecedented success.
Annals of surgical oncology, 2017
Nature reviews. Clinical oncology, 2014
For cancer therapies to succeed, induction of an anticancer immune response is required. Immuno-o... more For cancer therapies to succeed, induction of an anticancer immune response is required. Immuno-oncology approaches are shaping the treatment landscape for patients with advanced-stage melanoma and other solid tumours. These new approaches may enhance immune system activity to improve outcomes, including the potential to achieve long-term survival benefits in many patients.
Nature reviews. Clinical oncology, Jan 10, 2012
Melanoma has emerged as the paradigm tumor for drug development through mutation-targeted therapi... more Melanoma has emerged as the paradigm tumor for drug development through mutation-targeted therapies (inhibitors targeting BRAF, MEK, and c-KIT) and immunotherapy. Exploring the combinations of both approaches is a challenge that will require scientific rationale and the cooperation of the pharmaceutical industry. But, with these challenges comes another opportunity to change the paradigms in drug development.
Nederlands tijdschrift voor geneeskunde, Jan 21, 2002
Elective lymph node dissection is selectively performed in patients with clinically localised mel... more Elective lymph node dissection is selectively performed in patients with clinically localised melanoma. Randomised studies suggest that survival is improved only in a few subgroups of patients, whereas all patients are exposed to the substantial risk of operative morbidity. Sentinel node biopsy enables the early detection of lymph node metastases from melanoma with less morbidity. The technique has been standardised. The sentinel node can be identified in almost 100% of the patients. The tumour status of the node is the most important prognostic factor in patients with clinically localised melanoma. This information is essential for studies of adjuvant systemic treatment. Regrettably, there is confusion about the definition of a sentinel node. In addition, the sensitivity of the sentinel node approach is unclear. Furthermore, it is uncertain whether early lymph node dissection improves regional control and survival. Sentinel node biopsy is not yet the standard of care.
Journal of Clinical Oncology, 2006
Purpose A pegylated interferon, peginterferon alfa-2a (PEG-IFNα-2a; 40 kd), has the potential for... more Purpose A pegylated interferon, peginterferon alfa-2a (PEG-IFNα-2a; 40 kd), has the potential for improved tumor response and survival with lower toxicity than IFNα. This open-label, randomized study evaluated the safety, tolerability, and efficacy of subcutaneous PEG-IFNα-2a in patients with metastatic malignant melanoma (stage IV American Joint Committee on Cancer staging system). Patients and Methods PEG-IFNα-2a was administered subcutaneously at 180 (n = 48), 360 (n = 53), or 450 μg (n = 49) once weekly for 24 weeks, with maintenance therapy for responders. Efficacy was assessed by the proportion of patients with complete response (CR) or partial response (PR). Results The major response rate (CR or PR) was 6% in the 180-μg group (CR, 2%; PR, 4%), 8% in the 360-μg group (CR, 2%; PR, 6%), and 12% in the 450-μg group (CR, 6%; PR, 6%). The times to achieve a major response, duration of major response, rate of disease progression, and 12-month survival were similar between groups, a...
Journal of Clinical Oncology, 2012
Purpose Adjuvant pegylated interferon alfa-2b (PEG-IFN-α-2b) was approved for treatment of resect... more Purpose Adjuvant pegylated interferon alfa-2b (PEG-IFN-α-2b) was approved for treatment of resected stage III melanoma in 2011. Here, we present long-term follow-up results of this pivotal trial. Patients and Methods In all, 1,256 patients with resected stage III melanoma were randomly assigned to observation (n = 629) or PEG-IFN-α-2b (n = 627) for an intended duration of 5 years. Stratification factors were microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumor thickness, sex, and center. Recurrence-free survival (RFS; primary end point), distant metastasis-free survival (DMFS), and overall survival (OS) were analyzed for the intent-to-treat population. Results At 7.6 years median follow-up, 384 recurrences or deaths had occurred with PEG-IFN-α-2b versus 406 in the observation group (hazard ratio [HR], 0.87; 95% CI, 0.76 to 1.00; P = .055); 7-year RFS rate was 39.1% versus 34.6%. There was no difference in OS (P = .57). In stage I...
European Journal of Surgical Oncology (EJSO), 2009
Aim: Ocular melanoma prefers to metastasize to the liver and the liver is the sole site of metast... more Aim: Ocular melanoma prefers to metastasize to the liver and the liver is the sole site of metastatic disease in 80% of patients. Until now there has been no standard treatment available and these patients have a very poor prognosis (median survival 2e5 months). Isolated hepatic perfusion may be an option in patients with irresectable hepatic ocular melanoma metastases. The aim of this study was to evaluate applicability, toxicity and response in this selected group of ocular melanoma patients by treatment with isolated hypoxic hepatic perfusion with retrograde outflow (IHHP) with melphalan. Methods: From September 2002 until July 2006 eight consecutive patients were included in this study. IHHP was performed with inflow via the hepatic artery and retrograde outflow via the portal vein during 25 min with 1 mg/kg melphalan. The perfusion was followed by a complete wash-out procedure. Results: The median total operation time was 4 h with a median blood/fluid loss of 1100 ml. No postoperative mortality was observed. Median hospital stay was 9.5 days. Toxicity was moderate: WHO grade 3 leukocytopenia in 3 patients, grade 3 hepatic toxicity in 1 patient. In 37% of patients (3/8) a partial response could be demonstrated 3 months after IHHP. Stable disease was found in 3 patients and progressive disease in 2 patients. Median time to local progression was 6 months and the median survival was 11 months. Conclusion: Melphalan-based IHHP with retrograde outflow is a safe treatment option for patients with irresectable ocular melanoma metastases. Survival benefit seems to be comparable to classical IHHP.
British Journal of Surgery, 2012
Background The therapeutic value of immediate completion lymph node dissection (CLND) for sentine... more Background The therapeutic value of immediate completion lymph node dissection (CLND) for sentinel node (SN)-positive melanoma is unknown. The aim of this study was to evaluate the impact of immediate CLND on the outcome of patients with SN-positive melanoma. Methods Patients with SN metastases treated between 1993 and 2008 at ten cancer centres from the European Organization for Research and Treatment of Cancer Melanoma Group were included in this retrospective study. Maximum tumour size, intranodal location and penetrative depth of SN metastases were measured. Outcome in those who had CLND was compared with that in patients who did not undergo completion lymphadenectomy. Results Of 1174 patients with SN-positive melanoma, 1113 (94·8 per cent) underwent CLND and 61 (5·2 per cent) did not. Median follow-up for the two groups was 34 and 48 months respectively. In univariable survival analysis, CLND did not significantly influence disease-specific survival (hazard ratio (HR) 0·89, 95 ...
European Journal of Cancer, 2021
The Italian Network for Tumor Biotherapy (Network Italiano per la Bioterapia dei Tumori [NIBIT]) ... more The Italian Network for Tumor Biotherapy (Network Italiano per la Bioterapia dei Tumori [NIBIT]) Foundation hosted its annual 2020 Think Tank meeting virtually, at which representatives from academic, clinical, industry, philanthropic, and regulatory organisations discussed the role of neoadjuvant immunotherapy for the treatment of cancer. Although the number of neoadjuvant immunotherapeutic trials is increasing across all malignancies, the Think Tank focused its discussion on the status of neoadjuvant trials in cutaneous melanoma (CM), muscle-invasive urothelial bladder cancer (MIBC), head and neck squamous cell carcinoma (HNSCC), and pancreatic adenocarcinoma (PDAC). Neoadjuvant developments in CM are nothing short of trailblazing. Pathologic Complete Response (pCR), pathologic near Complete Response, and partial Pathologic Responses reduce 90-100% of recurrences. This is in sharp contrast to targeted therapies in neoadjuvant CM trials, where only a pCR seems to reduce recurrence. The pCR rate after neoadjuvant immunotherapy varies among the different malignancies of CM, MIBC, HNSCC, and PDAC and may be associated with different reductions of recurrence rates. In CM, emerging evidence suggests that neoadjuvant immunotherapy with anti-CTLA-4 plus anti-PD1 is a game changer in patients with palpable nodal Stage III or resectable Stage IV disease by curing more patients, reducing recurrences and the need for surgical interventions, such as lymph node dissections and metastasectomies. The Think Tank panel discussed future approaches on how to optimise results across different tumour types. Future approaches should include reducing monocyte-mediated (tumour-associated macrophages) and fibroblast-mediated (cancer-associated fibroblasts) barriers in the tumour microenvironment to facilitate the recruitment of immune cells to the tumour site, to reduce immune-suppressive mediators, and to increase antigen presentation at the site of the tumour.
Cancer Discovery, 2021
Summary: Comprehensive genomic and transcriptomic analysis for guiding therapeutic decisions prov... more Summary: Comprehensive genomic and transcriptomic analysis for guiding therapeutic decisions provide the basis of precision cancer medicine. In this issue of Cancer Discovery, continued progress in this field is demonstrated by two large collaborative studies: Horak and colleagues in the MASTER trial for patients with rare cancers and Van Tilburg and colleagues in the INFORM registry in pediatric tumors. See related article by van Tilburg et al., p. 2764. See related article by Horak et al., p. 2780.
Future Oncology, 2022
Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to ... more Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to deliver a controlled, sustained and preferential IL-2 pathway signal. Nivolumab (NIVO), a PD-L1 inhibitor, has been shown to prolong survival in patients with advanced melanoma and recurrence-free survival in the adjuvant setting. PIVOT-02 showed that BEMPEG plus NIVO was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. PIVOT-12 is a randomized, Phase III, global, multicenter, open-label study comparing adjuvant therapy with BEMPEG plus NIVO versus NIVO alone in adult and adolescent patients with completely resected cutaneous stage III/IV melanoma at high risk of recurrence. The primary objective is to compare the efficacy, as measured by recurrence-free survival, of BEMPEG plus NIVO versus NIVO.
European Journal of Cancer, 2019
Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multidiscipl... more Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multidisciplinary experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization of Research and Treatment of Cancer collaborated to develop recommendations on diagnosis and treatment of BCC. A new classification into 'easy-to-treat (common) BCC and 'difficult-to-treat' BCC is proposed. Diagnosis is based on clinicodermatoscopic features for 'easy-to-treat' BCCs. Histopathological confirmation is mandatory in ambiguous lesions and in BCCs located in high-risk areas. The first-line treatment of 'easy-to-treat' BCC is complete surgery. Microscopically controlled surgery shall be offered for high-risk BCC, recurrent BCC and BCC in critical anatomical sites. Topical therapies (5% imiquimod, 5% fluorouracil) and destructive approaches (curettage, electrocautery, cryotherapy, laser ablation) should be considered in patients with lowrisk superficial BCC. Photodynamic therapy is an effective treatment for superficial BCC and thin nodular BCC. The therapy for a 'difficult-to-treat' BCC should preferentially be discussed by a multidisciplinary tumour board. Hedgehog inhibitors, vismodegib or sonidegib, should be offered to patients with locally advanced and metastatic BCCs. Immunotherapy with antieprogrammed cell death 1 (PD-1) antibodies is a promising therapeutic option, currently being investigated in clinical trials. Radiotherapy represents a valid alternative to surgery for BCC on the face, especially in elderly patients. In patients with naevoid basal cell carcinoma syndrome (NBCCS), close surveillance and regular skin examinations are required to diagnose and treat BCCs at early stage. Long-term follow-up is recommended in patients with high-risk BCC subtypes, high-risk sites, multiple BCCs and NBCCS.
European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology, Jan 27, 2016
Worldwide, sentinel node biopsy (SNB) is the recommended staging procedure for stage I/II melanom... more Worldwide, sentinel node biopsy (SNB) is the recommended staging procedure for stage I/II melanoma. Most melanoma guidelines recommend re-excision plus SNB as soon as possible after primary excision. To date, there is no evidence to support this timeframe. To determine melanoma specific survival (MSS) for time intervals between excisional biopsy and SNB in SNB positive patients. Between 1993 and 2008, 1080 patients were diagnosed with a positive SNB in nine Melanoma Group centers. We selected 1015 patients (94%) with known excisional biopsy date. Time interval was calculated from primary excision until SNB. Kaplan-Meier estimated MSS was calculated for different cutoff values. Multivariable analysis was performed to correct for known prognostic factors. Median age was 51 years (Inter Quartile Range (IQR) 40-62 years), 535 (53%) were men, 603 (59%) primary tumors were located on extremities. Median Breslow thickness was 3.00 mm (IQR 1.90-4.80 mm), 442 (44%) were ulcerated. Median fol...
Journal of Clinical Investigation, 2016
instructions and acquired on a multicolor CyAn ADP 9 Color Flow Cytometer (Beckman Coulter). Anal... more instructions and acquired on a multicolor CyAn ADP 9 Color Flow Cytometer (Beckman Coulter). Analyses were performed using Flow Cytomix Pro 3.0 Software (eBioscience).
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Papers by Alexander Eggermont