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1. PIVOT-12: a Phase III study of adjuvant bempegaldesleukin plus nivolumab in resected stage III/IV melanoma at high risk for recurrence

Author

Eggermont, AMM, Ascierto, PA, Khushalani, NI, Schadendorf, D, Boland, G, Weber, J, Lewis, KD, Johnson, D, Rivalland, G, Khattak, A, Majem, M, Gogas, H, Long, GV, Currie, SL, Chien, D, Tagliaferri, MA, Carlino, MS, and Diab, A

Subjects
nivolumab, PD-L1, cutaneous melanoma, adjuvant, NKTR-214, IL-2 pathway, PD-1, immunotherapy, immune checkpoint inhibitor combinations, bempegaldesleukin
Abstract

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 Ill, 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. Lay abstract: Following surgery, patients with advanced melanoma may require further treatment to reduce the likelihood of disease recurrence. Nivolumab (NIVO), a checkpoint inhibitor, reduces the risk of melanoma recurrence by enhancing the ability of the immune system to fight disease. Despite the availability of NIVO and other therapies, many patients with melanoma still experience disease recurrence after surgery. This article presents information on a clinical trial named PIVOT-12, which aims to assess the effectiveness of a new investigational drug called bempegaldesleukin that modifies the immune system and is given with NIVO to patients with stage III/IV melanoma following surgery. The main end point being measured is recurrence-free survival, which measures the time between a patient starting the study and the date of disease recurrence.

Published
2022

2. Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase III trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma

Author

Eggermont, AMM, Meshcheryakov, A, Atkinson, V, Blank, CU, Mandala, M, Long, G, Barrow, C, Di Giacomo, AM, Fisher, R, Sandhu, S, Kudchadkar, R, Romero, PLO, Svane, IM, Larkin, J, Puig, S, Hersey, P, Quaglino, P, Queirolo, P, Stroyakovskiy, D, Bastholt, L, Mohr, P, Hernberg, M, Chiarion-Sileni, V, Strother, M, Hauschild, A, Yamazaki, N, van Akkooi, AC, Lorigan, P, Krepler, C, Ibrahim, N, Marreaud, S, Kicinski, M, Suciu, S, Robert, C, Eggermont, AMM, Meshcheryakov, A, Atkinson, V, Blank, CU, Mandala, M, Long, G, Barrow, C, Di Giacomo, AM, Fisher, R, Sandhu, S, Kudchadkar, R, Romero, PLO, Svane, IM, Larkin, J, Puig, S, Hersey, P, Quaglino, P, Queirolo, P, Stroyakovskiy, D, Bastholt, L, Mohr, P, Hernberg, M, Chiarion-Sileni, V, Strother, M, Hauschild, A, Yamazaki, N, van Akkooi, AC, Lorigan, P, Krepler, C, Ibrahim, N, Marreaud, S, Kicinski, M, Suciu, S, and Robert, C

Abstract

BACKGROUND: In the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence-free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I-V and of grade III-V immune-related adverse events (irAEs) was 37% and 7%, respectively. METHODS: Patients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence ≥6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes. RESULTS: At the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over ('crossover'). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence ≥6 months later, in which 20 (43%) entered the rechallenge part 2 ('rechallenge'). In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7-15.2) and the 3-year PFS rate was 32% (95% CI 25-40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48-83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6-NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I-IV irAE and 11 (6%) had a grade III-IV irAE. CONCLUSIONS: Pembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32%

Published
2021

3. 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

Author

Eggermont, AMM, Kicinski, M, Blank, CU, Mandala, M, Long, GV, Atkinson, V, Dalle, S, Haydon, A, Khattak, A, Carlino, MS, Sandhu, S, Larkin, J, Puig, S, Ascierto, PA, Rutkowski, P, Schadendorf, D, Koornstra, R, Hernandez-Aya, L, Di Giacomo, AM, van den Eertwegh, AJM, Grob, J-J, Gutzmer, R, Jamal, R, Lorigan, PC, Krepler, C, Ibrahim, N, Marreaud, S, van Akkooi, A, Robert, C, Suciu, S, Eggermont, AMM, Kicinski, M, Blank, CU, Mandala, M, Long, GV, Atkinson, V, Dalle, S, Haydon, A, Khattak, A, Carlino, MS, Sandhu, S, Larkin, J, Puig, S, Ascierto, PA, Rutkowski, P, Schadendorf, D, Koornstra, R, Hernandez-Aya, L, Di Giacomo, AM, van den Eertwegh, AJM, Grob, J-J, Gutzmer, R, Jamal, R, Lorigan, PC, Krepler, C, Ibrahim, N, Marreaud, S, van Akkooi, A, Robert, C, and Suciu, S

Abstract

IMPORTANCE: Whether immune-related adverse events (irAEs) indicate drug activity in patients treated with immune checkpoint inhibitors remains unknown. OBJECTIVE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: 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. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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

Published
2020

4. 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

Author

Eggermont, AMM, Blank, CU, Mandala, M, Long, GV, Atkinson, VG, Dalle, S, Haydon, AM, Meshcheryakov, A, Khattak, A, Carlino, MS, Sandhu, S, Larkin, J, Puig, S, Ascierto, PA, Rutkowski, P, Schadendorf, D, Koornstra, R, Hernandez-Aya, L, Di Giacomo, AM, van den Eertwegh, AJM, Grob, J-J, Gutzmer, R, Jamal, R, Lorigan, PC, van Akkooi, ACJ, Krepler, C, Ibrahim, N, Marreaud, S, Kicinski, M, Suciu, S, Robert, C, Eggermont, AMM, Blank, CU, Mandala, M, Long, GV, Atkinson, VG, Dalle, S, Haydon, AM, Meshcheryakov, A, Khattak, A, Carlino, MS, Sandhu, S, Larkin, J, Puig, S, Ascierto, PA, Rutkowski, P, Schadendorf, D, Koornstra, R, Hernandez-Aya, L, Di Giacomo, AM, van den Eertwegh, AJM, Grob, J-J, Gutzmer, R, Jamal, R, Lorigan, PC, van Akkooi, ACJ, Krepler, C, Ibrahim, N, Marreaud, S, Kicinski, M, Suciu, S, and Robert, C

Abstract

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Published
2020

6. The interval between primary melanoma excision and sentinel node biopsy is not associated with survival in sentinel node positive patients - An EORTC Melanoma Group study

Author

Oude Ophuis, Charlotte, Verhoef, Kees, Rutkowski, P, Powell, Bwem, van der Hage, JA, van Leeuwen, PAM, Voit, CA, Testori, A, Robert, C, Hoekstra, HJ, Grunhagen, DJ, Eggermont, AMM, van Akkooi, ACJ, Oude Ophuis, Charlotte, Verhoef, Kees, Rutkowski, P, Powell, Bwem, van der Hage, JA, van Leeuwen, PAM, Voit, CA, Testori, A, Robert, C, Hoekstra, HJ, Grunhagen, DJ, Eggermont, AMM, and van Akkooi, ACJ

Published
2016

8. Improved survival with vemurafenib in melanoma with BRAF V600E mutation

Author

Chapman, Pb, Hauschild, A, Robert, C, Haanen, Jb, Ascierto, P, Larkin, J, Dummer, R, Garbe, C, Testori, A, Maio, M, Hogg, D., Lorigan, P, Lebbe, C, Jouary, T, Schadendorf, D, Ribas, A, O'Day, Sj, Sosman, Ja, Kirkwood, Jm, Eggermont, Amm, Dreno, B, Nolop, K, Li, J, Nelson, B, Hou, J, Lee, Rj, Flaherty, Kt, Mcarthur, Ga, BRIM-3 Study Group, Cognetti, F, University of Zurich, Surgery, Erasmus MC other, and Cell biology

Subjects
Oncology, Adult, Male, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Keratoacanthoma, Indoles, Dacarbazine, Medizin, Ipilimumab, 610 Medicine & health, Antineoplastic Agents, 2700 General Medicine, Disease-Free Survival, adult, aged, aged, 80 and over, antineoplastic agents, dacarbazine, disease-free survival, female, humans, indoles, intention to treat analysis, male, melanoma, middle aged, mutation, proto-oncogene proteins B-raf, sulfonamides, survival analysis, vemurafenib, young adult, chemistry.chemical_compound, Young Adult, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Vemurafenib, Melanoma, Survival analysis, Aged, Cobimetinib, Aged, 80 and over, Sulfonamides, business.industry, 10177 Dermatology Clinic, General Medicine, Middle Aged, medicine.disease, Survival Analysis, Surgery, Intention to Treat Analysis, chemistry, Mutation, Female, business, V600E, medicine.drug
Abstract

BACKGROUND Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. METHODS We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. RESULTS At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P < 0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. CONCLUSIONS Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)

Published
2011

9. Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized Phase II study

Author

Lienard, D, Eggermont, AMM, Kroon, B, Towse, G, Schmitz, P, Steinmann, G, Rosenkaimer, F, Lejeune, FJ, Schraffordt Koops, H., and Faculteit Medische Wetenschappen/UMCG

Subjects
IFN-GAMMA, AUGMENTATION, RAT, TRIAL, HYPERTHERMIA, COMBINATION, TNF-ALPHA, CANCER, SARCOMA, TOXICITY
Abstract

This open, multicentre, randomized phase II trial was conducted to determine the effect of isolated limb perfusion (ILP) with tumour necrosis factor-alpha (TNF alpha) in combination with melphalan with or without interferon-gamma (IFN gamma) in patients with in-transit metastases of melanoma of the limbs (MD Anderson stage IIIA or IIIAB, AJCC stage III). The 64 patients included were randomized to receive either a two- drug regimen consisting of TNF alpha and melphalan (TM-ILP) or a three-drug regimen consisting of TNF alpha, melphalan and INF gamma (TIM-ILP). Patients randomized to receive IFN gamma were pretreated for 2 days before the ILP with once daily 0.2 mg IFN gamma subcutaneously and also received the same amount of IFN gamma during ILP. A total of 47 complete responses (73%) were reported, 22 (69%) of which occurred in the TM-ILP group and 25 (78%) in the TIM-ILP group; the difference was not significant. The 14 partial responses (22%) were split evenly between the treatment groups. In the TM-ILP group, two cases of stable disease and one case of progressive disease were reported. The overall response rate (complete plus partial responses) was 100% in the TIM-ILP group and 91% in the TM-ILP group, yielding an overall response of 95% for this study. In the historical control data, where 103 patients had received melphalan alone (M-ILP), there were 54 records of complete responses (52%) and 80 of complete or partial responses (78%). The median survival time estimated by the Kaplan-Meier method was 819 days for the TM-ILP group, > 705 days for the TIM-ILP group and 873 days for the combined study population; estimates for time to local progression or recurrence were 327 days, in excess of 498 days and 405 days, respectively. The corresponding figure for the historical controls was 338 days. These data suggest that TNF alpha associated with melphalan may be superior to melphalan alone for ILP. (C) 1999 Lippincott Williams & Wilkins.

Published
1999

10. Hyperthermic isolated limb perfusion with tumor necrosis factor alpha, interferon gamma, and melphalan for locally advanced nonmelanoma skin tumors of the extremities: a multicenter study

Author

Olieman, AFT, Lienard, D, Eggermont, AMM, Kroon, BBR, Lejeune, FJ, Hoekstra, HJ, Schraffordt Koops, H., and Surgery

Subjects
SOFT-TISSUE SARCOMAS, ACTIVATION, CELL-CARCINOMA, ISOLATED REGIONAL PERFUSION, SALVAGE, MELANOMA, CHEMOTHERAPY, COMBINATION
Abstract

Background: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor alpha (TNF-alpha), interferon gamma, and melphalan has proved to be useful in the treatment of recurrent malignant melanoma and of locally advanced soft tissue sarcomas of the extremities. Objective: To determine whether this modality is also effective in the treatment of locally advanced nonmelanoma skin tumors of the extremities. Patients and Methods: Fifteen patients with locally advanced primary, recurrent, or metastatic skin tumors of the extremities (12 with squamous cell carcinoma and 3 with Merkel cell carcinoma) underwent HILP with TNF-alpha, interferon gamma, and melphalan. Six tumors were localized in the upper extremity (40%), and 9 in the lower extremity (60%). Treatment-related complications, limb salvage rate, local recurrence, and regional and distant metastases were scored during a median follow-up of 20 months. Results: After HILP, 9 patients (60%) Showed a complete response (with histopathological confirmation). Four patients (27%) showed a partial response (with histopathological confirmation in 1 patient), and 2 patients (13%) showed no change (with histopathological confirmation in 1 patient and with clinical evidence in 1 patient). Two patients (13%) showed treatment-related complications. The limb salvage was achieved in 12 patients (80%), and the local recurrences developed in 4 patients (27%). During follow-up, regional lymph node metastases were observed in 2 patients (13%) and distant metastases in 2 patients (13%). Conclusion: Based on our results, HILP with TNF-alpha, interferon gamma, and melphalan should be considered as a limb-saving treatment modality in patients with locally advanced nonmelanoma skin tumors of the extremities who would otherwise be candidates for ablative surgery.

Published
1999

11. Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial

Author

Vaglini, M, Suciu, S, Kroon, BBR, Thompson, JF, Gohl, J, Eggermont, AMM, Di Filippo, F, Krementz, ET, Ruiter, D, Lejeune, FJ, Schraffordt Koops, H., and Surgery

Subjects
LYMPH-NODE DISSECTION, THICKNESS, MELPHALAN, MANAGEMENT, REGIONAL ISOLATED PERFUSION, Tumor pathology, Tumor pathologie, EFFICACY, MM, STAGE-I MELANOMA, EXTREMITY PERFUSION, MALIGNANT-MELANOMA
Abstract

Purpose: Patients with primary cutaneous melanoma greater than or equal to 1.5 mm in thickness are at high risk of having regional micrometastases at the time of initial surgical treatment. A phase III international study was designed to evaluate whether prophylactic isolated limb perfusion (ILP) could prevent regional recurrence and influence survival. Patients and Methods: A total of 832 assessable patients from 16 centers entered the study; 412 were randomized to wide excision (WE) only and 420 to WE plus ILP with melphalan and mild hyperthermia, Median age was 50 years, 68% of patients were female, 79% of melanomas were located on a lower limb, and 47% had a thickness greater than or equal to 3 mm. Results: Median follow-vp duration is 6.4 years. There was a trend for a longer disease-free interval (DFI) after ILP. The difference was significant for patients who did not undergo elective lymph node dissection (ELND), The impact of ILP was clearly on the occurrence - as first site of progression - of in transit metastases (ITM), which were reduced from 6.6% to 3,3%, and of regional lymph node (RLN) metastases, with a reduction from 16.7% to 12.6%, There was no benefit from lip in terms of time to distant metastasis or survival. Side effects were higher after ILP, but transient in most patients. There were two amputations for limb toxicity after ILP, Conclusion: prophylactic ILP with melphalan cannot be recommended as an adjunct to standard surgery in high-risk primary limb melanoma, J Clin Oncol 16:2906-2912. (C) 1998 by American Society of Clinical Oncology.

Published
1998

12. Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas - The cumulative multicenter European experience

Author

Eggermont, AMM, Klausner, JM, Kroon, BBR, Schlag, PM, Lienard, D, vanGeel, AN, Hoekstra, HJ, Meller, [No Value], Nieweg, OE, Kettelhack, C, BenAri, G, Pector, JC, Lejeune, FJ, Schraffordt Koops, H., and Faculteit Medische Wetenschappen/UMCG

Subjects
REGIONAL PERFUSION, PHASE-I, INTERFERON-GAMMA, RTNF-ALPHA, HUMAN-MELANOMA, FACTOR-ALPHA, CANCER-PATIENTS, RECURRENCE, TNF-ALPHA, THERAPY
Abstract

Objective The objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion (ILP) with tumor necrosis factor (TNF) + melphalan (M) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible. Summary Background Data To increase the number of limb-sparing resections in the treatment of locally advanced extremity soft tissue sarcoma, preoperative radiation therapy or chemotherapy or a combination of the two often are applied. The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results. The efficacy of the application of TNF in ILP markedly has changed this situation. Methods In 8 cancer centers, 186 patients were treated over a period oi almost 4.5 years. There were 107 (57%) primary and 79 (43%) recurrent sarcomas, mostly high grade (110 grade III; 51 grade II; and 25 very large, recurrent, or multiple grade I sarcomas). The composition of this series of patients is unusual: 42 patients (23%) had multifocal primary or multiple recurrent tumors; median tumor size was very large (16 cm); 25 patients (13%) had known systemic metastases at the time of the ILP. Patients underwent a 90-minute ILP at 39 to 40 C with TNF + melphalan. The first 55 patients also received interieron-tau. A delayed marginal resection of the tumor remnant was done 2 to 4 months after ILP. Results A major tumor response was seen in 82% of the patients rendering these large sarcomas resectable in most cases. Clinical response rates were: 33 complete response (CR) (18%), 106 partial response (PR) (57%), 42 no change (NC) (22%), and 5 progressive disease (PD) (3%). Final outcome was defined by clinical and pathologic response: 54 CR (29%), 99 PR (53%), 29 NC (16%), and 4 PD (2%). At a median follow-up of almost 2 years (22 months; range, 6-58 months), limb salvage was achieved in 82%. Regional toxicity was limited and systemic toxicity minimal to moderate, easily managed, with no toxic deaths. Conclusions In the setting of isolated limb perfusion, TNF is an active anticancer drug in patients. The ILP with TNF + melphalan can be performed safely in many centers and is an effective induction treatment with a high response rate that can achieve limb salvage in patients with locally advanced extremity soft tissue sarcoma.

Published
1996

13. Isolated limb perfusion with high-dose tumor necrosis factor-alpha in combination with interferon-gamma and melphalan for nonresectable extremity soft tissue sarcomas: A multicenter trial

Author

Eggermont, AMM, Lienard, D, Kroon, BBR, vanGeel, AN, Hoekstra, HJ, Lejeune, FJ, Schraffordt Koops, H., and Faculteit Medische Wetenschappen/UMCG

Subjects
REGIONAL PERFUSION, PHASE-I, RTNF-ALPHA, HUMAN-MELANOMA, SURVIVAL, LOCAL RECURRENCE, CANCER-PATIENTS, TNF-ALPHA, THERAPY, TOXICITY
Abstract

Purpose: 16 determine the efficacy of isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF) in combination with interferon-gamma (IFN) and melphalan as induction therapy to render tumors resectable and avoid amputation in patients with nonresectable extremity soft tissue sarcomas (STS). Patients and Methods: Among 55 patients with 30 sarcomas, primary and 25 recurrent sarcomas, there were 48 high-grade and seven grade I sarcomas (very large, recurrent, or multiple), The composition of this series of patients is unusual: 13 patients (24%) had multifocal primary sarcomas or multiple recurrent tumors; tumors were very large (median, 18 cm); and nine patients (16%) had known systemic metastases, IFN was administered subcutaneously on the 2 days before ILP with TNF, IFN, and melphalan. A delayed marginal resection of the tumor remnant was usually performed 2 to 3 months after ILP. Results: A major tumor response was seen in 87% of patients and rendered the sarcomas resectable in most cases, Clinical response rates were as follows: 10 (18%) completes responses (CRs), 35 (64%) partial responses (PRs), and 10 (18%) no change (NC), Final outcome was defined as follows by clinical and pathologic response: 20 (36%) CRs, 28 (51%) PRs, and seven (13%) NC, Limb salvage was achieved in 84% (follow-up duration, 20+ to 50+ months). In 39 patients, resection of the tumor remnant (n = 31) or of two to eight tumors (n = 8) after ILP was performed; local recurrence developed in five (13%), When no resection was performed (multiple tumors or systemic metastases), local recurrences were frequent (five of 16), but limb salvage was often achieved as patients died of systemic disease, Regional toxicity was limited and systemic toxicity minimal to moderate with no toxic deaths, Histology showed hemorrhagic necrosis; angiographies showed selective destruction of tumor-associated vessels. Conclusion: ILP with TNF, IFN, and melphalan is a safe and highly effective induction biochemotherapy procedure that can achieve limb salvage in patients with nonresectable extremity STS, TNF is an active anticancer drug in humans in the setting of ILP.

Published
1996

14. Phase 1/2 study of subcutaneous and intradermal immunization with a recombinant MAGE-3 protein in patients with detectable metastatic melanoma

Author

UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique, UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Unité d'oncologie médicale, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre du cancer, Kruit, WHJ, Van Ojik, Heidi H., Brichard, Vincent G., Escudier, B, Dorval, T, Dréno, B., Patel, P, van Baren, Nicolas, Avril, Marie-Françoise, Piperno, S, Khammari, A, Stas, M., Ritter, G., LETHE, Bernard, GODELAINE, Danièle, Brasseur, Francis, Zhang, Yi, van der Bruggen, Pierre, Boon, Thierry, Eggermont, AMM, Marchand, Marie, UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique, UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Unité d'oncologie médicale, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre du cancer, Kruit, WHJ, Van Ojik, Heidi H., Brichard, Vincent G., Escudier, B, Dorval, T, Dréno, B., Patel, P, van Baren, Nicolas, Avril, Marie-Françoise, Piperno, S, Khammari, A, Stas, M., Ritter, G., LETHE, Bernard, GODELAINE, Danièle, Brasseur, Francis, Zhang, Yi, van der Bruggen, Pierre, Boon, Thierry, Eggermont, AMM, and Marchand, Marie

Abstract

The purpose of this phase 1/2 study was to evaluate toxicity, tumor evolution and immunologic response following administration of a fixed dose of a recombinant MAGE-3 protein by subcutaneous and intradermal routes in the absence of immunologic adjuvant. Thirty-two patients with detectable metastatic melanoma expressing gene MAGE-3 were included and 30 received at least one injection with a fixed dose of a ProtD-MAGE-3 fusion protein. The immunization schedule included 6 intradermal and subcutaneous injections at 3-week intervals. Afterward, patients without major tumor progression who required other treatments received additional vaccinations at increasing time intervals. The vaccine was generally well tolerated. Among the 26 patients who received at least 4 vaccinations, we observed 1 partial response and 4 mixed responses. For these 5 responding patients, time to progression varied from 3.5 to 51+ months. An anti-MAGE-3 CD4 T-lymphocyte response was detected in 1 out of the 5 responding patients. The majority of patients had no anti-MAGE-3 antibody response. The clinical and immunologic responses generated by the vaccine are rather limited. Nevertheless, given the potential antitumor efficacy and the very mild toxicity of vaccinations, further studies combining MAGE proteins and/or peptides with potent immunologic adjuvants are warranted, not only in metastatic melanoma, but also in the adjuvant setting. (c) 2005 Wiley-Liss, Inc.

Published
2005

15. A RETROSPECTIVE COMPARATIVE-STUDY EVALUATING THE RESULTS OF MILD HYPERTHERMIC VERSUS CONTROLLED NORMOTHERMIC PERFUSION FOR RECURRENT MELANOMA OF THE EXTREMITIES

Author

KLAASE, JM, KROON, BBR, EGGERMONT, AMM, VANGEEL, AN, KOOPS, HS, OLDHOFF, J, LIENARD, D, LEJEUNE, FJ, BERKEL, R, FRANKLIN, HR, HART, AAM, and Groningen Institute for Organ Transplantation (GIOT)

Subjects
REGIONAL PERFUSION, RECURRENT MELANOMA, MELPHALAN, LIMBS, REGIONAL ISOLATED PERFUSION, MILD HYPERTHERMIA, MALIGNANT-MELANOMA
Abstract

The aim of this study was to investigate the role of mild hyperthermia (39-40 degrees C) in isolated cytostatic perfusion for patients with recurrent melanoma of the extremities. A total of 218 patients treated with mild hyperthermic perfusion was compared to 166 patients perfused under controlled normothermic conditions (37-38 degrees C). Only patients whose lesions had been excised before or at the moment of perfusion were eligible for this study. A variety of prognostic factors was controlled for in a Cox proportional hazards analysis. The application of mild hyperthermia did not influence limb recurrence-free interval nor survival (corrected P values 0.46 and 0.18, respectively). In this retrospective comparative study, no benefit for mild hyperthermia in regional isolated perfusion could be identified.

Published
1995

16. Immunisation of metastatic cancer patients with MAGE-3 protein combined with adjuvant SBAS-2 : A clinical report

Author

Marchand, M, Punt, CJA, Aamdal, S, Escudier, B, Kruit, WHJ, Keilholz, U, Håkansson, Leif, van Baren, N, Humblet, Y, Mulders, P, Avril, M-F, Eggermont, AMM, Scheibenbogen, C, Uiters, J, Wanders, J, Delire, M, Boon, T, Stoter, G, Marchand, M, Punt, CJA, Aamdal, S, Escudier, B, Kruit, WHJ, Keilholz, U, Håkansson, Leif, van Baren, N, Humblet, Y, Mulders, P, Avril, M-F, Eggermont, AMM, Scheibenbogen, C, Uiters, J, Wanders, J, Delire, M, Boon, T, and Stoter, G

Abstract

Fifty-seven patients with MAGE-3-positive measurable metastatic cancer, most of them with melanoma, were vaccinated with escalating doses of a recombinant MAGE-3 protein combined with a fixed dose of the immunological adjuvant SBAS-2, which contained MPL and QS21. The immunisation schedule included 4 intramuscular (i.m.) injections at 3-week intervals. Patients whose tumour stabilised or regressed after 4 vaccinations received 2 additional vaccinations at 6-week intervals. The vaccine was generally well tolerated. Among the 33 melanoma patients who were evaluable for tumour response, we observed 2 partial responses, 2 mixed responses and 1 stabilisation. Time to progression in these 5 patients varied from 4 to 29 months. In addition, a partial response lasting 10 months was observed in 1 of the 3 metastatic bladder cancer patients included. None of the tumour responses described above involved visceral metastases. Immunological responses to the vaccine will be reported separately. ⌐ 2002 Elsevier Science Ltd. All rights reserved.

Published
2003
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17. A MAGE-3 peptide presented by HLA-DR1 to CD4(+) T cells that were isolated from a melanoma patient vaccinated with a MAGE-3 protein

Author

UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique, Zhang, Y., Chaux, P, Stroobant, Vincent, Eggermont, AMM, Corthals, J, Maillere, B, Thielemans, K., Marchand, Marie, Boon, Thierry, van der Bruggen, Pierre, UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique, Zhang, Y., Chaux, P, Stroobant, Vincent, Eggermont, AMM, Corthals, J, Maillere, B, Thielemans, K., Marchand, Marie, Boon, Thierry, and van der Bruggen, Pierre

Abstract

"Cancer-germline" genes such as those of the MAGE family are expressed in many tumors and in male germline cells, but are silent in normal tissues. They encode shared tumor-specific Ags, which have been used in therapeutic vaccination trials of cancer patients. MAGE-3 is expressed in 74% of metastatic melanoma and in 50% of carcinomas of esophagus, head and neck, bladder, and lung. We report here the identification of a new MAGE-3 peptide, which is recognized by three different CD4(+) T cell clones isolated from a melanoma patient vaccinated with a MAGE-3 protein. These clones, which express different TCRs, recognize on HLA-DR1 peptide ACYEFLWGPRALVETS, which corresponds to the MAGE-3(267-282), and the MAGE-12(267)-(282) protein sequences. One of the T cell clones, which expresses LFA-1 at a high level, lysed tumor cells expressing DR1 and MAGE-3. Another of these DR1-restricted CD4(+) clones recognized not only the MAGE-3/12 peptide but also homologous peptides encoded by genes MAGE-1, 2, 4, 6, 10, and 11.

Published
2003

18. Immunisation of metastatic cancer patients with MAGE-3 protein combined with adjuvant SBAS-2: a clinical report

Author

UCL - ESPO/IAG - Département d'administration et de gestion, UCL - MD/MINT - Département de médecine interne, UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre du cancer, UCL - (SLuc) Unité d'oncologie médicale, Marchand, Maurice, Punt, CJA, Aamdal, Steiner, Escudier, B, Kruit, WHJ, Keilholz, U, Hakansson, L, van Baren, Nicolas, Humblet, Yves, Mulders, P, Avril, MF, Eggermont, AMM, Scheibenbogen, C, Uiters, J, Wanders, J, Delire, M., Boon, Thierry, Stoter, G., 36th Annual Meeting of the American-Society-of-Clinical-Oncology, UCL - ESPO/IAG - Département d'administration et de gestion, UCL - MD/MINT - Département de médecine interne, UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre du cancer, UCL - (SLuc) Unité d'oncologie médicale, Marchand, Maurice, Punt, CJA, Aamdal, Steiner, Escudier, B, Kruit, WHJ, Keilholz, U, Hakansson, L, van Baren, Nicolas, Humblet, Yves, Mulders, P, Avril, MF, Eggermont, AMM, Scheibenbogen, C, Uiters, J, Wanders, J, Delire, M., Boon, Thierry, Stoter, G., and 36th Annual Meeting of the American-Society-of-Clinical-Oncology

Abstract

Fifty-seven patients with MAGE-3-positive measurable metastatic cancer, most of them with melanoma, were vaccinated with escalating doses of a recombinant MAGE-3 protein combined with a fixed dose of the immunological adjuvant SBAS-2, which contained MPL and QS21. The immunisation schedule included 4 intramuscular (i.m.) injections at 3-week intervals. Patients whose tumour stabilised or regressed after 4 vaccinations received 2 additional vaccinations at 6-week intervals. The vaccine was generally well tolerated. Among the 33 melanoma patients who were evaluable for tumour response, we observed 2 partial responses, 2 mixed responses and 1 stabilisation. Time to progression in these 5 patients varied from 4 to 29 months. In addition, a partial response lasting 10 months was observed in 1 of the 3 metastatic bladder cancer patients included. None of the tumour responses described above involved visceral metastases. Immunological responses to the vaccine will be reported separately. (C) 2002 Elsevier Science Ltd. All rights reserved.

Published
2003

19. EFFECTS OF RECOMBINANT TUMOR-NECROSIS-FACTOR (RTNF-ALPHA) IN CANCER - OBSERVATIONS ON THE ACUTE-PHASE PROTEIN REACTION AND IMMUNOGLOBULIN-SYNTHESIS AFTER HIGH-DOSE RECOMBINANT TNF-ALPHA ADMINISTRATION IN ISOLATED LIMB PERFUSIONS IN CANCER-PATIENTS

Author

SWAAK, AJG, LIENARD, D, KOOPS, HS, LEJEUNE, FJ, EGGERMONT, AMM, and Faculteit Medische Wetenschappen/UMCG

Subjects
IL-6, ALPHA-1-ANTITRYPSIN, INTERLEUKIN-6 IL-6, INDUCTION, ALBUMIN, LYMPHOCYTES, TNF-ALPHA, SYSTEMIC LUPUS-ERYTHEMATOSUS, IMMUNOGLOBULINS, SERUM, DISEASE COURSE, INTERFERON-BETA-2, HORMONE, ALPHA-1-ACIDGLYCOPROTEIN, CELLS, ACUTE PHASE PROTEINS
Abstract

To obtain insight in the effect of TNF on the synthesis of acute phase proteins like CRP, alpha 1-antitrypsine, alpha 1-acidglycoprotein, C3 and C4 and the immunoglobulins (IgG-M-A), nine cancer patients who were treated with an isolated limb perfusion (ILP) with high dose recombinant TNF-alpha (rTNF-alpha) were investigated during a 7-day period after the end of the perfusion. Resorption of rTNF-alpha from out of these limbs into the circulation after the ILP induced within 30 min to 6 h in all patients elevated serum levels of IL6. At the same time C-reactive protein became detectable in serum. The highest serum levels were obtained at 48 h after ILP. The serum levels of the other acute phase proteins (alpha 1-acidglycoprotein, alpha 1-antitrypsine, C3, C4), rose more slowly and the highest serum levels were found at the third day. All investigated proteins declined after they had reached their peak levels. Levels of alpha(1)-acidglycoprotein and alpha(1)-anti-trypsin alpha(1)-acid declined slower than both complement component. In regard to the immunoglobulin levels a nearly continuous increase in the serum level of specifically IgM was observed. This study clearly shows the interrelationship between TNF-alpha and IL-6 in regard to the synthesis of the different acute phase proteins; and moreover also a striking effect on IgM synthesis.

Published
1993

20. High tPA-expression in primary melanoma of the limb correlates with good prognosis

Author

UCL, Ferrier, CM, Suciu, Stefan, van Geloof, WL, Straatman, H, Eggermont, AMM, Koops, HS, Kroon, BBR, Lejeune, FJ, Kleeberg, UR, van Muijen, GNP, Ruiter, DJ, UCL, Ferrier, CM, Suciu, Stefan, van Geloof, WL, Straatman, H, Eggermont, AMM, Koops, HS, Kroon, BBR, Lejeune, FJ, Kleeberg, UR, van Muijen, GNP, and Ruiter, DJ

Abstract

To investigate whether the course of primary melanoma disease correlates with expression of the various components of the proteolytic plasminogen activation (PA) system, immunohistochemical stainings for activators of plasminogen (tissue type (tPA) and urokinase type (uPA)), inhibitors of plasminogen activation (type 1 (PAI-I) and type 2 (PAI-2)) and the receptor for uPA (uPAR) were performed on 214 routinely processed melanoma lesions. All lesions were primary cutaneous melanomas, minimally 1.5 mm thick, and derived from patients with only local disease at the moment of diagnosis (clinically stage II (T3-4 NoMo), American Joint Committee on Cancer). Median patient follow-up was 6.1 years. Single variables as immunohistochemical staining results (extent of tumour cell staining, pattern of tumour cell staining and for some components also staining of stromal cells), histopathological and clinical parameters as well as treatment variables were analysed in order to assess their prognostic importance, in terms of time to recurrence, time to distant metastasis and duration of survival. The extent of tPA tumour cell positivity, categorized as 0-5%, 6-50% and 51-100%, appeared to be of importance for these endpoints. Lesions with 51-100% tPA-positive tumour cells were found to have the best prognosis, whereas lesions with 6-50% tPA-positive tumour cells had the worst. Moreover, the prognostic significance of Breslow thickness, microscopic ulceration and sex was confirmed in this study. Multivariate analyses, incorporating these relevant factors, showed that the extent of tPA tumour cell positivity was an independent prognostic factor for distant metastasis-free interval (P = 0.012) and for the duration of survival (P = 0.043). (C) 2000 Cancer Research Campaign.

Published
2000

21. What can we learn from phase II adjuvant trials in melanoma?

Author

UCL, Keilholz, U, Suciu, Stefan, Eggermont, AMM, UCL, Keilholz, U, Suciu, Stefan, and Eggermont, AMM

Abstract

In this issue of the Journal, McClay and colleagues report on a clinical trial of adjuvant treatment with cisplatin and tamoxifen in 153 melanoma patients stages II to IV (McClay et al, 2000). This study has several important limitations, since it is not randomized and has no control arm. The authors nevertheless suggest a beneficial;il effect of treatment on disease-free and overall survival. The design of this trial deserves consideration acknowledging the information available on adjuvant treatment of melanoma at the time the study was initiated, and the report needs to be examined from the perspective of today, the time the study is reported.

Published
2000

38. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial.

Author

Eggermont AMM, Suciu S, MacKie R, Ruka W, Testori A, Kruit W, Punt CJA, Delauney M, Sales F, Groenewegen G, Ruiter DJ, Jagiello I, Stoitchkov K, Keilholz U, Lienard D, EORTC (European Organisation for Research and Treatment of Cancer) Melanoma Group, Eggermont, Alexander M M, Suciu, Stefan, MacKie, Rona, and Ruka, Wlodzimierz

Abstract

Background: Individuals affected by melanoma with thick primary tumours or regional node involvement have a poor outlook, with only 30-50% alive at 5 years. High-dose and low-dose interferon alfa have been assessed for the treatment of these patients, with the former having considerable toxicity and a consistent effect on disease free survival, but not on overall survival, and the latter no consistent effect on either. Our aim was, therefore, to assess the effect of two regimens of interferon of intermediate dose versus observation alone on distant metastasis-free interval (DMFI) and overall survival in such patients.Methods: We did a randomised controlled trial in 1388 patients who had had a thick primary tumour (thickness > or = 4 mm) resected (stage IIb) or regional lymph node metastases dissected (stage III) and had been assigned to 13-months (n=553) or 25 months (n=556) of treatment with subcutaneous interferon alfa 2b, or observation (n=279). Treatment comprised 4 weeks of 10 million units (MU) of interferon alfa (5 days per week) followed by either 10 MU three times a week for 1 year or 5 MU three times a week for 2 years, to a total dose of 1760 MU. Our primary endpoint was DMFI. Analyses were by intent to treat.Findings: After a median follow-up of 4.65 years, we had recorded 760 distant metastases and 681 deaths. At 4.5 years, the 25-month interferon group showed a 7.2% increase in rate of DMFI (hazard ratio 0.83, 97.5% CI 0.66-1.03) and a 5.4% improvement in overall survival. The 13-month interferon group showed a 3.2% increase in rate of DMFI at 4.5 years (0.93, 0.75-1.16) and no extension of overall survival. Toxicity was acceptable, with 18% (195 of 1076) of patients going off study because of toxicity or as a result of refusal of treatment because of side-effects.Interpretation: Interferon alfa as used in the regimens studied does not improve outcome for patients with stage IIb/III melanomas, and cannot be recommended. With respect to efficacy of the drug, duration of treatment seemed more important than dose, and should be assessed in future trials. [ABSTRACT FROM AUTHOR]

Published
2005
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39. Current uses of isolated limb perfusion in the clinic and a model system for new strategies.

Author

Eggermont AMM, de Wilt JHW, ten Hagen TLM, Eggermont, Alexander M M, de Wilt, Johannes H W, and ten Hagen, Timo L M

Abstract

Isolated limb perfusion with melphalan is the treatment of choice for multiple (small) melanoma-in-transit metastases. The use of tumour necrosis factor alpha (TNFalpha) in isolated limb perfusion is successful for treatment of locally advanced limb soft-tissue sarcomas and other large tumours; this approach can avoid the need for amputation. TNFalpha was approved in Europe after a multicentre trial in patients with locally advanced soft-tissue sarcomas, deemed unresectable by an independent review committee; the response rate to isolated limb perfusion with TNFalpha plus melphalan was 76% and the limb was saved in 71% of patients. Moreover, the trial showed the efficacy of isolated limb perfusion of TNFalpha and melphalan against various other limb-threatening tumours such as skin cancers and drug-resistant bony sarcomas. Laboratory models of isolated limb perfusion have helped to elucidate mechanisms of action and to develop new treatment modalities. They have identified TNFalpha-mediated vasculotoxic effects on the tumour vasculature and have shown that addition of TNFalpha to the perfusate results in an increase of three to six times in uptake of melphalan or doxorubicin by tumours. New vasoactive drugs and new mechanisms of action are being discovered. Moreover, isolated limb perfusion is an effective modality for gene therapy mediated by an adenoviral vector. Various clinical phase I-II studies can be expected in the next few years. [ABSTRACT FROM AUTHOR]

Published
2003
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40. Sunscreen use and duration of sun exposure: a double-blind, randomized trial.

Author

Autier P, Dore J, Negrier S, Lienard D, Panizzon R, Lejeune FJ, Guggisberg D, Eggermont AMM, Autier, P, Doré, J F, Négrier, S, Liénard, D, Panizzon, R, Lejeune, F J, Guggisberg, D, and Eggermont, A M

Abstract

Background: In epidemiologic studies, sunscreen use is associated with increased risk of cutaneous melanoma, basal cell skin cancer, and higher numbers of nevi. It has been proposed that sunscreens may encourage prolonged sun exposure because they delay sunburn occurrence. We examined whether, under habitual conditions of sunscreen use, the sun-protection factor (SPF) had an influence on sun-exposure duration.Methods: Before the 1997 summer holidays, we randomly assigned 87 French and Swiss participants who were 18-24 years of age to receive an SPF 10 or an SPF 30 sunscreen. Neither medical personnel nor study participants were aware of their sunscreen assignment. Participants were asked to complete daily records of their sun exposure. To avoid influencing the recreational sun-exposure habits of the study participants, no recommendation was made about sun exposure or sun protection. Furthermore, participants were told that the trial end point was the number of pigmented skin lesions before and after the holidays. One subject was lost to follow-up. All statistical tests were two-sided.Results: The SPF 10 (n = 44) and SPF 30 (n = 42) groups had equivalent mean holiday durations (19.4 days versus 20.2 days) and mean quantities of sunscreen used (72.3 g versus 71.6 g). The mean cumulative sun exposures for the two groups were 58.2 hours and 72.6 hours, respectively (P =.011). The mean daily durations of sunbathing were 2.6 and 3.1 hours, respectively (P =.0013), and, for outdoor activities, they were 3.6 and 3.8 hours, respectively (P =.62). There was no difference in sunburn experience between the two groups.Conclusions: Use of higher SPF sunscreen seems to increase the duration of recreational sun exposure of young white Europeans. [ABSTRACT FROM AUTHOR]

Published
1999

42. Lack of efficacy of Doxil® in TNF-a-based isolated limb perfusion in sarcoma-bearing rats.

Author

Hagen, TLM ten, Hoving, S., Ambagtsheer, G., Tiel, ST van, and Eggermont, AMM

Subjects
ANTINEOPLASTIC agents, TUMOR necrosis factors, MACROPHAGES, CANCER research, DOXORUBICIN, EXTREMITIES (Anatomy)
Abstract

Here we show that Doxil® has minimal antitumour activity in the isolated limb perfusion (ILP) setting and its activity was not enhanced by the addition of tumour necrosis factor (TNF). Doxil® accumulation in tumour tissue was low and also not augmented by TNF. In contrast, activity of free conventional doxorubicin was enhanced by TNF. We conclude that application of Doxil® in a TNF-based ILP is not a useful alternative to free conventional doxorubicin or melphalan.British Journal of Cancer (2004) 90, 1830-1832. doi:10.1038/sj.bjc.6601688 www.bjcancer.com [ABSTRACT FROM AUTHOR]

Published
2004
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43. Cancer Core Europe: A translational research infrastructure for a European mission on cancer

Author

Institut Català de la Salut, [Eggermont AMM] Gustave Roussy Cancer Campus Grand Paris, Villejuif, France Cancer Core Europe, France. [Apolone G] Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy. [Baumann M] German Cancer Research Center (DKFZ), Heidelberg, Germany. [Caldas C] Department of Oncology, Cancer Research UK Cambridge Institute, University of Cambridge, UK. [Celis JE] Danish Cancer Society Research Centre, Copenhagen, Denmark. [de Lorenzo F] European Cancer Patient Coalition, Brussels, Belgium. Italian Federation of Cancer Patients Organisations, Rome, Italy. [Tabernero J] Hospital Universitari Vall d'Hebron, Barcelona, Spain. Vall d'Hebron Institut d'Oncologia, Barcelona, Spain., and Hospital Universitari Vall d'Hebron

Subjects
Neoplasms [DISEASES], Other subheadings::/organization & administration [Other subheadings], Centres d'investigació, Health Care Economics and Organizations::Organizations::Academies and Institutes [HEALTH CARE], Salud Ambiental::Ingeniería Ambiental::Desarrollo Tecnológico::Investigación [SALUD PÚBLICA], economía y organizaciones para la atención de la salud::organizaciones::academias e institutos [ATENCIÓN DE SALUD], Neoplasias [ENFERMEDADES], Environmental Health::Environmental Engineering::Technological Development::Research [PUBLIC HEALTH], Otros calificadores::/organización & administración [Otros calificadores], Càncer - Investigació
Published
2021

44. Circulating melanoma cells and distant metastasis-free survival in stage III melanoma patients with or without adjuvant interferon treatment (EORTC 18991 side study)

Author

Fusi A, Collette S, Busse A, Suciu S, Rietz A, Santinami M, Kruit WHj, Testori A, Punt CJh, Dalgleish AG, Spatz A, Eggermont AMm, and Keilholz U

Abstract

AIM: To evaluate the prognostic and predictive importance of detection of melanoma cells in peripheral blood using reverse transcriptase polymerase chain reaction (RT-PCR) in stage III cutaneous melanoma patients after sentinel or regional lymph node dissection. PATIENTS AND METHODS: Serial testing for tyrosinase and Mart-1/Melan-A transcripts in peripheral blood was performed every 6 months over a maximum period of 60 months in a subset of patients enrolled in EORTC 18991 phase 3 trial, comparing pegylated interferon-alpha-2b with observation. Univariate and multivariate analyses were performed to estimate the role of RT-PCR as prognostic and predictive factor for distant metastasis-free survival (DMFS). RESULTS: Among 299 patients who underwent RT-PCR analyses, 109 (36.5%) had at least one positive sample, either at time of randomisation (N=17) or subsequently (N=92). The cumulative rate of positive results was similar in the two treatment groups, as the DMFS from first RT-PCR positivity. RT-PCR result, positive versus negative, at a given time point, had no prognostic impact on subsequent DMFS. Cox time-dependent analysis indicated a significantly higher risk of developing distant metastasis in patients with a positive sample as compared to those with a negative one: hazard ratio (HR) of 2.23 (95% confidence interval (CI), 1.40-3.55; p<.001). These results were comparable in the 2 treatment groups, indicating that RT-PCR assessment was not predictive for treatment outcome. CONCLUSION: Detection of circulating tumour cells by RT-PCR for tyrosinase and Mart-1/Melan-A was a time-dependent moderate prognostic factor for subsequent development of distant metastasis in stage III melanoma patients. [ABSTRACT FROM AUTHOR]

Published
2009
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45. LDH correlation with survival in advanced melanoma from two large, randomised trials (Oblimersen GM301 and EORTC 18951)

Author

Agarwala SS, Keilholz U, Gilles E, Bedikian AY, Wu J, Kay R, Stein CA, Itri LM, Suciu S, and Eggermont AMM

Abstract

PURPOSE: In a randomised study (GM301; dacarbazine with/without oblimersen), patients with advanced melanoma were stratified based on performance status, metastatic site and lactate dehydrogenase (LDH). Progression-free survival and response and durable response rates showed a highly significant difference favouring dacarbazine-oblimersen and a nearly significant survival difference. All efficacy parameters significantly favoured dacarbazine-oblimersen in patients with normal baseline LDH [1.1xupper limit of normal (ULN)]. Each stratification factor was assessed for an interaction with treatment on survival and an interaction was detected only for LDH. EXPERIMENTAL DESIGN: Baseline LDH values in Study GM301 treatment groups were combined and analysed using cutoffs above and below 1xULN. Baseline LDH in EORTC study 18951 (dacarbazine, cisplatin, interferon-alfa-2b with/without interleukin-2 in advanced melanoma) was independently analysed using the same approach. In Study GM301, the relation between treatment effect and LDH, treatment effect and tumour size, LDH and tumour size and LDH and disease site were determined. RESULTS: In Study GM301 (N=760) and Study 18951 (N=325), LDH was within the upper range of normal for a large number of patients. This was not exhibited in the general population, suggesting such values may be elevated rather than normal in melanoma. A highly ordered and monotonic relationship was apparent between LDH and survival: survival worsened as LDH became more elevated, even when LDH remained within normal range. LDH and tumour size were poorly correlated; elevated LDH was not associated with any one disease site. LDH was highly predictive of oblimersen effect. CONCLUSION: In designing studies, LDH should be considered, regardless of tumour size or disease site. [ABSTRACT FROM AUTHOR]

Published
2009
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46. Cancer Core Europe: A translational research infrastructure for a European mission on cancer

Author

Fabien Calvo, Ingemar Ernberg, Carlos Caldas, John Rowell, Ulrik Ringborg, Julio E. Celis, Emile E. Voest, Giovanni Apolone, Michael Baumann, Francesco De Lorenzo, Alexander M.M. Eggermont, Josep Tabernero, Institut Català de la Salut, [Eggermont AMM] Gustave Roussy Cancer Campus Grand Paris, Villejuif, France Cancer Core Europe, France. [Apolone G] Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy. [Baumann M] German Cancer Research Center (DKFZ), Heidelberg, Germany. [Caldas C] Department of Oncology, Cancer Research UK Cambridge Institute, University of Cambridge, UK. [Celis JE] Danish Cancer Society Research Centre, Copenhagen, Denmark. [de Lorenzo F] European Cancer Patient Coalition, Brussels, Belgium. Italian Federation of Cancer Patients Organisations, Rome, Italy. [Tabernero J] Hospital Universitari Vall d'Hebron, Barcelona, Spain. Vall d'Hebron Institut d'Oncologia, Barcelona, Spain., Hospital Universitari Vall d'Hebron, Caldas, Carlos [0000-0003-3547-1489], Apollo - University of Cambridge Repository, and Vall d'Hebron Barcelona Hospital Campus

Subjects
0301 basic medicine, Cancer Research, Centres d'investigació, Salud Ambiental::Ingeniería Ambiental::Desarrollo Tecnológico::Investigación [SALUD PÚBLICA], Review Article, infrastructure, Translational Research, Biomedical, Other subheadings::/organization & administration [Other subheadings], 0302 clinical medicine, Cost of Illness, Multidisciplinary approach, Neoplasms, oncopolicy, Cooperative Behavior, Review Articles, Clinical Trials as Topic, alliance, General Medicine, Public relations, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Otros calificadores::/organización & administración [Otros calificadores], innovation, Europe, Oncology, 030220 oncology & carcinogenesis, General partnership, Molecular Medicine, Neoplasias [ENFERMEDADES], medicine.medical_specialty, Health Care Economics and Organizations::Organizations::Academies and Institutes [HEALTH CARE], economía y organizaciones para la atención de la salud::organizaciones::academias e institutos [ATENCIÓN DE SALUD], Translational research, Environmental Health::Environmental Engineering::Technological Development::Research [PUBLIC HEALTH], lcsh:RC254-282, 03 medical and health sciences, Political science, Genetics, medicine, Humans, salud ambiental::ingeniería ambiental::salud ambiental::ingeniería ambiental::laboratorios::técnicas de laboratorio clínico::investigación [SALUD PÚBLICA], Cancer prevention, business.industry, Cancer, medicine.disease, Data sharing, Clinical trial, Neoplasms [DISEASES], 030104 developmental biology, Economía en Atención de Salud y Organizaciones::Organizaciones::Academias e Institutos [ATENCIÓN DE SALUD], Outcomes research, business, Càncer - Investigació
Abstract

Alliance; Cancer research; Infrastructure Aliança; Recerca oncològica; Infraestructura Alianza; Investigación oncológica; Infraestructura Cancer Core Europe is a European legal alliance consisting of seven leading cancer centres - most of them Comprehensive Cancer Centres (CCCs) - with a single portal system to engage in various research projects with partners. Cancer Core Europe was established to create a sustainable, high-level, shared research infrastructure platform hosting research collaborations and task forces (data sharing, clinical trials, genomics, immunotherapy, imaging, education and training, and legal and ethical issues), with a controlled expansion agenda. Translational cancer research covers the cancer research continuum from basic to preclinical to early clinical, late clinical, and outcomes research. Basic-preclinical research serves as the 'engine' for early clinical research by bridging the early translational research gap and is the primary and current focus of the consortium as exemplified by the launching of the Basket of Baskets trial, Europe's largest precision cancer medicine trial. Inspired by the creation of Cancer Core Europe, the prevention community established Cancer Prevention Europe, a consortium of ten cancer prevention centres aimed at supporting the complete prevention research continuum. Presently, Cancer Core Europe and Cancer Prevention Europe are integrating therapeutics and prevention strategies to address in partnership the widening cancer problem. By providing innovative approaches for cancer research, links to healthcare systems, development of quality-assured multidisciplinary cancer care, and assessment of long-term outcomes, the virtual infrastructure will serve as a hub to connect and interact with other centres across Europe and beyond. Together, Cancer Core Europe and Cancer Prevention Europe are prepared to function as a central engine to tackle, in collaboration with various partners, a potential 'mission on cancer' addressing the cancer burden.

Published
2019

48. The Role of CDCA2 in tumor genesis, prognosis and future treatments.

Author

Lin X, Zou Z, Zhong J, Wang T, Ma W, Hu T, Sun W, Xu Y, Eggermont AMM, and Chen Y

Subjects
Humans, Prognosis, Nuclear Proteins genetics, Nuclear Proteins metabolism, Molecular Targeted Therapy methods, Carrier Proteins, Neoplasms genetics, Neoplasms therapy, Neoplasms pathology, Neoplasms metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism
Abstract

The Cell Division Cycle Associated 2 (CDCA2) gene is responsible for encoding a targeting subunit of cell-cycle associated protein. CDCA2 plays a crucial role in various cellular processes, including chromosome segregation and decondensation, nuclear envelope reassembly, microtubule assembly, and DNA damage response. Additionally, CDCA2 is involved in multiple signaling pathways such as the PI3K/Akt pathway and p53 pathway. Undoubtedly, there exists a strong association between CDCA2 and cancer. Numerous studies have reported that elevated levels of CDCA2 are correlated with poor prognosis and several clinicopathological characteristics like tumor size and TNM stage across different types of cancer. Therefore, CDCA2 holds great potential as both a biomarker for diagnosis and a therapeutic target for interventions such as targeted therapies or immunotherapy. Given its promising prospects in scientific research and clinical applications, it is imperative for researchers to delve into the underlying mechanisms of CDCA2 and explore its utilization., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for European Journal of Cancer and was not involved in the editorial review or the decision to publish this article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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49. Efficacy of anti PD-1 therapy in children and adolescent melanoma patients (MELCAYA study).

Author

Mandalà M, Ferrari A, Brecht IB, Suijkerbuijk KP, Maschke L, Giannarelli D, Indini A, Ubaldi M, Pecci G, Atkinson V, Helgadottir H, Chiaravalli S, Benannoune N, Robert C, Teterycz P, Rutkowski P, Puig S, Madonna G, Kebudi R, Grynberg S, Arantes LM, Bien E, Krawczyk M, Pasquale MD, Dierselhuis MP, Massi D, Long GV, Ascierto PA, and Eggermont AMM

Subjects
Humans, Adolescent, Child, Male, Female, Child, Preschool, Retrospective Studies, Skin Neoplasms drug therapy, Skin Neoplasms pathology, Skin Neoplasms mortality, Progression-Free Survival, Antineoplastic Agents, Immunological therapeutic use, Antineoplastic Agents, Immunological adverse effects, Melanoma drug therapy, Melanoma mortality, Melanoma pathology, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors adverse effects, Programmed Cell Death 1 Receptor antagonists & inhibitors
Abstract

Background: Data on the efficacy and safety of anti PD-1 antibodies in children and adolescents (CA) with melanoma are lacking. The aim of this study was to determine outcomes of CA melanoma patients receiving anti PD-1 antibodies., Methods: Melanoma patients ≤18 years treated with anti PD-1 were retrospectively retrieved from 15 academic centers. Information on histopathological diagnosis, surgical treatment, systemic therapy, objective response rate (ORR), safety profile was collected. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier method., Results: Between April 2016 and March 2024, 99 patients treated with systemic therapy were retrieved, 81 treated with anti PD-1 therapy. Median age was 14 years (range 2-18 years), 37 pts were ≤12 yrs. Overall, 38 CA patients received anti PD-1 in adjuvant setting, and the 3-year PFS and OS were 70.6 % and 81.1 %, respectively. Two patients received anti-PD-1 based neoadjuvant treatment, both had a pathologic complete response and remain disease free. Fifty-six received a systemic therapy for advanced disease and among them, 43 received anti PD-1-based therapy for advanced disease in 1st line, while 12 and 5 pts received a 2nd and 3rd line, respectively. Among patients receiving a 1st line therapy with anti PD-1 monotherapy the ORR was 25 %, and the 3-year OS was 34 %. Toxicities were consistent with previous studies in adult melanoma patients., Conclusions: Our study provides the first evidence of efficacy of anti PD-1 in CA melanoma patients and supports the use of anti PD-1 therapy in pts ≤18 years, included those <12 years., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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50. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): long-term, health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial.

Author

Bührer E, Kicinski M, Mandala M, Pe M, Long GV, Atkinson V, Blank CU, Haydon A, Dalle S, Khattak A, Carlino MS, Meshcheryakov A, Sandhu S, Puig S, Schadendorf D, Jamal R, Rutkowski P, van den Eertwegh AJM, Coens C, Grebennik D, Krepler C, Robert C, and Eggermont AMM

Subjects
Humans, Female, Male, Double-Blind Method, Middle Aged, Aged, Chemotherapy, Adjuvant, Antineoplastic Agents, Immunological therapeutic use, Antineoplastic Agents, Immunological adverse effects, Adult, Time Factors, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized adverse effects, Melanoma drug therapy, Melanoma pathology, Melanoma surgery, Quality of Life, Neoplasm Staging, Skin Neoplasms drug therapy, Skin Neoplasms pathology, Skin Neoplasms surgery, Skin Neoplasms mortality
Abstract

Background: In the European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 study, adjuvant pembrolizumab improved recurrence-free survival and distant-metastasis-free survival in patients with resected stage III melanoma. Earlier results showed no effect of pembrolizumab on health-related quality of life (HRQOL). Little is known about HRQOL after completion of treatment with pembrolizumab, an important research area concerning patients who are likely to become long-term survivors. This study reports long-term HRQOL results., Methods: This double-blind, randomised, controlled, phase 3 trial compared adjuvant pembrolizumab with placebo in patients aged 18 years or older with previously untreated stage IIIA, IIIB, or IIIC resected cutaneous melanoma and an Eastern Cooperative Oncology Group performance status score of 1 or 0, recruited from 123 academic centres and community hospitals in 23 countries. Patients were randomly assigned (1:1) with a minimisation technique stratified for stage and geographical region to receive 200 mg of intravenous pembrolizumab or placebo every 3 weeks for up to 18 doses. Investigators, patients, and those collecting or analysing data were masked to group assignment. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, measured with the EORTC Quality of Life Questionnaire-Core 30. All patients with a baseline HRQOL evaluation available who were alive 108 weeks from randomisation were included in this analysis of long-term HRQOL. Long-term HRQOL included assessments measured every 6 months between 108 weeks and 48 months after randomisation. The threshold of clinical relevance for all HRQOL scales used was an average change of 5 points. The trial is ongoing, recruitment is completed, and HRQOL data collection is finalised. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37., Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were randomly assigned to pembrolizumab (n=514) or placebo (n=505). Completion of the HRQOL evaluation at baseline exceeded 90% (481 [94%] patients in the pembrolizumab group and 467 [92%] in the placebo group), and ranged between 60% and 90% for post-baseline timepoints. Among patients with a baseline HRQOL evaluation, 365 (39%) were female and 583 (61%) were male. The mean change from baseline to long-term HRQOL was -0·56 (95% CI -2·33 to 1·22) in the pembrolizumab group and 1·63 (-0·12 to 3·38) in the placebo group. The difference between the two groups was -2·19 (-4·65 to 0·27, p=0·081). Differences for all other scales were smaller than 5 and not statistically significant., Interpretation: Adjuvant pembrolizumab did not have a significant impact on long-term HRQOL compared with placebo in patients with resected stage III melanoma. These findings, together with earlier results on efficacy and HRQOL, support the use of pembrolizumab in this setting., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests EB's spouse and daughter hold shares in Sandoz, Galenica, Alcon, Roche, and Novartis. MK reports study funding paid to the institution by Merck Sharp & Dohme (MSD) since the initial planning of the work, and study funding paid to the institution from Bristol Myers Squibb (BMS), Immunocore, Johnson & Johnson, and Pierre Fabre in the past 36 months. MM reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sun Pharma. GVL reports consulting fees from Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, BMS, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics, IOBiotech, Immunocore, Innovent Biologics USA, MSD, Novartis, PHMR, Pierre Fabre, Regeneron, Scancell, and SkylineDX BV. VA reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, MSD, Novartis; support from BMS for attending meetings or travel; participation on a data safety monitoring board or advisory board for BMS, MSD, Novartis, and Immunocore; CUB reports personal fees from MSD, grants and personal fees from Novartis and BMS, personal fees from Roche, GSK, AstraZeneca, Pfizer, Lilly, GenMAB, Pierre Fabre, and Third Rock ventures, grants from NanoString and 4SC, during the conduct of the study. CUB has patents pending (WO 2021/177822 A1 and WO 2023/022596 A1), and reports stock ownership: co-founder of Immagene BV and Signature Oncology. AH reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, and Novartis; payments for participation on a data safety monitoring board or advisory board with BMS, MSD, and Novartis. SD reports research funding from BMS, MSD, and Pierre Fabre to the institution; payment or honoraria to the institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS and MSD; support for attending meetings or travel from BMS and MSD; trim 24 patent pending; participation on a data safety monitoring board or advisory board at BMS and MSD, with payments made to the institution; spouse being a Sanofi employee. AK reports consulting fees for an advisory role at Moderna and speaker honorarium from MSD. MSC reports honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, MSD and Novartis; having served on advisory boards for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi. AM reports support of scientific and educational conference from Janssen. SS reports grants or contracts from Novartis/Advanced Accelerator Applications (AAA), AstraZeneca, MSD, Genentech, Senhwa, and Pfizer; funding goes to the institution to undertake investigator initiated clinical trial and translational research. SS reports participation on advisory boards for MSD, BMS, AstraZeneca—fees for attending go to research funds at the institution. SS is the chair of DSMB for two Novartis/AAA sponsored phase 3 trials—no fee accepted for chair role. SP reports payment or honoraria to her and her institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, and Novartis, and to her partner and her institution from Amgen and Phylogen; payments to her institution for participation on a data safety monitoring board or advisory board with MSD; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid from GEM, EORTC melanoma group, and ASEICA. DS reports research grants to his institution from Amgen, Array/Pfizer, BMS, MSD, Novartis, and Roche; consulting fees paid personally from 4SC, Amgen, Array Biopharma, AstraZeneca, BMS, Daiichi Sankyo, Haystack, Immunocore, InFlarX, Innovent, Labcorp, Merck Serono, MSD, Nektar, Neracare, Novartis OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, and Sun Pharma; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, Merck Serono, Novartis, Roche, Sanofi, and SunPharma; personal support for attending meetings or travel from BMS, Merck Serono, MSD, Novartis, Sanofi, and Pierre Fabre; personal payments for participation on a data safety monitoring board or advisory board at 4SC, Amgen, Array Biopharma, AstraZeneca, BMS, Daiichi Sankyo, Haystack, Immunocore, InFlarX, Merck Serono, MSD, Nektar, Neracare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, and Sun Pharma; leadership or fiduciary role, paid or unpaid, at Dermatologic Cooperative Oncology Group, German Cancer Society, Hiege Stiftung, Deutsche Hautkrebsstiftung, Nationale Versorgungskonferenz Hautkrebs eV, and European Melanoma Registry; drug supply (nivolumab, ipilimumab) from BMS. RJ reports research funding from Iovance Biotherapeutics; honoraria for advisory role or speaker presentation from Merck, BMS, Medison, Pfizer, and Novartis. PR reports consulting fees paid to himself from MBS, MSD, Novartis, Pierre Fabre, Philogen, and Pfizer; honoraria for lectures, presentations, speakers bureau, manuscript writing, or educational events paid to himself from BMS, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, MSD, and AstraZeneca; speakers bureau Pfizer, Novartis, Pierre Fabre, MSD, and BMS paid to himself; support for attending meetings or travel from Orphan Europe and Pierre Fabre paid to himself; research funding to his institution from Novarits, Pfizer, Roche, and BMS. AJMvdE reports study grants from BMS and Idera; travel expenses from Ipsen; advisory board from BMS, MSD Oncology, Ipsen, Pierre Fabre, and Janssen Cilag BV. CC reports support for attending meetings or travel from Orphan Europe and Pierre Fabre. DG reports stock or stock options from Merck & Co. CK reports stock or stock options from Merck & Co and being an employee of Merck & Co. CR reports consulting fees (payments made to her) from BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Merck, Sunpharma, Ultimovacs, Regeneron, Egle, Philogen, Maat Pharma, and IO Biontech; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events (payments made to her) from Pierre Fabre, Sanofi, BMS, MSD, and Novartis; support for attending meetings or travel from Pierre Fabre; participation on a data safety monitoring board or advisory board (payments made to her) with BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Merck, Sunpharma, Ultimovacs, Regeneron, Egle, Philogen, and Maat Pharma. AMME reports honoraria for scientific advisory board or independent data monitoring committee functions from Agenus, BioInvent, BioNTech, Boehringer Ingelheim, Brenus, CatalYm, Ellipses, EikonTX, Eurobio, Galecto, IO Biotech, IQVIQ, ISA Pharmaceuticals, Merck & Co, MSD, Pfizer, Pierre Fabre, Scorpion TX, Sairopa, Sellas, SkylineDX, TigaTx, and Trained Therapeutics Discovery; honoraria from Acetra, GenOway, GSK, Moderna, and Trained Immunity Tx; equity from IO Biotech, Sairopa, and SkylineDx; being the Editor in Chief of the European Journal of Cancer. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Published
2024
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