Ipilimumab versus placebo after complete resection of stage III melanoma: Long-term follow-up results the EORTC 18071 double-blind phase 3 randomized trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2512-2512 ◽  
Author(s):  
Alexander M. M. Eggermont ◽  
Vanna Chiarion-Sileni ◽  
Jean Jacques Grob ◽  
Reinhard Dummer ◽  
Jedd D. Wolchok ◽  
...  
Keyword(s):  
Lymph Node ◽  
Complete Resection ◽  
Phase Iii ◽  
Stage Iii ◽  
Long Term Results ◽  
Double Blind ◽  
Free Survival ◽  
Stage Iii Melanoma

2512 Background: Since 2015, ipilimumab (Ipi) is an approved treatment for stage III melanoma based on a significantly (P=0.0013) prolonged recurrence-free survival (RFS) (Eggermont et al, Lancet Oncology, 2015). At a median follow-up of 5.3 years, RFS (HR=0.76) and distant metastasis-free survival (DMFS) (HR=0.76), assessed by an IRC, and overall survival (OS) (HR=0.72) were prolonged in the Ipi group as compared to the placebo (Pbo) group (Eggermont et al, NEJM, 2016), despite a 53.3% (Ipi) vs 4.6% (Pbo) treatment discontinuation rate due to adverse events. Methods: In this randomized double-blind trial, eligible patients (pts) included those ≥18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to Ipi 10 mg/kg (n=475) or placebo (Pbo, n=476) q3w for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. Here, we report the comparison between the Ipi and Pbo groups regarding the long-term efficacy outcomes using the local investigator assessments. Results: Overall, 20%/44%/36% of pts had AJCC-7 stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement. Median follow-up was 6.9 yrs. The RFS, DMFS and OS benefit observed in the Ipi group was long-lasting (almost 10% difference at 7 years) and consistent across subgroups: no significant predictive factors could be detected. Conclusions: In this phase III trial, Ipi, administered at 10 mg/kg, as adjuvant therapy provided, at a 6.9 yr median follow-up, a sustained improvement in the RFS, DMFS, and OS long-term results in patients with high-risk stage III melanoma. Clinical trial information: NCT00636168. [Table: see text]

Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: New recurrence-free survival results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial at three-year median follow-up.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10000-10000 ◽  
Author(s):  
Alexander M. Eggermont ◽  
Christian U. Blank ◽  
Mario Mandalà ◽  
Georgina V. Long ◽  
Victoria Atkinson ◽  
...  
Keyword(s):  
Lymph Node ◽  
High Risk ◽  
Complete Resection ◽  
Phase Iii ◽  
Stage Iii ◽  
Recurrence Free Survival ◽  
Stage Iiia ◽  
Free Survival ◽  
Stage Iii Melanoma

10000 Background: We conducted the phase 3 double-blind EORTC 1325/KEYNOTE-054 trial to evaluate pembrolizumab vs placebo in patients (pts) with resected high-risk stage III melanoma. Based on 351 recurrence-free survival (RFS) events and at a median follow-up of 1.25 years (yrs), pembrolizumab improved RFS (hazard ratio (HR) 0.57, P<0.0001) as compared to placebo (Eggermont, NEJM 2018). This led to the approval of pembrolizumab adjuvant treatment by EMA and FDA. Methods: Eligible pts included those ≥18 yrs of age with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as AJCC-7 stage IIIA (at least one lymph node metastasis >1 mm), IIIB or IIIC (without in-transit metastasis). A total of 1019 pts were randomized (stratification by stage and region) to pembrolizumab at a flat dose of 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year) or until disease recurrence or unacceptable toxicity. The 2 co-primary endpoints were RFS in the intention-to-treat overall population and in pts with PD-L1-positive tumors. Here, we report an updated RFS analysis based on a longer follow-up. Results: Overall, 15%/46%/39% of pts had stage IIIA/IIIB/IIIC. At 3.05-yr median follow-up, pembrolizumab (190 RFS events) compared with placebo (283 RFS events) prolonged RFS, in the overall population and in the PD-L1 positive tumor subgroup (see Table). RFS was consistently prolonged across subgroups, in particular according to AJCC-7 staging, BRAF-V600 E/K mutation status. Conclusions: Pembrolizumab, administered at 200 mg every 3 weeks for up to 1 year as adjuvant therapy, provided, at a 3-yr median follow-up, a sustained improvement in RFS, which was clinically meaningful, in resected high-risk stage III melanoma. This improvement was consistent across subgroups. In the overall population, the 3-yr cumulative incidence of distant metastasis being the first recurrence was 22.3% (pembrolizumab group) vs 37.3% (placebo group) (HR 0.55, 95% CI 0.44-0.69). Clinical trial information: NCT02362594. [Table: see text]

scholarly journals 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

2020 ◽  
Vol 38 (33) ◽  
pp. 3925-3936 ◽  
Author(s):  
Alexander M. M. Eggermont ◽  
Christian U. Blank ◽  
Mario Mandala ◽  
Georgina V. Long ◽  
Victoria G. Atkinson ◽  
...  
Keyword(s):  
Lymph Node ◽  
High Risk ◽  
Phase Iii ◽  
Stage Iii ◽  
Recurrence Free Survival ◽  
Meaningful Improvement ◽  
Free Survival ◽  
Stage Iii Melanoma ◽  
The Impact

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.

Long-Term Results of the Randomized Phase III Trial EORTC 18991 of Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation in Resected Stage III Melanoma

2012 ◽  
Vol 30 (31) ◽  
pp. 3810-3818 ◽  
Author(s):  
Alexander M.M. Eggermont ◽  
Stefan Suciu ◽  
Alessandro Testori ◽  
Mario Santinami ◽  
Wim H.J. Kruit ◽  
...  
Keyword(s):  
Pegylated Interferon ◽  
Interferon Alfa ◽  
Stage Iii ◽  
Long Term Results ◽  
Free Survival ◽  
Pegylated Interferon Alfa ◽  
Stage Iii Melanoma ◽  
Resected Stage

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 III-N1 ulcerated melanoma, RFS (HR, 0.72; 99% CI, 0.46 to 1.13; P = .06), DMFS (HR, 0.65; 99% CI, 0.41 to 1.04; P = .02), and OS (HR, 0.59; 99% CI, 0.35 to 0.97; P = .006) were prolonged with PEG-IFN-α-2b. PEG-IFN-α-2b was discontinued for toxicity in 37% of patients. Conclusion Adjuvant PEG-IFN-α-2b for stage III melanoma had a positive impact on RFS, which was marginally significant and slightly diminished versus the benefit seen at prior follow-up (median, 3.8 years). No significant increase in DMFS or OS was noted in the overall population. Patients with ulcerated melanoma and lower disease burden had the greatest benefit.

Chemotherapy plus radiotherapy (CT-RT) versus RT alone for patients with anaplastic oligodendroglioma: Long-term results of the RTOG 9402 phase III study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2008b-2008b ◽  
Author(s):  
J. Gregory Cairncross ◽  
Meihua Wang ◽  
Edward G. Shaw ◽  
Robert B. Jenkins ◽  
Bernd W. Scheithauer ◽  
...  
Keyword(s):  
Combined Therapy ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Long Term Results ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Entire Cohort ◽  
Phase Iii Study

2008b Background: Anaplastic oligodendrogliomas, pure (AO) and mixed (AOA), are chemosensitive tumors, especially if co-deleted for chromosomes 1p and 19q, but whether addition of CT to RT prolongs overall survival (OS), is unknown. Methods: In the RTOG 9402 Phase III trial, patients (pts) with AO/AOA were randomly assigned to PCV [procarbazine, CCNU (lomustine) and vincristine] followed by immediate RT vs. immediate RT alone. Early analysis showed no OS benefit for the PCV+RT group but combined therapy was associated with a longer progression-free survival (PFS). It also showed that the finding of 1p/19q co-deletion was associated with a longer OS independent of treatment. The current analysis has a median follow up of 11.3 years (yrs). Results: Two hundred ninety-one patients were randomized, 148 to PCV+RT and 143 to RT. PCV+RT was associated with longer PFS [2.5 vs. 1.7 yrs, hazard ratio (HR) 0.68, 95% confidence interval (CI) (0.53, 0.88), P = 0.003] and the 1p/19q co-deletion with a longer Median Survival Time (MST) [8.7 vs. 2.7 yrs, HR 0.41, 95% CI (0.30, 0.55), P < 0.001]. For the entire cohort, there was no difference in MST by treatment [4.6 yrs for PCV+RT vs. 4.7 yrs for RT, HR 0.79, 95% CI (0.60, 1.04), P = 0.1]. However, patients with 1p/19q co-deleted tumors lived much longer after PCV+RT (n = 59) than after RT (n = 67) [14.7 vs. 7.3 yrs, HR 0.59, 95% CI (0.37, 0.95), P = 0.03]. There was no difference in MST by treatment in pts without the 1p/19q co-deletion [n=137; 2.6 vs. 2.7 yrs, HR 0.85, 95% CI (0.58, 1.23), P = 0.39]. Re-operation rates upon progression were similar between treatment arms in co-deleted pts (43%, PCV+RT vs. 54%, RT) but salvage CT rates were higher in the RT arm [57% vs. 81% (P = 0.04)]. Conclusions: PCV followed by immediate RT was a highly effective therapy for patients with 1p/19q co-deleted AO/AOA. In this setting, 1p/19q co-deletion was both prognostic and predictive, and the early PFS benefit in co-deleted cases was a harbinger of their longer OS. [This work was supported by RTOG grants U10 CA21661 and U10 CA32115, NCCTG grant U10 CA25224, ECOG grants CA17145 and CA21115, SWOG grant CA32102, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI)]

Ipilimumab versus placebo after complete resection of stage III melanoma: Initial efficacy and safety results from the EORTC 18071 phase III trial.

2014 ◽  
Vol 32 (18_suppl) ◽  
pp. LBA9008-LBA9008 ◽  
Author(s):  
Alexander M. Eggermont ◽  
Vanna Chiarion-Sileni ◽  
Jean Jacques Grob ◽  
Reinhard Dummer ◽  
Jedd D. Wolchok ◽  
...  
Keyword(s):  
Lymph Node ◽  
High Risk ◽  
Adjuvant Therapy ◽  
Complete Resection ◽  
Advanced Melanoma ◽  
Phase Iii ◽  
Stage Iii ◽  
Phase Iii Trial ◽  
Risk Of Recurrence ◽  
Stage Iii Melanoma

LBA9008 Background: Ipilimumab (Ipi), a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses, is an approved treatment for advanced melanoma. Here, we report the results of a phase III trial designed to evaluate Ipi as an adjuvant therapy for resected stage III melanoma at high risk of recurrence. Methods: In this randomized, double-blind trial, eligible patients (pts) included those ≥18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to receive Ipi 10 mg/kg (n=475) or placebo (Pbo, n=476) every 3 wks for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. The primary endpoint was recurrence-free survival (RFS), analyzed on the intent-to-treat population. 512 RFS events (recurrence or death) were needed to provide 90% power to detect an Ipi vs Pbo hazard ratio (HR) of 0.75 (2-sided α=5%). Results: Overall, 20%/44%/36% of pts had stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement. At a median follow-up of 2.7 yrs, Ipi significantly improved RFS vs Pbo. RFS benefit was consistent across subgroups (e.g., stage IIIB or IIIC, ulcerated primary). Most common grade 3/4 immune-related adverse events (irAEs) in the Ipi and Pbo arms were gastrointestinal (15.9% vs 0.8%), hepatic (10.6% vs 0.2%), and endocrine (8.5% vs 0%). Most irAEs were managed and resolved using established algorithms. Of 471 pts who started Ipi, 245 (52%) discontinued treatment due to AEs [182 (38.6%) within 12 weeks]; 5 (1.1%) died due to drug-related AEs. Conclusions: In this phase III trial, Ipi as adjuvant therapy provided a clinically and statistically significant improvement in RFS vs Pbo for pts with stage III melanoma at high risk of recurrence. AE profile was generally consistent with that observed in advanced melanoma, although with a higher incidence of endocrinopathies. Clinical trial information: NCT00636168. EudraCT Number: 2007-001974-10. [Table: see text]

EORTC 18991: Long-term adjuvant pegylated interferon-alpha2b (PEG-IFN) compared to observation in resected stage III melanoma, final results of a randomized phase III trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8504-8504 ◽  
Author(s):  
A. M. Eggermont ◽  
S. Suciu ◽  
M. Santinami ◽  
W. Kruit ◽  
A. Testori ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Dose Intensity ◽  
Phase Iii ◽  
Stage Iii ◽  
Nodal Involvement ◽  
Free Survival ◽  
Ifn Therapy ◽  
Stage Iii Melanoma ◽  
Grade 3

8504 Background: EORTC 18991 is the largest adjuvant trial ever conducted in stage III melanoma. It assessed the efficacy and toxicity of long term PEG-IFN vs Observation (Obs.). Methods: PEG-IFN (Induction at 6μg/Kg/wk, sc, 8 weeks; followed by Maintenance at 3μg/Kg/wk, sc) for a total treatment duration of 5 years was compared to Obs. in 1256 patients (pts) with stage III melanoma (anyTN1–2M0 without in-transit metastases). Randomization was stratified for nodal involvement N1 (microscopic) vs N2 (palpable nodes), # of nodes, Breslow and ulceration of primary, sex and center. Distant Metastasis-Free Survival (DMFS) was the primary endpoint. Relapse-Free Survival (RFS) was the pre-specified regulatory primary endpoint. Overall survival (OS) was the secondary endpoint. Intent-to-treat analysis was performed. Results: Median follow-up was 3.8 yrs: HR = Hazard Ratio; NR = Not Reached In N1-pts (n=543) the benefit of PEG-IFN seemed more pronounced than in N2-pts (n=713): RFS (HR 0.73 p=0.02 and HR 0.86 p=0.12 for N1 and N2, respectively), DMFS (HR 0.75 p=0.03 and HR 0.94 p=0.53) and OS (HR 0.88 p=0.43 and HR 1.01 p=0.91). PEG-IFN therapy relative dose intensity (actual/planned dose while treated) reached median 88% (induction) and 83% (maintenance). 251 pts (40 %) stopped PEG-IFN because of toxicity. Grade 3–4 - mostly grade 3 - toxicities were reported in 45% (PEG-IFN), vs 12% (Obs.), including most frequently fatigue (15%), hepatotoxicity (10%) and depression (6%) with ECOG 0–1 Performance Status maintained in 83% of pts during maintenance. Conclusions: Long term PEG-IFN therapy in stage III melanoma had a significant and sustained impact on RFS, but not on DMFS and OS. Pts with only microscopic nodal involvement (Sentinel Node positive) seemed to have greater benefit in terms of both RFS and DMFS. Similar better effects of adjuvant IFN therapy in pts with lower disease burden are observed in 2 consecutive EORTC trials (18952 and 18991) involving 2644 pts. [Table: see text] [Table: see text]

scholarly journals Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600–Mutant Stage III Melanoma

2018 ◽  
Vol 36 (35) ◽  
pp. 3441-3449 ◽  
Author(s):  
Axel Hauschild ◽  
Reinhard Dummer ◽  
Dirk Schadendorf ◽  
Mario Santinami ◽  
Victoria Atkinson ◽  
...  
Keyword(s):  
Stage Iii ◽  
Disease Stage ◽  
Cure Rate ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Distant Metastasis Free Survival ◽  
Baseline Factors ◽  
Stage Iii Melanoma

Purpose Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo (hazard ratio [HR], 0.47; P < .001) in patients with resected BRAF V600–mutant stage III melanoma (BRF115532; COMBI-AD; ClinicalTrials.gov identifier: NCT01682083). We present an updated RFS analysis on the basis of extended study follow-up and a cure-rate model analysis to estimate the fraction of patients expected to remain relapse free long term. Methods In this phase III trial, patients with resected BRAF V600–mutant stage III melanoma were randomly assigned to 12 months of adjuvant dabrafenib plus trametinib versus placebo. We report updated RFS (primary end point) and distant metastasis–free survival. RFS was also analyzed by subgroups defined by baseline disease stage (American Joint Committee on Cancer 7th and 8th editions), nodal metastatic burden, and ulceration status. The fraction of patients who remained relapse free long term was estimated using a Weibull mixture cure-rate model. Results At median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), 3- and 4-year RFS rates were 59% (95% CI, 55% to 64%) and 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm and 40% (95% CI, 35% to 45%) and 38% (95% CI, 34% to 44%) in the placebo arm, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). Distant metastasis–free survival also favored dabrafenib plus trametinib (HR, 0.53; 95% CI, 0.42 to 0.67). The estimated cure rate was 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm compared with 37% (95% CI, 32% to 42%) in the placebo arm. Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration. Conclusion Longer follow-up confirmed RFS benefit with dabrafenib plus trametinib. Subgroup analysis suggested that dabrafenib plus trametinib benefited patients regardless of baseline factors.

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