Prognostic and predictive value of non-steroidal anti-inflammatory drugs in the EORTC 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma.

Pain is common in patients with cancer. The World Health Organisation recommends paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) for mild pain and combined with other agents for moderate/severe pain. This study estimated associations of NSAIDs with recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and the incidence of immune-related adverse events (irAEs) in high-risk patients with resected melanoma in the EORTC 1325/KEYNOTE-054 phase III clinical trial. Patients with AJCC7 stage IIIA, IIIB or IIIC resected melanoma were randomized to receive 200 mg of adjuvant pembrolizumab (N = 514) or placebo (N = 505) 3-weekly for one year or until recurrence. As previously reported, pembrolizumab prolonged RFS and DMFS. NSAID use was defined as administration between 7 days pre-randomization and starting treatment. Multivariable Cox and Fine and Gray models were used to estimate hazard ratios (HRs) for associations of NSAIDs with RFS, DMFS and irAEs. Of 1019 patients randomized, 59 and 44 patients in the pembrolizumab and placebo arms, respectively, used NSAIDs. NSAIDs were not associated with RFS (HR 0.91, 95% CI 0.58-1.43) or DMFS in the pembrolizumab (HR 1.03, 95% CI 0.65-1.66) or placebo arms (for RFS, HR 0.76, 95% CI 0.48-1.20; for DMFS, HR 0.80, 95% CI 0.49-1.31). NSAIDs were associated with the incidence of irAEs in the placebo arm (HR 3.06, 95% CI 1.45-6.45) but not in the pembrolizumab arm (HR 0.94, 95% CI 0.58-1.53). NSAIDs were not associated with efficacy outcomes nor the risk of irAEs in patients with resected high-risk stage III melanoma receiving adjuvant pembrolizumab.

Kennedy OJ ，Glassee N ，Kicinski M ，Blank CU ，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 ，Boers-Sonderen M ，Giacomo AMD ，van den Eertwegh AJM ，Grob JJ ，Gutzmer R ，Jamal R ，van Akkooi ACJ ，Gandini S ，Buhrer E ，Suciu S ，Robert C ，Eggermont AMM ，Mandala M ，Lorigan P ，Valpione S ... -  《-》

Prognostic and predictive value of β-blockers in the EORTC 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma.

β-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of β-adrenoreceptor blockade by β-blockers in the EORTC1325/KEYNOTE-054 randomised controlled trial. Patients with resected stage IIIA, IIIB or IIIC melanoma and regional lymphadenectomy received 200 mg of adjuvant pembrolizumab (n = 514) or placebo (n = 505) every three weeks for one year or until recurrence or unacceptable toxicity. At a median follow-up of 3 years, pembrolizumab prolonged recurrence-free survival (RFS) compared to placebo (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.47-0.68). β-blocker use was defined as oral administration of any β-blocker within 30 days of randomisation. A multivariable Cox proportional hazard model was used to estimate the HR for the association between the use of β-blockers and RFS. Ninety-nine (10%) of 1019 randomised patients used β-blockers at baseline. β-blockers had no independent prognostic effect on RFS: HR 0.96 (95% CI 0.70-1.31). The HRs of RFS associated with β-blocker use were 0.67 (95% CI 0.38-1.19) in the pembrolizumab arm and 1.15 (95% CI 0.80-1.66) in the placebo arm. The HR of RFS associated with pembrolizumab compared to placebo was 0.34 (95% CI 0.18-0.65) among β-blocker users and 0.59 (95% CI 0.48-0.71) among those not using β-blockers. This study suggests no prognostic effect of β-blockers in resected high-risk stage III melanoma. However, β-blockers may predict improved efficacy of adjuvant pembrolizumab treatment. The combination of immunotherapy with β-blockers merits further investigation. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.

Kennedy OJ ，Kicinski M ，Valpione S ，Gandini S ，Suciu S ，Blank CU ，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 JJ ，Gutzmer R ，Jamal R ，van Akkooi ACJ ，Robert C ，Eggermont AMM ，Lorigan P ，Mandala M ... -  《-》

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.

The American Joint Committee on Cancer-8 (AJCC) classification of melanoma was implemented in January 2018. It was based on data gathered when checkpoint inhibitors were not used as adjuvant therapy in stage III melanoma. The European Organization for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 double-blind phase III trial evaluated pembrolizumab vs placebo in AJCC-7 stage IIIA (excluding lymph node metastasis ≤1 mm), IIIB or IIIC (without in-transit metastasis) patients after complete lymphadenectomy. Patients (n = 1019) were randomised 1:1 to pembrolizumab 200 mg or placebo every 3 weeks (total of 18 doses, ∼1 year). At 1.25-year median follow-up, pembrolizumab prolonged relapse-free survival (RFS) in the total population (1-year RFS rate: 75.4% vs 61.0%; hazard ratio [HR] 0.57; logrank P < 0.0001) and consistently in the AJCC-7 subgroups. Prognostic and predictive values of AJCC-8 for RFS were evaluated in this study. Patient distribution according to the AJCC-8 stage subgroups was 8% (IIIA), 34.7% (IIIB), 49.7% (IIIC), 3.7% (IIID) and 3.8% (unknown). AJCC-8 classification was strongly associated with RFS (HRs for stage IIIB, IIIC and IIID vs IIIA were 4.0, 5.7 and 12.2, respectively) but showed no predictive importance for the treatment comparison regarding RFS (test for interaction: P = 0.68). The 1-year RFS rate for pembrolizumab vs placebo and the HRs (99% confidence interval) within each AJCC-8 subgroup were as follows: stage IIIA (92.7% vs 92.5%; 0.76 [0.11-5.43]), IIIB (79.0% vs 65.5%; 0.59 [0.35-0.99]), IIIC (73.6% vs 53.9%; 0.48 [0.33-0.70]) and IIID (50.0% vs 33.3%; 0.69 [0.24-2.00]). AJCC-8 staging had a strong prognostic importance for RFS but no predictive importance: the RFS benefit of pembrolizumab was observed across AJCC-8 subgroups in resected high-risk stage III melanoma patients.

Eggermont AMM ，Blank CU ，Mandala M ，Long GV ，Atkinson VG ，Dalle S ，Haydon A ，Lichinitser M ，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 AJ ，Grob JJ ，Gutzmer R ，Jamal R ，Lorigan PC ，Lupinacci R ，Krepler C ，Ibrahim N ，Kicinski M ，Marreaud S ，van Akkooi AC ，Suciu S ，Robert C ... -  《-》

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.

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 JJ ，Gutzmer R ，Jamal R ，Lorigan PC ，van Akkooi ACJ ，Krepler C ，Ibrahim N ，Marreaud S ，Kicinski M ，Suciu S ，Robert C ... -  《-》

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.

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 JJ ，Gutzmer R ，Jamal R ，Lorigan PC ，Krepler C ，Ibrahim N ，Marreaud S ，van Akkooi A ，Robert C ，Suciu S ... -  《-》