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.

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]

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]

Survival analysis of adjuvant chemotherapy with S-1 plus cisplatin for stage III gastric cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 107-107 ◽  
Author(s):  
Daisuke Takahari ◽  
Tetsuya Hamaguchi ◽  
Kenichi Yoshimura ◽  
Hitoshi Katai ◽  
Seiji Ito ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Survival Rate ◽  
Adjuvant Chemotherapy ◽  
Survival Rates ◽  
Phase Iii ◽  
Stage Iii ◽  
Recurrence Free Survival ◽  
Stage Iiia ◽  
Free Survival ◽  
Post Surgery

107 Background: The efficacy of S-1 for stage II-III gastric cancer has been shown. However, the survival of stage III remains unsatisfactory (the 3-year recurrence free survival rates in stage IIIA and IIIB receiving S-1 were 68.0% and 49.8%, respectively). We already reported the feasibility of S-1 plus cisplatin as adjuvant chemotherapy for Stage III gastric cancer after curative resection (ASCO-GI 2009, Cancer Chemother Pharmacol 2011). Here we evaluate the recurrence and survival as secondary endpoints. Methods: Japanese patients with stage III gastric cancer who underwent D2 gastrectomy were enrolled. Treatment consisted of 3 cycles of S-1 (40 mg/m2 po) twice daily on days 1-21 and CDDP (60 mg/m2 iv) on day 8 and S-1 monotherapy was given on days 1-28 every 6 weeks until 1 year post surgery. Results: From August 2007 to September 2009, 63 patients were accrued. 35 patients were stage IIIA, the rest 28 patients were IIIB. After a median follow-up 2.9 years, 15 patients experienced recurrence, and 12 patients died. The 3-year recurrence free survival rate was 76.4% (95%CI:63.0-85.4%, IIIA 88.8%, IIIB 60.1%). The 3-year overall survival rate was 78.5% (95%CI:63.4-87.9%, IIIA 85.0%, IIIB 71.9%). The site of recurrence was mainly peritoneum (n=10), liver (n=3), and lymph node (n=3). Conclusions: Our results indicated that adjuvant therapy with S-1 plus 3 cycles of cisplatin may reduce recurrence and improve survival of stage III gastric cancer. This treatment should be considered as an experimental arm comparing with S-1 monotherapy for the next postoperative adjuvant phase III trial.

The use of PET/CT to detect early recurrence after resection of high-risk stage III melanoma, prior to the start of adjuvant therapy and during follow-up.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22039-e22039
Author(s):  
Bernies Van Der Hiel ◽  
Emma H.A. Stahlie ◽  
Marcel P Stokkel ◽  
Michel W.J.M. Wouters ◽  
Yvonne Schrage ◽  
...  
Keyword(s):  
High Risk ◽  
Adjuvant Therapy ◽  
Complete Resection ◽  
Stage Iiib ◽  
Stage Iii ◽  
Asymptomatic Patients ◽  
Pet Ct ◽  
Melanoma Patients ◽  
Stage Iii Melanoma

e22039 Background: To date, international consensus concerning the use of PET/CT as a surveillance tool in the follow-up of high-risk melanoma patients after complete resection of disease is lacking. Moreover, with the rise of adjuvant therapy it seems appropriate to investigate the role of this imaging modality to exclude newly developed metastases after resection and prior to starting treatment. The aim of this study was to investigate the use of PET/CT as surveillance tool in the follow-up and prior to adjuvant therapy in asymptomatic patients with complete resection of stage IIIB and IIIC melanoma. Methods: Prospectively two cohorts were set up with stage III melanoma patients with complete resection of disease. In the first cohort (stage IIIB/C AJCC 7th) surveillance PET/CT was performed 6-monthly for two years if patients stayed asymptomatic with normal serum S100B, with a final scan at three years. In the second cohort (stage IIIB/C/D AJCC 8th) patients underwent one screening PET/CT after resection and prior to starting adjuvant treatment. Results: Eighty patients entered follow-up in cohort 1. Of these, the majority did not undergo surveillance scans, because they required treatment for newly detected clinical metastases. Thirty-five patients remained asymptomatic and were included in surveillance cohort one (105 scans) with a median follow-up of 33 months. Twelve patients (34%) developed a recurrence, seven (20%) of which were detected on the first scan at six months. Seven recurrences involved stage IIIC patients, five stage IIIB patients. Sensitivity and specificity were 92% and 100% respectively. Forty-two patients were included in cohort 2. Recurrence was suspected on nine scans, four (10%) of which were true positive. One patient proceeded to undergo a node dissection and then started adjuvant therapy. The other three patients had progressed to stage IV and therefore started radiotherapy and/or systemic immunotherapy. Five (12%) scans were false positive, the suspected lesions were not related to the preceded surgery. The number of scans needed to find one asymptomatic recurrence were 8.8 and 10.5 in cohort one and two, respectively. Conclusions: This study shows that PET/CT is a useful surveillance tool for detecting recurrence in asymptomatic high-risk resected stage III melanoma patients, especially within the first six months after surgery and therefore should be considered when monitoring these patients during follow-up as well as prior to starting adjuvant therapy.

scholarly journals Central radiology assessment of the randomized phase III open-label OVHIPEC-1 trial in ovarian cancer

2020 ◽  
Vol 30 (12) ◽  
pp. 1928-1934
Author(s):  
Simone N Koole ◽  
Leigh Bruijs ◽  
Cristina Fabris ◽  
Karolina Sikorska ◽  
Maurits Engbersen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Peritoneal Cancer Index ◽  
Disease Recurrence ◽  
Phase Iii ◽  
Ct Scans ◽  
Recurrence Free Survival ◽  
Open Label ◽  
Free Survival ◽  
Peritoneal Cancer

IntroductionHyperthermic intraperitoneal chemotherapy (HIPEC) improved investigator-assessed recurrence-free survival and overall survival in patients with stage III ovarian cancer in the phase III OVHIPEC-1 trial. We analyzed whether an open-label design affected the results of the trial by central blinded assessment of recurrence-free survival, and tested whether HIPEC specifically targets the peritoneal surface by analyzing the site of disease recurrence.MethodsOVHIPEC-1 was an open-label, multicenter, phase III trial that randomized 245 patients after three cycles of neoadjuvant chemotherapy to interval cytoreduction with or without HIPEC using cisplatin (100 mg/m2). Patients received three additional cycles of chemotherapy after surgery. Computed tomography (CT) scans and serum cancer antigen 125 (CA125) measurements were performed during chemotherapy, and during follow-up. Two expert radiologists reviewed all available CT scans. They were blinded for treatment allocation and clinical outcome. Central revision included Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 measurements and peritoneal cancer index scorings at baseline, during treatment, and during follow-up. Time to centrally-revised recurrence was compared between study arms using Cox proportional hazard models. Subdistribution models compared time to peritoneal recurrence between arms, accounting for competing risks.ResultsCT scans for central revision were available for 231 patients (94%) during neoadjuvant treatment and 212 patients (87%) during follow-up. Centrally-assessed median recurrence-free survival was 9.9 months in the surgery group and 13.2 months in the surgery+HIPEC group (HR for disease recurrence or death 0.72, 95% CI 0.55 to 0.94; p=0.015). The improved recurrence-free survival and overall survival associated with HIPEC were irrespective of response to neoadjuvant chemotherapy and baseline peritoneal cancer index. Cumulative incidence of peritoneal recurrence was lower after surgery+HIPEC, but there was no difference in extraperitoneal recurrences.ConclusionCentrally-assessed recurrence-free survival analysis confirms the benefit of adding HIPEC to interval cytoreductive surgery in patients with stage III ovarian cancer, with fewer peritoneal recurrences. These results rule out radiological bias caused by the open-label nature of the study.

scholarly journals Sentinel lymph node biopsy for high-risk cutaneous squamous cell carcinoma: Analysis of recurrence-free survival

Medicina ◽  
2016 ◽  
Vol 52 (5) ◽  
pp. 276-282 ◽  
Author(s):  
Donatas Samsanavičius ◽  
Vygintas Kaikaris ◽  
Simonas-Jonas Norvydas ◽  
Rokas Liubauskas ◽  
Skaidra Valiukevičienė ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Lymph Node ◽  
High Risk ◽  
Sentinel Lymph Node ◽  
Sentinel Lymph Node Biopsy ◽  
Lymph Node Biopsy ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Recurrence Free Survival ◽  
Free Survival ◽  
Node Biopsy

Prognostic and predictive value of AJCC-8 staging in the phase III EORTC1325/KEYNOTE-054 trial of pembrolizumab vs placebo in resected high-risk stage III melanoma

2019 ◽  
Vol 116 ◽  
pp. 148-157 ◽  
Author(s):  
Alexander M.M. Eggermont ◽  
Christian U. Blank ◽  
Mario Mandala ◽  
Georgina V. Long ◽  
Victoria G. Atkinson ◽  
...  
Keyword(s):  
High Risk ◽  
Predictive Value ◽  
Phase Iii ◽  
Stage Iii ◽  
Stage Iii Melanoma
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